Good afternoon, and, welcome to the UBS Biopharma Conference. I'm Colin Bristow, one of the biotech analysts here. It's my pleasure to have Vertex Pharmaceuticals with us here today. On behalf of the company, we have Charlie Wagner, CFO, and David Altshuler, the Chief Scientific Officer. So thank you both for your time today. Pleasure. You know, maybe we can just kick off with cystic fibrosis. Obviously, you know, a sort of major franchise for you guys. Continue to show impressive quarter-over-quarter growth. But from an investor perspective, it feels that this is, you know, this is well understood. It's pretty well modeled. As you look at consensus estimates and you speak to investors, what do you think is underappreciated about this opportunity, if anything? Yeah, Colin, thanks for the question. Maybe I'll start. Just to recap for folks, we just increased guidance for the year in CF to an approximate estimate of $9.85 billion for the year. Importantly, that gets us to 10% growth, and it's our ninth consecutive year of at least double-digit growth. So continued strong growth there. You know, yeah, I think it's—I think the trajectory in CF is fairly well understood. I think the thing that we need to continue to remind people is that there is further growth from here. If you look at what's driving the growth this year, it's annualization of patients who came on medicine last year in markets where we had new reimbursement. It's younger age groups. We have the approval for TRIKAFTA in two to five this year. We're expecting approval in two to five in the U.K. and Europe later this year. And importantly, we continue to increase our estimate of the number of patients worldwide with CF. Patients are living longer, the patient population is growing. And so all of those factors, more patients, younger age groups, new reimbursements, have driven the growth to date, and will continue to drive the growth into 2024. I think the other thing I would point out, obviously, we're awaiting data on the vanza triple. That represents an opportunity for patients. It also represents an opportunity not only for patients to switch to a better medicine, but also for patients who previously discontinued one of our medicines. There are roughly 6,000 or so of those folks, who would have the opportunity to come back on a new medicine. And then lastly, I'm sure we'll touch on it, we're moving forward in the clinic with our mRNA therapy, which would benefit the 5,000 or so patients who don't produce a protein. So what we see from here is continued attractive growth in CF, even though we've put up great numbers for a long time, there's more growth to go, and I hope that that's fully, understood. Great. A common question we, you know, we get from investors, especially as they're sort of, you're trying to understand or handicap the growth for CF, is just what's the exclusivity period? And, you know, as the older products lose exclusivity, how does that impact the more novel agents like TRIKAFTA, et cetera? So help us think through that and some of the timelines. Yeah, I mean, I guess it's important to know TRIKAFTA is such a fantastic medicine, that in geographies where it's approved for down to younger age groups, the vast majority of patients switch as soon as they can. And you can see it in the numbers, obviously, the, you know, more than 90% of the revenues are coming from TRIKAFTA at this point. And TRIKAFTA IP goes out to 2037. So we're not in a situation we're worried about loss of exclusivity like other companies necessarily. The franchise is growing, is durable, is long-lasting, and then with vanza, we'd have the opportunity to take IP out even further. We haven't commented on that specifically. So, I think we're just in a fantastic position overall, with the portfolio. Maybe the only other thing to add to that from a science and medical point of view is that remember that there is no other medicine that's approved than other than TRIKAFTA, for people who have only one copy of Delta F, which is about half of the population. And then the people who have two copies of the Delta F allele have about a 4% increase in FEV1 with SYMDEKO, but a 14% FEV1 difference, which is night and day with TRIKAFTA. So between half the population not having another approved medicine and the other half having just a totally transformative difference between TRIKAFTA and the other medicines, if the other medicines, you know, some of them have earlier patent exclusivity, then no one's going to take those medicines instead. So you touched on the vanza triple already. Can you just, one, remind us on the timing of when we should expect to see the top line, and two, what should we expect to get in the top line? Oh, sure. It's a disclosure question. It'll be early 2024 when we'll have that completed, and we've to obviously analyze the data, and then we'll disclose it. And, you know, the top line, as we've said before, we're very confident that vanza should have higher levels of CFTR function in patients for two reasons. One, using our human bronchial epithelial cell assay in the laboratory, which has quantitatively translated through a dozen different molecules in many clinical trials, vanza has higher levels of CFTR function at clinically relevant concentrations than does TRIKAFTA. That's the preclinical data. The clinical data is we did phase II studies with vanza. We did separate phase II studies with TRIKAFTA, and we did the correct comparison, which really requires doing PK/PD analysis because they're different patients, different, you know, PK... not identical PKs. You can't just compare the raw numbers, you have to do the right PK/PD. We see that vanza has higher efficacy than TRIKAFTA when we do it right. So preclinically and clinically, there's strong evidence for more efficacy. The way we've designed this study is, it's not yet known how much more FEV1, that's the measure that people have historically used, which is how much air you can blow through a straw at one second, which has been the regulatory endpoint. It's not clear if there's a ceiling effect or not. We just don't know, 'cause no one's ever dosed up this high the curve. The way we designed the study is a non-inferiority study, because we don't know if there's more FEV1 to have, but then with secondary endpoint of sweat chloride, which is actually the measure of CFTR function, as well as potential for superiority and other things. So we'll obviously read out the top-line results. But the other point I wanna make, just to close, is that you might ask, Well, why is this medicine have the potential for being better for patients? And what if there isn't more FEV1? I'm not saying it won't be, we just don't know yet. And the key thing that we know is that more CFTR function leads to better outcomes for patients. And the reason we know that is, one, natural history. If you look at people who carry different mutations, who have different levels of CFTR function, higher levels of CFTR function means better outcomes. Second, if we look at our clinical trial data, we know that while a fraction of people on TRIKAFTA have essentially normal or carrier levels of CFTR function, a majority do not, and the clinical trial data says that we can move those people to even higher levels of CFTR function, they have better outcomes. So it's very, we're very confident that the key thing for patients is more CFTR function to approach carrier levels, and that will lead to better outcomes. The exact profile of what that looks like, we're gonna have to learn from the first study in history of vanza that has the potential to go even higher than TRIKAFTA. So in terms of your expectations for the results, is your sort of base case non-inferiority on FEV1, superiority on sweat chloride? Is that fair? Is that what I'm hearing? I think what I'm confident in is, one, we should see higher levels of CFTR function as read out by sweat chloride. Two, that the profile of the medicine will be quite confident, will be better for patients overall. I'm not gonna speculate on exactly which measure and exactly which way, because it's really just that when we got from ORKAMBI and SYMDEKO-like levels to TRIKAFTA-like levels, that was a new day in the disease, and we learned what that could do. Now we have the potential to go even higher than that, and we're gonna have to learn from the 1,000-person, year-long clinical program in phase III, but that's gonna tell us what that profile is, and I believe it'll be better for patients, but I'm not gonna speculate on exactly what number and what thing, because we just don't know. So, under the outcome of in just on sweat chloride alone, sort of superiority, directional, improvement, you know, is that enough from a commercial perspective in your mind? Sure. We've done commercial research that has asked doctors what they think of this and what everyone, you know, what that data shows, and it's what we believe, is that the community understands that the disease is caused by abnormalities in CFTR function caused by inherited mutations. That people who are carriers are completely well. They have absolutely no nothing. They're healthy. And that patients, therefore, and doctors want to get to highest levels of carrier CFTR function. And so I do believe that commercially, you know, that seeing that you can normalize CFTR function is going to be compelling for doctors and patients. Obviously, they're gonna wanna see the clinical data and understand what it means, but I think that there is an understanding, just as like in other settings, you want to normalize the underlying disease. You don't wanna be left with the residual disease, and some fraction of people, even on TRIKAFTA, have residual defects in CFTR function that we wanna boost up. Colin, I was gonna say, the reason I deferred to David on that question is because the decision to switch is really between a patient and a physician. We're not driving it in any way. So with TRIKAFTA, we have seen the vast, vast majority of patients switch to TRIKAFTA because it's a superior medicine, offers a greater benefit, greater profile. That's not been driven by the company in any way. Similarly, with vanza, we're dealing, thankfully, with an incredibly well-educated patient population, physician population as well. They will be the ones to make that decision and drive that, and again, we'll see soon. So you just—you literally answered my next question in terms of, you know, assuming approval, the, you know, the move would be to switch the TRIKAFTA population over to vanza. There will be switching. We won't be driving it- Sure. -candidly. You said you've not disclosed the IP situation for vanza at this time? Not yet. One of the other benefits of the vanza triple is obviously a margin uplift for you guys. Can you just talk about that a little bit and help us quantify it? Yeah, so across our existing portfolio, we have a royalty burden in the high single digits. We would expect with vanza, given its chemical composition, that it would have a royalty burden meaningfully lower in the single digits. Okay. That's helpful. Moving to VX-522, when will we next see... You know, when will we see the initial phase I data? And, you know, what should we expect it to be in that? So VX-522, as you know, but just for the group, is a medicine aimed at the 5,000 or so people with CF who don't make any protein, and therefore, can't respond to our CFTR modulators. And so in that setting, where we've worked with Moderna for many years to develop an inhaled LNP mRNA medicine that could restore CFTR expression to the lungs of people with CF, and that would only be for the 5,000 or so people. We're in a single ascending dose in patients with that medicine, and then assuming good data, we would move to the multiple ascending dose. We don't expect, could be, but we don't expect to see meaningful efficacy after a single dose just because it's too short. So it'll probably be, it'll be some time, we hope, next year when we've got the multiple ascending dose data. The meaningful measurement will be obviously efficacy and safety. Efficacy would be, you know, FEV1. Safety, obviously, you know, traditional safety measures. It's an inhaled medicine, not a systemic medicine, so you can't measure sweat chloride, so it's going to be about lung function. Okay, that's helpful. And just last one on CF. Last week, the U.K.'s NICE published a draft guidance, saying that the Vertex CF drugs are not cost-effective. I was just wondering, you know, what you thought about that report, what were maybe some of the shortcomings that drove that conclusion? Yeah, importantly, that's a draft document from NICE. Not unexpected. We entered into our reimbursement agreement in the U.K. four years ago. Part of the agreement and part of the process, we expected that to be occurring around this time. You know, that said, obviously disappointed with the draft report, and we see, you know, serious issues with the methodology that was used. You know, we have provided tremendous patient benefit in the U.K. over the last four years. We have accumulated with TRIKAFTA globally, tens of thousands of patient years of real-world evidence that show the incredible and transformative impact of the medicine. And that's not fully appreciated in the methodology that NICE uses. So we're in the process. We've had conversations with them before, but, you know, we are committed to ensuring sustainable access for patients in the U.K. and in all the markets that we serve. I'm confident that the strength and the profile of the medicine will carry the day, and we'll continue through the conversation. Great. Maybe we could switch gears and move to pain. So, you know, this is obviously front and center for you and investors. You know, I would say that your tone around this feels very positive. And could you just articulate to us what's sort of driving that confidence and positive tone? Yeah, I'll start with, you know, the unmet need is very great in pain, as we know, both acute pain, where opioids are used or not being used as much in many cases because of the safety and tolerability and addiction potential. So there's a lot of unmet need there, and also in particular, in sort of moderate to severe, what's called neuropathic pain, either diabetic or, what's known as lumbosacral radiculopathy, sciatica, things like that. There's just a lot of unmet need. And, it's been clear for about 20 years that there are, two targets, and I'll focus on one of them. They're partners with each other, but what's called, the selective sodium channel NaV1.8 and NaV1.7, that are sort of people in genetics, sometimes for human genetics purposes, like God's gift to pain research. We say that because the genes are only expressed... If you're sort of trying to design the perfect target for any therapy, what you'd want is something that's only expressed in the tissue of interest and nowhere else, so you can't have side effects, that is necessary for the function you're trying to interrupt and has no other function such that it would be dangerous to inhibit it. And that's what NaV1.8 is. It's a selective sodium channel only expressed on the nociceptors, which are the peripheral pain-sensing neurons. Based on human genetics and now our pharmacology data from five out of five positive phase II studies, inhibiting this channel can block the transmission of pain signals from the periphery to the brain, and critically, it's not expressed in the brain. So you know, most pain medicines, if you think about pain medicines that are used today, they're either your sort of aspirin, ibuprofen, NSAID, NSAIDs, and Tylenol, all of which act as sort of anti-inflammatories, blocking the tissue distally, or they're things that affect your cognition. Like, anti, you know, Lyrica and the gabapentin, they're anticonvulsants, they're not pain medicines. Opioids block the brain's perception of pain. Tricyclics are antidepressants. They don't actually, are not pain medicines. They're basically affecting your cognition. That's why there's so many side effects. So having medicines that have this unique target, that are highly selective, that have five out of five positive phase II studies and a clean safety profile to date, makes us optimistic. Obviously, we haven't yet seen any of the phase III data yet for acute pain. We haven't yet seen the phase II data for neuropathic pain. So you know, we, like everyone else, are very excited to do that, but our confidence is based on the unmet need, the human biology, and the pharmacology to date. On the sort of mechanism and the pharmacology, your drug design and chemistry has always been something that's been extremely highly regarded and I think has driven a lot of your success to date. How has that been sort of translatable or leverageable in the context of pain and NaV1.8? Yeah, it's a great question. Actually, inside of Vertex, it's understood that we've been working on pain as long as we've been working on CF, that it's the same people. So Paul Negulescu and Sabine Hadida, who together with Fred Van Goor, won the Breakthrough Prize this year, and the Wiley Prize, which are two of the most prestigious prizes in science for their discovery of the CF medicines. Paul and Sabine have led the pain program as well for 20 years. So it's the same people. They both use human genetically validated targets. They both use human cells as the assay technique. So in CF, that's the human bronchial epithelial cells. In pain, it's actually human dorsal root ganglion neurons, which are when people pass away, they donate their tissues sometimes to science, and we use those as these. We don't use cell lines, we don't use artificial cancer cells, we use human dorsal root ganglion, which are the exact cells in which the drug is meant to act. Our chemistry approach, you know, we use every—we were the original structure-based drug design company 35 years ago. We've been doing what people now call AI and drug discovery for 30 years. We use all of the techniques, you know, of human cells, cryo-EM, AI, but also having spent many years studying these targets, you know, we're not trying to cover the landscape. What a lot of companies seem to do is say: We'll have 100 targets, and we'll do a shot and go and see if any of them work. We're not experts in any one. Whereas we've been drilling deep on this target for many years, so I think we have, you know, as much expertise in pain as we do in CF, and I think that's why we've discovered medicines that no one else has been able to discover. So we've seen some phase II data for the abdominoplasty and bunionectomy populations, and I think, you know, that the, the publication had some... There's this balanced commentary, right? And then so, in some of the focal areas of, not concern, but just questions were around time to onset, and efficacy relative to standard of care, I think. Could you walk us through each of those and, and how you're thinking about them? Yeah. I mean, we personally find data extremely encouraging, and actually also putting it in the context of those, those were the only two phase II studies done to date with VX-548. But there was a previous molecule, VX-150, which binds to the same site and has the same mechanism of action, that we had three out of three proof of concept studies. And the reason we didn't move that one forward was just it was turned out with dose ranging, it was a very high dose, so it wasn't an ideal medicine. So we didn't pursue it. But when we look at the data, what we see are five out of five studies positive. They all have, if you look across them, and it was commented by one of the commentaries, not the other, the safety profile is thus far clean. So every other pain medicine has side effects. And these to date, you know, mid-phase II studies—we'll see more data with phase III—look very clean. And the efficacy is five out of five, met the primary endpoint, five out of five times, clinically meaningful efficacy. And, you know, we used in all of the acute pain studies, the two that were published in the journal and the 150 study previously, a reference arm, which was a clinically used opioid, not as a comparator. This study was a phase II study, so it wasn't powered for superiority, but it was there, and you can see equal or greater efficacy of our medicine in those studies. So we saw it as very positive, you know, and some of the commentary in that New England Journal article is actually about phase II studies for pain. It actually wasn't really about our drug. If you read the article, it was sort of about like how much, you know, smaller studies, what can you learn from them? But we're not trying to learn from one study. We're trying to learn from the mechanism, what we know about the non-clinical data and the five proof of concept studies, and all that makes us feel confident. But again, we haven't seen the phase III data yet, so it's always this is a business where, you know, we, we-- everything is making us confident, but in the end, we have to see the data, and when we see the data, we'll know what it is, and then we'll be able to act. But the other thing is, the Vertex strategy is always to do serial innovation. Just as in CF, we went KALYDECO, ORKAMBI, SYMDEKO, TRIKAFTA, now we have vanzacaftor. We have in pain, just as we've had in AAT, as we had in AMKD and all of our programs, we have follow-on molecules that are even better. So when we look at the opportunity, it's, you know, VX-548 is great, but we also have already invested in the next thing, some of which are in the clinic. So we feel very good about the long-term prospects as well as the short-term readout. on the point around sort of onset of pain relief- Mm-hmm. Relative to standard of care. Yeah. It's actually rapid, you know, is the bottom line. Yeah. If you look at the data, actually, it's rapid. So it doesn't seem meaningful to us, and if you look, it's very early on, the DC efficacy. David, there was a disparity, at least, you know, from a sort of PK perspective in terms of Tmax between bunionectomy and abdominoplasty. Right. Can you just, you know, just speak to why that is? I can at least tell you what might be the case. I can't know. Yeah. But, look, bunionectomy is a bony surgery on the bone of the foot, and so, it's local anesthesia, and people eat afterwards. People who have abdominoplasty, which is abdominal surgery, tend to have delayed gastric emptying. So if I had to speculate, I would speculate that, in a disease where there's no effect on digestion, you might have more rapid absorption, but it's not really about the medicine, it's probably about the patient. In the context of one of the goals here is to kind of remove opioids from the equation, is, you know, a non-inferiority outcome in the acute pain setting a win? Absolutely. I think that the profile that we believe would be transformative, and frankly, everyone we talk to would believe be transformative, would be to replace opioids, which have, in addition to their challenges with addiction that are very well documented, have many side effects, ranging from confusion, nausea, respiratory depression, constipation, rash, all which limit use of opioids beyond the addiction potential. A clean profile with meaningful, you know, clinically meaningful pain relief from moderate to severe pain is a transformative medicine. So we're going to get the DPN data before year-end, and then the acute pain data, I think, 1Q 2024 is your latest guide there. Correct. Yep. Is there anything that, when we get the DPN data, is there anything other than safety and even though the doses are different, is there anything that you'll be looking at or that we should be looking at in terms of reading through to the efficacy outcomes in acute? Basically, no. I mean, it's in this following sense. There are different indications, there are different patients, and while we have every reason to think they will be positive because we've done a previous neuropathic pain study with VX-150, and obviously, we've done the three previous studies in acute pain with VX-150 and VX-548, they are different indications. And so, you know, it's. I don't think there's any real read-through, you know, in terms of this study and that study. Also, one is a phase two study that's smaller, and the others are large phase three studies. And I think the other thing we announced this week is we're starting a study in lumbosacral radiculopathy, which is just to give you context, of neuropathic pain, which is a very large opportunity. Peripheral diabetic peripheral neuropathy is about 20%, is our estimate of that indication, of that field. Lumbosacral radiculopathy, which people often think of sciatica, that's lumbosacral radiculopathy is the nerves coming out of the spinal cord, getting into the periphery. They have to go through a little hole in the spine called the foramen. If it's the level that is the sciatic nerve, then it's called sciatica, but sometimes it's above and below that, and the totality is called lumbosacral radiculopathy. That's a disease where the nerve is pinched, and about 90% of people do not need surgery and don't get surgery. They just suffer for a long period of time with pain until it eventually sometimes resolves. So that's a very large opportunity as well, and we're starting a phase II study of that. And again, while my... If I had to guess, I would expect it to be positive in both based on the mechanism of action. There's not really a direct read-through from one to the other because they are different patients with different mechanisms of action. So I think each one is a big opportunity on its own. Obviously, our hope and, and would, you know, is that it will work in all of them, and we can help lots and lots of patients with pain. But each one is a meaningful opportunity, and each one is sort of a different opportunity based on the fact that the patients are different. The marketing a drug in pain would be, you know, a very different setup than to what you guys are used to and what you're doing in CF, obviously. Can you speak to the strategy there and the infrastructure build? Yeah, I guess we get this question a lot, and I would tell you the commercial model is not as different as people think. CF, of course, is highly concentrated, and we have commented from time to time that we have fewer than 20 salespeople in the U.S. to cover the market for CF. It's a very well, as I mentioned earlier, a well-educated patient population and physician population, so it is highly concentrated. But importantly, every disease area that we've chosen to focus on, whether it is sickle cell disease, Beta Thalassemia, pain, AMKD, et cetera, fits our specialty commercial model. So we see an opportunity to segment the market in a way where we can work with a specialty commercial model. We don't need thousands and thousands of salespeople. It's a relatively smaller sales effort. In the case of pain, we've commented, if you look at. Maybe we'll take acute pain, for example. There are 80,000,000 people a year who are treated for moderate to severe acute pain, somewhere between 1 billion and 1.5 billion treatment days. But importantly, two-thirds of those days are, the prescriptions are either written or influenced in an institution. So either at a hospital or a surgery center, perhaps at time of discharge, might be filled in a retail setting. But the concentration of the prescription is in that setting. And then just some quick math, you know, there are maybe 2,000 or so hospitals that roll up into 200 IDNs that represent 80% of the market as well. So you're, you know, you're talking about a sales force of maybe a couple hundred people to cover something like that in the U.S., not thousands and thousands and thousands. And importantly, we would be engaging not only at the hospital level, but at the IDN level. And then additionally, as a company, we're engaging at the state and federal level as well. And there have been restrictions on opioid prescriptions for some time. Increasingly, there are now incentives for prescription of non-opioids. And we've talked about the benefit of the NOPAIN Act, which was passed back in December, which creates an add-on payment to provide the opportunity for economics to not get in the way of prescribing a non-opioid. Now, there aren't any effective non-opioids available. We would hope to have the first. But we think with this engagement at the federal level, state level, IDN level, and a continued campaign of education around the profile of a medicine like this, that we can serve it with our specialty model very well. It's also perhaps why we're not going everywhere with pain. So we've talked about the example I gave you there was acute pain, and then people tend to think of acute and chronic. But within chronic, we've subsegmented into neuropathic pain because we think that can be served with a specialty model as well. So DPN, LSR. Other forms of chronic pain, so maybe musculoskeletal pain, you know, often served in more of a GP setting. We don't think we can cover that with a specialty model, so that's not part of our focus initially. You know, over time, we do think, based on some of the comments that David has made with previous trials, that the medicine could be effective for some of those chronic pain states, but it doesn't fit our specialty model. So it's possible that, in the future, we would look at other ways to access that, perhaps through partnership or licensing. But the opportunity in acute and neuropathic that is right in front of us is large enough and fits our model. That's where we're focused. The only thing I'd add to that is moderate to severe pain, excuse me, is a high-value indication. So in addition to being a specialty indication, because once somebody has moderate to severe pain, they're either in a hospital setting, like having surgery, in which case it's a specialist, a surgeon, or an anesthesiologist, or they're seeing an orthopedist or a neurosurgeon for their spine, or they're seeing a pain specialist. But also they have the greatest need. And I think one lesson of pain medicines over the years is, like, going where the need is greatest and therefore the value is greatest, I don't just mean commercially, I mean medically, you know, is the place to go. If you go to people with very mild pain, it's just a different benefit risk scenario. It is different value. So I've always thought myself that helping the people with the really intractable pain was the greatest benefit to society. It happens also to be a commercial specialty model and have high value. So I, I think it's, like, the right place to be. One question we had since your quarterly updates and the, you know, the additional information, you're starting a trial at LSR, was, you know, do you have the DPN data in-house? Have you seen it? Is that what's giving you the confidence to start this- No. Okay, I just needed- Somebody, people will have a little bit of commentary, though. So the answer is no, we don't have the DPN data, and we don't know what it is, obviously, what the results are. We know what the data study is, but we don't know what the results are. The timing of this, I get why people have a question about it. Right. I think there's sort of two components. One is, you know, that, we starting LSR now, because LSR has evolved in the regulators and the community's mind over the last decade, where it used to be thought of as a musculoskeletal condition because it involves the spine, but we've always thought of it as a neuropathic condition. So we needed to interact with regulators to make sure that we had a shared understanding of what we were doing. Having had some of those discussions, we feel now confident going forward with LSR. It has nothing to do with the DPN trial. Another question would be, though: Well, why not wait for the DPN trial and then you'll know? Again, one is a metabolic nerve condition based on diabetes. The other one is a mechanical nerve condition based on the spine. There's not direct read-through, so even... Each one is a large opportunity commercially. So, if you do the decision tree, and you go, well, if DPN is positive, would you do LSR? Yes. If DPN was negative, would you do LSR? Yes. So might as well get started. Okay, that makes sense. Another actually phase II data question just came to my mind. The abdominoplasty phase II comparator arm looked like it underperformed versus kind of historical, you know, data sets we've seen. That didn't appear to be the case in bunionectomy. Just any comments there? I personally think it's noise. It's sampling variation. Yeah. You know, these are phase II studies. I don't know if you know this, but just like, these are phase II studies, dose ranging. Each arm is pretty small, and that's 'cause we're and they're just not large enough for a study to really get highly precise estimates. And so I think that the way I look at them is, we're looking to see, is the drug active? We're trying to get the profile, we're trying to get the, you know, the safety and everything, but you can't really get a highly precise estimate. So myself, I tend not to try and read too much into things that I think are sampling variation. But when I look at all of the studies, it gives me high confidence that every study's been positive and met the primary endpoint and similar overall results, similar safety profiles. I'm very confident in that. What can you say about the powering and the hierarchy of testing of the endpoints in the phase III? What I can say about the powering is it's very well powered, and, and what I mean by that is the phase III studies. And what I mean by that is that if you look at our phase two studies, as I said, which are on the order of... They're all different, but on the order of 100 and 200 people and have multiple arms, they have all met their primary endpoint and been very clear separation of the drug from placebo. Because the phase three program has to meet safety criteria, we have 1,000 people in each of abdominoplasty and 1,000 people in bunionectomy, and a 250-person safety and efficacy study in a broad range of endpoints, 'cause that's what we agreed with the regulators would potentially support a broad acute pain label. From the point of view of, like, meeting the primary endpoint, the study is exceedingly well powered. Okay. Your ongoing trials, we've seen, there's an article, VX-708, which just completed phase I. Mm-hmm. Can you just share a little- Yeah A bit more on this? What's the mechanism feature? Yeah. So we have actually VX-708, and there actually are others we don't report out now, you know, phase I assets, you know, that early stage of development, just 'cause of the stage of the company. But it's a NaV1.8 inhibitor. We have other NaV1.8 inhibitors, and they, as we always do, we're looking to serially innovate and find molecules that have even better properties or additional characteristics that might be desirable, and VX-708 is such a molecule. And we continue to discover such molecules in our labs. And, you know, I tend to think of pain where we are with pain today is a bit like where we were with CF in 2010 or so. You know, in the sense that we didn't yet then have an approved medicine, but we had multiple assets that would prove out to be valuable between KALYDECO or ORKAMBI, SYMDEKO, and also it built a foundation that led eventually to TRIKAFTA, where we are today. And when I look at our pain program, you know, I see VX-548 in acute, nearing the end of its phase III, 548 in neuropathic pain, with both the DPN study that will read out this quarter and also another study, another big indication, and then other molecules behind that have the potential to augment or extend what we can do. And that gives me... You know, I tend to think long term, been around the company now, one way or another, for 12 years. So it's like, you know, it gives me great confidence we're going to get there. I have, I have very good confidence, excellent confidence in VX-548, but it's also like, you know, we have the whole, the foundation for really transforming the lives of people with pain, and that, that's exciting.... It's really been, it's our approach in every disease area. We focus on serial innovation. We don't go one asset at a time and then regroup. We are typically pursuing multiple assets based on our knowledge of the biology, so that we have the greatest chance not only of succeeding, but also moving fast. Actually, also, the other thing we expect is that if we succeed, and we're, you know, confident that that's a very likely outcome, other people who run more me-too companies, where they wait for someone else to innovate, and they try and jump on the bandwagon. I've never actually understood why other companies will innovate and then wait to see the data and then let everyone else be at the same place they are. The actual investment required to make sure you're five years ahead of everybody else, it's why we are where we are with CF. Like, we just keep rolling along. If everything were to fail in some various, you know, way, you could always stop. But you have to plan for success, and so we are already planning for success and saying: Well, if others are copying what we're doing now, we got to be years ahead of them, and we are. Maybe let's switch to another program, the CRISPR-based DMD program. You know, it's... We follow the DMD space closely. We've been very interested in the technology acquired for Exonics. It's been four years since that acquisition, and I'm just- perhaps, what are some of the, you know, unanticipated challenges you've had getting that to the clinic? Yeah. I mean, I think I'd say that, DMD remains, unfortunately, a disease with tremendous unmet need. And, you know, it was disappointing to everyone, I think, last week's data readout, where, you know, microdystrophin didn't show it meet its primary endpoint. And, but that our hypothesis four years ago was that, we didn't invest in microdystrophins because, you know, dystrophin is the largest protein in the genome. It's a shock absorber that connects the outside of the muscle to the inside of the muscle cell, and we just never were confident that a quarter the size. There was never any human data or animal data that really indicated microdystrophins would work. So it's not terribly surprising, but disappointing for patients, that it doesn't appear, like it to be very, effective. So our approach has always been, and remains, to use an approach, gene editing, to restore near full-length dystrophin, because near full-length dystrophin is known to benefit patients. 'Cause there's something called Becker muscular dystrophy, where people inherit a near full-length dystrophin of the sort that you could recreate with gene editing, and they are- they do very well. They may have symptoms, but they're much, much, much better. So that's what our strategy has been. And there's sort of two components to any genetic therapy. There's the payload, can you achieve the sort of gene modification you seek? And there's delivery. And I think that from the point of view of the payload, made really great progress and feel good about the gene editing as an approach, and the ever more committed to this idea based on recent data of near full-length dystrophin. From the point of view of delivery, you know, clearly high-dose AAV, one thing that's evolved in the recent years is just observing everybody who's gone in the clinic with high-dose AAV. And you know, based on our preclinical data, we think more work is needed before we'd be prepared to go forward with that. So a lot of the focus will be on that, and delivery is the key concept. Any new timelines that you can speak to? And is it still very much a when versus an if, in terms of this therapy making it to the clinic? Yeah, I mean, it's too early to say what the timeline is, 'cause obviously, we just got these recent data, and we're still understanding them and figuring out the next steps are. Our commitment to trying to bring this forward remains, full on, both because of the unmet need and the current state of the field, and also the potential of the therapy we have. So we're very committed to that, but I can't say exactly what the timeline is, just too soon after getting the recent results. Switching gears again to the diabetes programs, VX-264 and clinical studies are underway. When do we start to see some data on that? And, you know, I imagine with that, you'll open up the kimono, and we'll understand a little bit more of the design, the materials, that you've kind of alluded to. We've not given any timing on data for VX-264 at this point. Okay. Well, at least conceptually, is it fair to say that, you know, you released one patient's worth of data at, you know, I think in these sort of settings, small numbers of patients can be very meaningful. You know, is that at least something you're open to? It's true that the, like, in cell and gene therapy, the trials tend to have smaller patient numbers. We don't have any intention of disclosing patient-by-patient data- Mm-hmm. for VX-264. We, when we have the appropriate cohort size and the appropriate time, that's when we'll release the data. Okay. Switching gears to exa-cel, just trying in the last couple of minutes- Mm-hmm. to move through a couple of things. Well, congrats on the recent AdCom. Thank you. Can you walk us, frame the opportunity here in terms of patient numbers, market size, and how should we think about the, you know, the cadence of a launch in this population? Yeah. Yeah, listen, we're really excited, obviously, with the outcome of the adcom and for sickle cell disease, specifically looking forward to the December eighth PDUFA date. We've commented previously that across North America and Europe, there are roughly, you know, 160,000 people with sickle cell disease and beta thalassemia. We think that roughly 20% of them, or 32,000, would be appropriate candidates for a therapy like exa-cel right out of the gates. And so that alone represents a very significant multibillion-dollar opportunity. We did take some time on the earnings call this week to just talk about the patient journey a bit. While there's a lot of excitement among patients, physicians, we are very excited, the sort of-... There is a journey for patients as they meet with their hematologist, decide that they are interested in a therapy. They go through a battery of tests to make sure that they're appropriate. They would get referred to an Authorized Treatment Center that has worked with us to be a point of entry for patients in this journey. And then they go through, for those that advance, they go through cell collection, gene editing, manufacturing, infusion, et cetera. And importantly, you know, people ask me typically about revenue. Revenue occurs at infusion. So you've got these patients who are going through a multi-stage, multi-month process, and so we just wanted to set that expectation. But in terms of our readiness, and I think patient readiness, very high. So we are gonna be ready to go on December eighth, assuming successful approval. We will have Authorized Treatment Centers signed up. All of our commercial organization is in place. All of our manufacturing capabilities are in place and ready. And so we'll be eager, you know, to see patients queuing up essentially, post-approval. We also are very confident that there will be access and reimbursement in place as well. So there are no rate limiters other than it takes patients a little bit of a while to go through the journey. And 2024 will be a foundational year. We are, you know, focused on making sure that everything goes really well for patients and physicians. You know, I think with this community, there is an element... You know, some folks are perhaps gonna wanna see some success stories. They're interested in the success stories from the clinical trials, but even locally, in some of the treatment centers, there's a, you know, there's a local patient community. So, you know, we're very excited about helping folks through the journey and, and just wanted to lay that expectation out. Maybe one last question for you, Charlie. You've got your $12 billion cash on the balance sheet, incredible cash flow generation. Just, you know, how are you thinking about priorities now and, and, you know, share buybacks, potential dividend? And then just given where the biotech market backdrop is, you know, do you see greater opportunity and/or an increased appetite to do business development? Yeah, we've been very consistent and I think very disciplined, and I also think very successful with our capital allocation strategy to date. We've said that our top priority is investment in innovation, both internally and externally. With some of the cell and gene therapy programs, there is a larger CapEx component, so we are earmarking some capital dollars for that. We have been very active in BD over the last several years. And I think it's important to note, I know people tend to like to characterize some of the BD as earlier stage. That said, if you look at our clinical pipeline, 40% of the programs in the clinic have benefited from BD that we've done in recent years. So this is not BD that pays off at some point in the future. This is BD that's in the clinic now. We've had actually a very active year. I think we're approaching eight or nine transactions this year on the BD side. So that's gonna continue to be our primary focus, is investment in innovation. We have carved out some capacity for share buybacks. We have a larger authorization in place. We have a $3 billion authorization in place, and we've been active executing against that throughout the year. We continue to be active buyers. So that focus, that dual focus of innovation with a little bit of room for share buybacks is appropriate for us. We have no intention of initiating a dividend at this point. The strategy's worked well, and we're gonna stick with it. Fantastic. Thank you. Well, thank you for your time. Congrats on all the progress. We, we look forward to paying and, Yeah. Thank you, everyone. Thank you. Thank you all. Take care. Thank you.