Good evening, everyone. My name is Susie Lisa, and I'm the Senior Vice President of Investor Relations for Vertex Pharmaceuticals. Thank you so very much for those of you here in the room for joining us in Philadelphia at the American Society of Anesthesiologists for our Vertex suzetrigine update. Thank you as well to all of you on the webcast. Tonight, Vertex is extremely pleased to have two physicians here for you to share their views on the phase III data, the PAIN landscape, and the potential for suzetrigine. Our first speaker will be Dr. Todd Bertoch. He is a Diplomate of the American Board of Anesthesiology, and he is CEO of CenExel JBR Clinical Research based in Utah. It's a clinical research organization based in Utah, excuse me. Dr. Bertoch is a principal investigator for the suzetrigine phase III randomized studies in acute pain. We're also joined by Dr. Ashraf Habib, Professor of Anesthesiology, Professor of Obstetrics and Gynecology, and Chief of Division of Women's Anesthesiology at Duke University Hospital. We'll also provide some highlights on our commercial strategy in acute pain. For that, I'm excited to introduce to you tonight Duncan McKechnie, who is our Senior Vice President, Head of North America Commercial. Duncan leads all of our commercial efforts in North America across all of our CF products, including Trikafta, as well as for Casgevy, as well as for the pain franchise. Duncan's been with Vertex for over a decade, having joined after thirteen years of leadership roles at Novartis, and began his career at GlaxoSmithKline. For the Q&A session, we ask that you focus your questions primarily while we have the physicians here for Doctors Bertoch and Habib. But they'll also be joined by Duncan, as well as our CFO, Charlie Wagner, and Paul Negulescu, who's SVP and leader of our pain program and a member of Vertex's research leadership team. For those on the webcast, we recommend that you access the webcast slides as you listen to the call, and the 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 Friday's press release and in our filings with the Securities and Exchange Commission. And with that, I'll now turn the call over to Dr. Todd Bertoch. Thank you. As mentioned, my name is Todd Bertoch. I'm an anesthesiologist, and I'm the principal investigator for the clinical trials that I'll be discussing here tonight. I'm also a consultant for Vertex Pharmaceuticals, so there are at least nine distinct voltage-gated sodium channels in humans. The NaV1.8 channel, expressed on peripheral nociceptors and DRGs, has a critical role in transmitting pain signals. Suzetrigine, which we'll be discussing tonight, is a potent oral, non-opioid, small molecule that selectively inhibits peripheral NaV1.8 nociceptors. Because NaV1.8 channels are not expressed in the brain, suzetrigine, unlike opioids, doesn't have the potential for addictive potential, so suzetrigine has the potential to be the first treatment for moderate to severe acute pain from a new pharmacologic class in over two decades. Today, I'm excited to report on the two-phase clinical phase III acute pain clinical trials studying suzetrigine in over 2,000 subjects, making them the largest ever phase III trials in their respective indications. Those indications, abdominoplasty and bunionectomy, are well-established models accepted by the FDA as representative of acute pain states in general. Subjects underwent either full abdominoplasty under general anesthesia or bunionectomy under continuous popliteal nerve block with sedation. Upon experiencing moderate to severe postoperative pain, subjects were randomized to receive either suzetrigine with a 100 milligram loading dose followed by 50 milligrams every 12 hours, or hydrocodone-acetaminophen 5-325 every 6 hours, or placebo. The moderate-strength opioid combination drug, hydrocodone-acetaminophen, was chosen because it is the most commonly prescribed opioid after these procedures. Subjects were then allowed to receive ibuprofen 400 milligrams every 6 hours, as needed for breakthrough pain. The primary and key secondary endpoints for this were the same in both clinical trials. The primary endpoint was SPID over 48 hours for suzetrigine compared to placebo. SPID is a measure of the total pain reduction after treatment using a zero to 10 numeric pain rating scale, and it's the most commonly used and FDA-preferred endpoint in acute pain clinical trials. The first key secondary endpoint was SPID48 for suzetrigine versus hydrocodone-acetaminophen. The next key secondary endpoint was the time to meaningful pain relief. This was defined by a two-point or greater reduction in pain from the baseline pain compared to placebo. These data were then analyzed to assess suzetrigine's efficacy, both as a monotherapy, and an additional ad hoc analysis was done of ibuprofen rescue medication to estimate the potential impact of suzetrigine as a component of a multimodal analgesia regimen. The demographics and baseline characteristics were balanced across treatment groups within each trial. You'll note here on the slide that the average baseline pain in the abdominoplasty trial was higher than in the bunionectomy trial, and we'll discuss the implications of that on an upcoming slide. Both studies met the primary efficacy endpoint by demonstrating statistically significant pain reduction compared to placebo with very highly significant p-values. The top half of this table that you're looking at represents the efficacy of suzetrigine as a monotherapy. The bottom half of the table is an estimate of its potential impact as part of a multimodal analgesia regimen with ibuprofen. It's important to note that because ibuprofen was given sporadically and only at high pain levels during this clinical trial, these data significantly understate how effective suzetrigine might be in a true multimodal analgesia regimen when concomitant ibuprofen is administered on a regular schedule. These are the graphic representations of the change in pain intensity from baseline pain over 48 hours for the abdominoplasty trial. On these graphs, lower Y values reflect greater pain relief. The blue line is suzetrigine, the black line is placebo. The mean pain intensity difference as a monotherapy compared to placebo was minus 3.4 points or a 47% reduction from baseline. Just for reference, the commonly accepted definition of clinically meaningful pain relief is a minus 2-point reduction. The graph on the right shows a similar result when suzetrigine's efficacy is estimated as a component of multimodal analgesia with ibuprofen. For bunionectomy, suzetrigine also showed clinically significant pain reduction at 48 hours, with a mean pain intensity difference of minus 3.4 points, or a 51% reduction from baseline, and with similar implications for multimodal analgesia, as shown on the graph to the right. Suzetrigine did not meet the key secondary endpoint of superiority to hydrocodone-acetaminophen. However, in an upcoming slide, we'll talk about some of the differences in safety profiles, which I think might be even more clinically meaningful. In both studies, suzetrigine achieved clinically meaningful pain relief much sooner than placebo. It's important to note that these onset times you see here do not reflect the time to the first perception of pain relief, but rather when that relief met the protocol definition of being clinically significant or clinically meaningful. So what appears to be, In this slide, you'll see it looks like there's a significant difference, in onset time between the abdominoplasty and the bunionectomy trials, and I'll address that on the next slide. You might recall that earlier I pointed out that the average baseline pain in abdominoplasty patients was quite a bit higher than in bunionectomy patients. But if we analyze the onset time in the subgroup of bunionectomy patients whose baseline pain score was closer to the average baseline pain score in abdominoplasty patients, we find that the onset times for suzetrigine are consistent across both indications. The bottom half of this graph suggests that onset times are more favorable when suzetrigine is assessed as a potential component of multimodal analgesia, and that makes sense. So turning our attention to the safety data. You'll see here that suzetrigine was generally safe and well tolerated. In fact, there was actually a lower incidence of adverse events with suzetrigine than both hydrocodone- acetaminophen, and placebo. I've been the principal investigator for over a hundred and fifty clinical trials in my career. This is the first time I've seen a study drug have fewer adverse events than placebo. I find that remarkable, particularly in a clinical trial with such a large sample size. So concluding the discussion on the RCT study, suzetrigine, a novel, orally administered, non-addictive inhibitor of peripheral NaV1.8 nociceptors, was evaluated in historically large phase III clinical trials for acute pain. Suzetrigine treatment resulted in a statistically significant and clinically meaningful reduction in moderate to severe acute pain over 48 hours, and it was shown to be effective both as monotherapy and as potentially as a component of multimodal analgesia with ibuprofen. Suzetrigine was generally safe and well tolerated, with a lower incidence of adverse events than both hydrocodone- acetaminophen and placebo. And so, based on these data, I believe that suzetrigine has the potential to represent the first new pharmacologic class of treatment for moderate to severe acute pain in over two decades. On behalf of the authors of the RCT study, I'd like to offer sincere thanks to all the trial participants and their families and the site investigators that are listed here on this slide. Also, just gonna take a few minutes and discuss the open label companion study of suzetrigine in other surgical and nonsurgical conditions. This study looked at safety and patient satisfaction over a 14-day outpatient treatment period in a much broader range of acute pain conditions. Patients received the same regimen, a 100 mg loading dose of suzetrigine, followed by 50 mg orally every 12 hours for 14 days, or until resolution of pain, whichever occurred first. Ibuprofen and acetaminophen were available as needed for pain, and importantly, opioids were not part of this perioperative treatment. The indications that were looked at in this trial included postoperative pain after orthopedic, plastic, ENT, general, and urologic surgery. In addition, there were a wide range of nonsurgical painful conditions, essentially from head to toe. Of the 256 subjects enrolled, only four subjects withdrew from the study due to a lack of efficacy of the treatment regimen. So to me, the key takeaway from this is that the overwhelming majority of patients went through the entire 14 days of treatment postoperatively without a single dose of opioids. There were 2 serious adverse events, both determined by investigators to be unrelated to suzetrigine, and the most common regular adverse event noted during the month-long duration of the trial was headache. As you can see here, there was a very high percentage of patients who rated the effectiveness of suzetrigine for treating pain as good, very good, or excellent. This is just a tabular rendition of the same data, with over 83% of patients rating effectiveness as good, very good, or excellent. And so to conclude, based on these SASI data and the RCT data, suzetrigine, a novel, orally administered, non-addictive inhibitor of peripheral NaV1.8 nociceptors, has the potential to represent the first new pharmacologic class of treatment for moderate to severe pain in over two decades. And with that, I'll turn the time over to Dr. Habib. Thank you, Dr. Bertoch. Good evening, everyone. Thank you for being here. My name is Ashraf Habib. I am a professor of anesthesiology and professor of obstetrics and gynecology at Duke University, and also the chief of the Division of Women's Anesthesia, which is the Division of Obstetric Anesthesia. I'll tell you a little bit about my practice. While I'm an obstetric anesthesiologist, I also practice in the general surgical population in patients undergoing gynecologic surgery, urologic surgery, and a broad range of other surgical models. I have a clinical and research interest in acute pain. Over the years, I have conducted many studies looking at interventions to optimize the management of acute pain, pain after the surgery, looking at interventions from numbing medications, local anesthetic techniques, or systemic drug administration. I performed a number of meta-analysis on the topic as well. I've also, in my institution, led the development of enhanced recovery protocols, which rely on the use of multimodal analgesic regimens, primarily in the gynecologic patient population and in the cesarean delivery patient population. Also been part of a national expert group with the Society of Obstetric Anesthesia and Perinatology, devising the multimodal recommendations for pain management after cesarean delivery. How do we manage acute pain today? I mentioned the word multimodal analgesia, enhanced recovery, a couple of times. What does this mean? We, our aim for managing acute pain is to improve the management, improve the pain relief that the patients get, while minimizing the side effects that they get from their pain medications. One of the most commonly used pain medications, as we know, are opioids. Opioids are associated with a number of adverse events, ranging from nausea, vomiting, sedation, constipation, respiratory depression, which could be life-threatening. Many data have come over the last few years showing that actually, there's a risk of persistent opioid use. For many patients, the trigger for starting to be addicted to opioids or suffering from opioid use disorder, starts actually from the prescription opioids that they get after their surgery. Because of all of that, we try to use interventions that either abolish or minimize as part, as much as possible, the use of opioids, what we call opioid-sparing techniques. If we look at the way we manage pain, the pain pathway is complex and involves a number of different receptors. There are different targets within the central nervous system where we can manage pain and address pain management. The basic principle of multimodal analgesia is if you use drugs that work on different areas or different receptors within this pathway, with the goal of, number one, improving pain relief, because you're addressing it from different angles, and number two, you use a lower dose from each drug in order to achieve this goal. There are a number of cocktails that are used for pain management. As an anesthesiologist, I start this in the preoperative period. We give some medications to patients before they go to surgery, and typically, we give them nonsteroidals, acetaminophen, Tylenol, before surgery, and then we use a number of medications during the procedure to help to optimize pain management. Then post-operatively, we put them on, again, a multimodal regimen, which typically, nowadays, consists of nonsteroidals and acetaminophen, and try to keep the opioids for rescue. If there is a surgical model or a type of surgery where we can use numbing medications, local anesthetic techniques, nerve blocks, we do that as well during the procedure. Post-operatively is the same concept. We use nonsteroidals, we use acetaminophen, and we try to keep opioids for rescue. So basically, we try to minimize the use of opioids as much as possible. One issue that the anesthesia community has encountered. Yes, we try to use drugs from different classes, but there are some drugs that have side effects. I'll give you an example. A few years ago, when enhanced recovery protocols became popular, gabapentin, you might have heard of gabapentin, is a medication that's mainly an antiepileptic, but it has analgesic effect, and we used it a lot in the context of enhanced recovery protocols, only to realize a few years later we knew that it had a sedative effect. It actually increased the risk of respiratory depression, with slowing of breathing and could be potentially life-threatening when used in conjunction with opioids. So there are many medications that, yes, could be used, but have side effects. So we have to be careful with the concept of, yes, maximizing pain relief, but in the same time, paying particular attention to the side effect profile. That's why I think the suzetrigine presents a really an exciting development in this area. For many years, I think I mentioned a couple of times, what we currently have are the nonsteroidals and the acetaminophen, which we have a reasonable safety profile. We try to give them to every patient. And then this could be adequate for some patients, but from some other patients, from some other types of surgery, those are really not adequate to provide pain relief. So what is our next stop? Our next stop currently is opiates, and for all the reasons, for all the side effects that happens with opiates, we try to minimize that, but we don't have anything in the middle. So we're stuck if we don't get good pain relief with nonsteroidals and acetaminophen, we don't have something to fill the gap in the middle. We just go directly to opiates with the potential of side effects that we discussed. That's why I think suzetrigine is an exciting addition to potential addition to our field for what we currently have. How would I use it? What's what I think is the potential role of suzetrigine in acute pain management. As I thought about it, I thought, you know, probably I will think about it in three ways. The first one, we try to spare opioids or reduce the amount of opiates that we use as much as possible. So I would see it as an addition to the use of nonsteroidals and acetaminophen. So if I had it available, I will add it to these two agents in order to and give it on a regular basis, in order to avoid or reduce the use of opioids as much as possible. The second scenario would be, let's say, it is not possible for whatever reason, not for availability, for cost, whatever reason it is, it's not practical to use it on a regular basis for my patients. I will have it as a second step. If the patients get their nonsteroidals and their acetaminophen, and they don't get adequate pain relief, then I will have suzetrigine given next, before, hopefully, to avoid giving the opioids subsequently. The third way I think of its use is, it's implementation in some patients who cannot take nonsteroidals. Nonsteroidals are great agents. They have shown to have maybe 20%-30% opiate-sparing effect, but unfortunately, they have- they are associated with side effects. There are some patients who cannot take them. Patients who have renal dysfunction, for instance, patients who might have a bleeding risk. There are some types of surgery where the surgeons are not keen on giving their patients nonsteroidals after the surgery because they are concerned about the bleeding risk of those patients. Some patients who have surgery on their bowel, some surgeons are concerned about the anastomosis that they do, so there are a number of patients. Some older patients might be sensitive to the effect on the kidneys from giving nonsteroidals. All of these patients, yes, nonsteroidals are great, but I might not be able to use them, so I find that suzetrigine might be a great agent to fill the gap for those particular patients, to give them this in conjunction with acetaminophen, because I have not been able to give nonsteroidals to those patients. So these are the three ways I think that the potential role for suzetrigine in acute pain management. I think it's an exciting development in our field, and I will turn now to Duncan McKechnie. Thank you. Great. Thank you. All right. Good evening, everybody. Thank you, Dr. Bertoch and, Dr. Habib. So it's my pleasure to share with you some of our thinking on the commercial preparations for suzetrigine. So I'll start off with some numbers. I'll orientate you to the right-hand side of the slide. There's around about eighty million people in the U.S. each year suffer from acute pain, and of those, eighty million patients, around about forty million, or obviously half of them, are given opioids for moderate to severe pain. As you can see on the left-hand side of the slide, and as you just heard from Doctors Habib and Bertoch, although we know opioids are effective in mitigating pain, albeit by altering the perception of the pain rather than treating the pain, we know that they also come with significant tolerability and side effect profiles, as just recently mentioned, including things like nausea, vomiting, constipation, and respiratory depression, as well, of course, as the rather well-known issues regarding dependency and addiction. So the schema at the bottom of the slide really describes where we're thinking that suzetrigine offers a new modality in the treatment of moderate to severe acute pain, pending FDA approval. You can see you've got Tylenol and ibuprofen on the one hand, and you've got opioids on the other hand, and we believe that for those eighty million patients there's a great opportunity for suzetrigine in between those two existing modalities. To understand that a little bit better, we recently conducted a survey called the State of Pain Survey where we interviewed around about five hundred and fifty HCPs in the US and just over a thousand patients. This was entirely focused on acute pain only, and I'll just touch on some of the results here. You can see on the left-hand side, just under 90% of physicians reporting that their concerns around side effects of current medications lead them to feel that they are inadequately treating acute pain. And indeed, just under 80% of them expressed concerns around the potential for addiction from opioids, even with the use of opioids for moderate to severe acute pain. And on the right-hand side, you can see that patients also expressed a desire for new alternatives to treat their pain, particularly ones that were non-opioid in nature. So in summary, we believe that suzetrigine, which we'll be describing as a pain signal inhibitor, offers the opportunity to be a treatment modality in between acetaminophen and Tylenol on the one hand, and opioids on the other hand. And I'm sure you've seen these stats from us before, but there's around about a billion calendar days worth of treatment in the acute pain market here in the U.S. Two-thirds of those patients are treated in institutional settings, and about half of the prescriptions originate in those institutional settings. So by institution, think hospital or ambulatory surgical center. And there's around about 2,000 high volume hospitals that really drive the majority of the market. And those 2,000 hospitals, around about 60% of them, ladder up to one or other of the 150 or so IDNs that exist in the U.S. So we believe that the acute pain market is a specialty market for us to access. So in terms of our launch readiness, as you would expect, we are well underway at this point in time. The target action date from the FDA for suzetrigine is January the thirtieth next year, so just a few months away at this point. We have hired appropriate field-based teams, so we have a strategic account lead team focused on the IDNs. We also have the territory account managers focused on the hospitals. They are all fully employed, trained, engaging with customers in a compliant way. We've also started our contracting conversations, both with the GPOs for hospitals as well as the PBMs and the GPOs that align to each of the PBMs. We have a broad range of initiatives, we're building in order to support patient access immediately post-approval. And recognizing, of course, that this is a treatment for acute pain, so people can't wait for two or three weeks or even two or three days for treatment, we're working with the various retailers to ensure retail distribution, so essentially, we're trying to ensure there is both physical and financial access to suzetrigine immediately at approval, and as you know, we continue to engage with the state policymakers as well as the federal policymakers on legislation such as the NOPAIN Act, as well as the Alternatives to PAIN Act and in those regards, I think you probably already know that Pain stands for Prevent Addiction in the Nation, so in summary, we are excited about the opportunity that suzetrigine offers as the first new modality in moderate to severe acute pain in twenty years. But even though we're excited about suzetrigine, it's our first NaV1.8 coming to the market, we have a lot of other products in the pipeline as well, and Susie's just gonna talk through those very briefly. Thanks, Duncan. You are very welcome. Yep. One final slide. Consistent with our commitment to serial innovation, there's a broad portfolio of development. At the top here, with respect to suzetrigine or VX-548, you can see the phase III study that's completed in acute pain, about which you got all the details today from Dr. Bertoch. And then, we have begun enrollment already in the field of peripheral neuropathic pain, for which about 10 million Americans every year receive a prescription medicine. We've begun enrollment in our phase III study in diabetic peripheral neuropathy, and then we have completed enrollment in our phase II study of VX-548 in lumbosacral radiculopathy or, LSR or sciatica. And we remain on track to provide the phase II results by the end of this year. Then we're also excited to already be into our next generation, NaV1.8 inhibitor, so that's VX-993, and you can see the suite of studies there as well. It's currently in a phase I study in an IV formulation in acute pain, as well as in two different phase II studies. In acute pain, it's being studied in bunionectomy, and then in the field of peripheral neuropathic pain, it's also being studied initially in diabetic peripheral neuropathy. We have additional NaV1.8 inhibitors that will enter the clinic soon, and then we're also continuing to work on NaV1.7 inhibitors that could be used standalone or in combination with our NaV1.8 inhibitors. So I think that's a good place to wrap up, and then we're happy to take your questions. We have about, let's see here, about thirty minutes. We'd ask that we'll spend twenty-five or so while we have the physicians in the room, again, focused on acute pain and the data you've seen today, but we will leave questions for the entire program for about the final five minutes. So begin there, and maybe as we get organized here in the room, Dr. Bertoch, we did have one question that came in by email to start. If you could talk a little bit more about the onset of action- Yeah. with suzetrigine and any concerns or thoughts there, if you could go into that a little bit more. Yeah. Historically, for acute pain and for analgesics, the determination of time to onset has been done using what's called the double stopwatch technique. It's quite precise when it's used correctly, but there are a lot of operational challenges, especially as you get into a big study, and so in light of those operational challenges, for this study, we tried a novel approach to assess the time till a patient achieved a two-point or greater reduction in pain on the NPRS scale. And we defined as the time to the first perception of pain relief, a one-point change in pain on that NPRS scale. While this did help with the operational challenges associated with the stopwatch technique, in my opinion, I think it significantly overstates the time to onset. There are points that we could talk about more in detail if you want, about why that is. But, in my personal opinion, I've done many, many of these acute pain clinical trials using the double stopwatch technique and this method. I think that those times are significantly overstated. Kristin, you have... Maybe Jess, we'll start there. If you could state your name and question for the webcast, please. Hey, great. It's Jessica Fye, JP Morgan. I think there was some discussion around this during the presentation earlier today, but just coming back to the mean pain intensity difference score graphs in bunionectomy and sort of time to onset, can you talk a bit more about any impact of ropivacaine and the initial effect of suzetrigine? Is there some interaction there, and was that expected? And then also, just wanted to confirm. I'm not sure if I've seen this number. What was the proportion of patients across each arm in these trials that had rescue therapy? I think I had heard that it was maybe around 80% and really balanced, but just wanted to confirm that. Thank you. Yeah, I'll answer your second question first. It was around 80%, that rescued, and that was pretty similar across all the arms of the study. Back to your question, there were some differences in. Now, there are two points here. So I want to make sure I answer the question that you're asking. Are you talking about the differences between bunionectomy and abdominoplasty in the SPID numbers, or are you talking about differences in what appeared to be efficacy in the bunionectomy study versus the hydrocodone- acetaminophen versus the suzetrigine? More the latter, but kind of related? They kind of are, they kind of aren't. The differences that you see between the abdominoplasty study and the bunionectomy study with regards to suzetrigine versus hydrocodone and acetaminophen, okay? What we postulate is for the bunionectomy clinical trial, there was a popliteal nerve block, a continuous popliteal nerve block with a long-acting local anesthetic, ropivacaine. That ropivacaine was administered the entire first day after surgery, through that night. It was discontinued the morning of surgery. At some point after surgery, the patient achieved a qualifying pain level and which allowed randomization and the beginning of dosing. What we postulate is that there's still some circulating ropivacaine, local anesthetic, in the system that is having some impact because ropivacaine local anesthetics are very non-selective inhibitors of sodium channels in general. So, what we believe is that there's some still residual circulating ropivacaine impacting some percentage of the NaV1.8 channel. So, you know, after suzetrigine is dosed, the efficacy appears to be diminished because you can't inactivate a channel that's already inactivated by the ropivacaine, if that makes sense. If you think about the hydrocodone and acetaminophen arm, neither of those drugs, hydrocodone nor acetaminophen, are impacted by that ropivacaine, right? Because there's a very different mechanism of action for their pain relief. And so while the ropivacaine is making suzetrigine look less effective, it's actually additive to the apparent effectiveness of the opioid comparator drug. As evidence of that, if you look back at the abdominoplasty data, where a long-acting local anesthetic was not used, you don't see that impact at all. That doesn't happen there. Okay, we'll go here, and then to the- Yeah. Thanks. Joon Lee from Truist Securities. Just following up on that question, were regional blocks not done for abdominoplasty? Because the efficacy there is very different than bunionectomy. So why is that the case? And part 2 of that question is, if you were to use a long, even a longer-acting bupivacaine, like liposomal formulated, how could that have impacted the study outcome? Okay, great questions. Great questions. So for the abdominoplasty study, to answer your first question, there was a field block with a short-acting local anesthetic used, basically to get the patient into the PACU relatively pain-free, to allow them to be more awake and alert when it was time to dose, okay? So no, no long-acting local anesthetic in the abdominoplasty study. And no, TAP blocks or any abdominal wall blocks were done in that study. The second question is: what is the impact of a longer-acting local anesthetic in the face of suzetrigine? In my opinion, these are just additive, right? So when you're, when we're doing the clinical trials, we want to eliminate any concomitant analgesics that might be impacting our ability to assess the efficacy of suzetrigine as a monotherapy by itself. So we want... That, that's kind of a bother for us. But in clinical treatment, we want to maximize that, and so that would be additive with whatever local anesthetic that you have on board. Go ahead, Tazeen. Hi, good evening. I'm Tazeen Ahmad, Bank of America. Question is for both Dr. Habib and Dr. Bertoch. So based on everything that you've said, do you still plan on using, if you're allowed to use suzetrigine, a local anesthetic as part of how patients are treated pre and during surgery? And can you also give us your opinion on whether or not suzetrigine will be obvious to P&T committees that they should be using it? Because in the past, there have been other attempts from other companies to use non-opioids. EXPAREL comes to mind. Why is this going to be different, and do you have any influence over your P&T committees on that? Thanks. I'll take it over. So your first question about the use of suzetrigine in addition to the other multimodal pain therapy that we are currently using. Can you repeat it again? Yeah. Do you plan on still using local anesthetics pre and during surgery? Local anesthetic, like nerve blocks? Yes. Yes. I mean, I think it's a good question. So if there is a surgical model where it is amenable to the use of local anesthetics, I would still plan to use it. It's, you know, it's these are tackling the pain pathway from different perspectives. So basically, any additive impact of a local anesthetic plus a systemic administration of drug would be welcome. I would plan to use it this way. Your other question relates to? P&T committees. P&T committees, yes. So P&T committees basically, you know, look at a number of things in order to approve a drug. Number one, does it fill a gap in what we currently have? Does it reduce the risk to the patients? And what is obviously the financial impact of using this particular drug? So for a non-opioid alternative, there are a number of arguments in favor of introducing a non-opioid with a favorable side effect profile. So I think for suzetrigine, with the data that we currently have, the data are very encouraging in terms of number one, showing efficacy, both as a monotherapy, as in the post-hoc analysis in the combination therapy, and number two, a very good safety profile. For you know, EXPAREL, for instance, we have it approved in our institution. It's institution dependent based on the P&T committees. But I think for a non-opioid with proven efficacy and good side effect profile, it would be approved by P&T committees, at least in my institution. I'll jump on there. I agree. I would continue to use local anesthetics, nerve blocks. Let's just hit this as hard as we can. As far as P&T committees, formulary, administrators, I think, you know, some other analgesics that have struggled with this in the past have not been orally administered like this. Their safety profile hasn't been the same. It's a really different medication. So these are gonna be prescribed postoperatively as outpatients. There are about three reasons why surgeons are really, or physicians are really pressured. We really need something else. We're a little bit in between a rock and a hard place when it comes to this. We are, for social optics, really discouraged from using opioids. There are now legal ramifications for us using opioids. There are side effects from opioids that, you know, we'd rather not have to deal with, obviously, in our patients. And so there's a lot of pressure on physicians to have something else, and I think that pressure is gonna be translated to P&T committees, and I really feel optimistic that something like this is gonna get adoption from those committees. Cool. I mean, I'll add another comment I recall as Dr. Bertoch was talking. I can think of one instance in the last few years where we struggled in our P&T committee with an agent. But this was because of the... It didn't prove to reduce side effect profile. It was an opioid, but it was supposed to work on a different pathway, a different way. And it didn't prove that it reduced the side effects compared to opioids. The quality of the data was not good. So basically, I think one of the important things that P&T committee looks at is the quality of the data that's being produced, how robust the clinical trials have been done. And the encouraging things about the suzetrigine trials, number one, the data, the studies were very rigorous, and the data was consistent across all the studies that have been done so far. And this is very important, and you don't see it consistently in acute pain trials. Chris, let's go to Will and then Gena. Hi, Will Pickering from Bernstein. Thank you for the presentation. My question is, what are the patient characteristics and overall clinical presentation that will be most informative in deciding whether to use suzetrigine or opioids? Thank you. You wanna take that one? Yeah, sure. So, what patient characteristics, you know, or surgical models to use suzetrigine? So in my practice, the principal what we try to achieve across the board for all surgical, all types of surgery, is opioid sparing, for all the reasons that we have highlighted earlier on. So for me, for instance, I use nonsteroidals and Tylenol for all of my patients across all the surgical models that I use, whether those patients have had a local anesthetic block as part of their procedure or not. So I try to maximize the opioid sparing as much as possible. So when I have suzetrigine, I would add it on top of the nonsteroidals and the Tylenol across the board for all of my patients, because I want to maximize this across all my patients. Some patients will do well with just those non-opioid options, and this is great. Some patients might still use opioids, and this is what we're trying to avoid. Yeah, I would add, I think that where we struggle right now is with the patients that. You know, there are some mild pain states where acetaminophen and/or an NSAID are adequate, right? There's no reason to add suzetrigine to that. But where we really need help is when we have a pain state that doesn't respond to acetaminophen and an NSAID. And my next step, you know, right now, is an opioid. There's nothing else out there. And so being able to fill that gap is hugely important, and there are a lot of people out there right in that little sweet spot, and I don't wanna have to give them an opioid. Go, Gena. Gena Wang from Barclays. Maybe follow up this question, you know, the, you want to have a step, you know, nonsteroids and then the opiates, right? So in between, maybe give us a sense, what percentage-- I think, we saw the number 80 million. What percentage of those patient population you will start with a nonsteroids, and then you will have to require to use opiates? So maybe that, that's the number one question. And the second, I think that the, for the companies, the economic part is very important, the pricing part. I think in the past, I think, the range was mentioned was between $10- $20 per day. Is that still the case, or what is the latest feedback from the payers? So your first question is- Yeah. -what percentage of patients we're giving nonsteroidals would go on to need opioids, correct? So I'll give you a couple of concrete data, actually, from my practice. In our cesarean delivery patients, we have optimized our use of nonsteroidals and acetaminophen. We changed the time of administration, we changed the how often we use it and when, when we start it. And we managed to reduce the need for opioids, especially in the early postoperative period, from about 80% to about 60%. So still, despite optimizing this in this particular patient population, 60% of my patients currently still need opioids in, you know, in the first few days after their C-section, and sometimes they're discharged home with it as well. Gena, we haven't commented on price specifically, and we won't tonight. But we are having a number of, I think, really important conversations with payers and other decision-makers, and maybe Duncan can provide just a little bit of color around some of those conversations. Sure. Yeah, we started engaging with payers on suzetrigine in November last year, so November 2023, and also began our engagements with the IDN, so the formulary decision-makers at IDNs in October last year as well. So we've been talking to these folks for quite a while. We've also, of course, engaged with the GPOs that we have to negotiate with for hospital purchasing. So those conversations are going very well indeed. We recognize that, of course, we're looking for broad access, no prior authorization, 'cause clearly that would be a barrier to quick access for the patients to get the product when they really need it. So we're engaging in rebate conversations with payers, as you'd expect. Those conversations are going well, and as Charlie said, we'll be announcing the price when we have approval. One or two more questions on acute. Go ahead. Hi, thank you. Jenna Li here from Jefferies on behalf of Michael Yee. Two quick ones from us. In addition to pricing, could you also talk about other parameters, like bookends and stuff that we should be thinking about, and perhaps maybe some, comps to look at in figuring out what the first year could look like? And another one would be, a future chronic pain launch. How would that be perhaps different from the acute pain launch coming up? And could you describe the difference of dynamics of the two markets? Thank you. I, I appreciate the question, though let's move on to a different question. Let's try to get the most out of the time that we have with the doctors here, and we can take questions offline about comps and other launch dynamics. Let's go here. Hi, Sadia Rahman from Mohit Bansal's team at Wells Fargo. So both trials were done predominantly in women. Curious if the data in the male subgroup is similar, or if that analysis hasn't been done yet, would you expect differences in men? And then can you comment on the potential for combining NaV1.8 with NaV1.7? Is there potential for increased potency while, you know, increasing the therapeutic window for the combo? Yeah, I'll answer the first question, and I'll defer the second one. As far as male-female ratio, while that's critically important in clinical research to make sure we're looking at both sexes and the impact on both sexes, what we do know from the literature is that historically, you know, for analgesics, there has not ever been shown to be a big difference between men and women as far as response to analgesics. So we don't anticipate that to be a problem. Obviously, because of the nature of these clinical trials and these models that are actually approved and almost demanded by the FDA for us to study these use in these clinical trials, there isn't an imbalance. But I think particularly for analgesics, personally, I don't think you're gonna see a big difference based on history. Paul, you want to take the second question on combo? Sure. So on the question of combination, there's a rationale for combining one seven and one eight together because those two channels are expressed in many of the same pain-sensing neurons. So I think when we get as far along as having the one seven, we'll certainly consider looking at combinations. Cool. Good. Here in the middle, Keeley. And then we'll go to the back, Kristin. Chris Yu here on behalf of Terence Flynn, Morgan Stanley. Questions for the doctors: so suzetrigine is also being studied in LSR. Just want to see whether you think it's gonna be successful in LSR, and if you want to see clinically meaningful results, what is the data that you want to see between Suzy and placebo? Thank you. I will just say this. We're here to discuss these studies. I'm specifically here to discuss the results from this study. I will say I've been doing this a very long time. It's quite uncommon for medication, analgesics that work in somatic pain, with very few exceptions, to not work in other pain types. So I would not be surprised if it worked, but I can't comment to any specific data. Thank you. In the back, Kristin. Hi, Malcolm Hoffman here for Evan Siegerman from BMO Capital Markets. I have a question for Dr. Habib. You mentioned a third scenario, patients who may not be able to use NSAIDs either because of liver dysfunction or bleeding risk. Is there any way you can sort of quantify what percent of, percentage of patients fit into this category, and how important is it for these patients to have another option, other than opioids specifically? Thank you. Yeah. The quantifying the patients really varies. There are two way to look at it. One would be the surgeries where actually the surgeon is not keen to give nonsteroidals. So in this patient population, it would be 100% of the patients. Some examples would be plastic surgeries. Commonly, the surgeons are not keen with, with flaps or some of breast surgeries. They are not keen on nonsteroidals. So in this patient population, it will be 100% of the patients. In other subset of patients where it's not the surgery-specific, but it is patient-specific, where you cannot give them nonsteroidals, I will say probably, again, it varies. If it's a surgery predominantly in an elderly patient population, so it would be a higher proportion of those patients cannot get nonsteroidals. So it would be more in the region of 70% if it's a predominantly elderly patient population. If it's a predominantly younger patient population, this would be much, much less than that. It would be probably, I would say, maybe 15%-20%. And then, your other question was? That was it. That was it. Yeah, that was it. Debjit? Hey, good evening, and thanks for taking the questions. Debjit from Guggenheim. I'm just curious as to what happens to these patients post-discharge. So do these patients go home with another five to seven days of prescription pain medicines? And in that setting, would you prioritize suzetrigine over NSAIDs, or acetaminophen, or opioids? Yeah, I talked about a little bit about the open label study at the end of my presentation, where basically we were looking at outpatient dosing of suzetrigine over fourteen days postoperatively. Roughly half of patients in that study, their pain resolved somewhere during that fourteen-day period, and another half still had some pain after that fourteen-day period. Those people then, suzetrigine was discontinued, obviously, because it was the end of the study or the end of the dosing period for the study, and then they were discharged on standard care medication. So, as far as predicting how I might treat that, that person moving forward, it, it really is on a patient-to-patient basis, and physicians are gonna have to decide how they wanna use that, that medication and, if, if and when it's approved by FDA. Anything else? Hi, this is Angela Chan from Canaccord for Whitney Ijem. A follow-up to Debjit's question. So upon discharge, if they are given a script for suzetrigine, patients. You mentioned patients aren't gonna wait two to three days, but realistically, they're not even gonna wanna wait two to three hours at the pharmacy in the event that it could not be covered immediately or if it's too expensive. So for Dr. Habib, Dr. Bertoch, are you thinking about, like, a potentially increased workload with pharmacies calling and asking for, you know, a new script or, you know, something else? How are you thinking about reducing that potential friction when the time comes? Yeah, if I understand your question correctly, and Dr. Habib could probably speak to this better than I can, but you know, my impression is that I would treat this like another... Physicians in general will treat this like other analgesics that they prescribe. They'll call in a prescription. It's almost always done electronically now, so it's almost immediate. You'll call in that prescription. There should not be a large a big delay. As far as payers and how that's gonna impact that, I really can't speak to that, but I don't see much of a difference in the way physicians will prescribe this compared to other analgesics. I agree. I mean, I think, I think patients are discharged with, you know, a script for an analgesic of some sort, and this would follow the same pathways of a script being phoned to a pharmacy or depending on the particular institution. Or they can get the script from the hospital pharmacy as well. In some institutions, they can get their script from the hospital pharmacy, but it will be... I would see this being along the same ways of any script that being placed for the patients. I will add that over, you know, the over-the-counter drugs, Tylenol and the NSAIDs that are over the counter, obviously, patients can go acquire them- Yeah. -at their own leisure, right? But if you're talking about maybe, more difficulty getting suzetrigine than a prescribed opioid, believe me, it's getting harder and harder for patients to get a prescribed opioid postoperatively. There's long delays. So I don't see that impacting usage very much, in my opinion, anyway. The other point about opioids as well, there are now restrictions on how many, how much opioids you're allowed to give the patient as a script. Actually, the workload regarding reordering opioids is much more than a non-opioid, non-regulated medication, where you can order a supply for a longer period of time compared to what we're allowed now to do with opioids. Maybe I can add to your question with regard to retail and the payers. I can't quite see you at the back there. As I alluded to earlier, we are working with retailers to ensure that there will be broad physical availability of suzetrigine, and we are also putting in place, as you'd expect, copay assistance and financial assistance programs to ensure that patients will be able to get it when they turn up at the pharmacy counter. Great. I think that's a perfect place to end. Dr. Bertoch, Dr. Habib, Duncan, Charlie, Paul, thank you very much, and thanks again for all of you being here in Philadelphia. Thank you. Thank you.