Okay, welcome everyone. I'm Joe Schwartz from Leerink Partners Biopharma Equity Research Team. It's my pleasure to host this fireside chat with Amicus Therapeutics. We're pleased to have Simon Harford, CFO, and Jeff Castelli, Chief Development Officer, with us today. Thanks for joining us. Thank you. Thank you, Joe. So, last year was pretty transformative for you guys, with the long-awaited approval of Pombiliti and Opfolda. So, maybe to start, can you briefly remind us about the label you received and, and how you think this sets you up for success in this, in this market? Yeah, thanks, Joe. I'll start, Simon, and then please jump in. So, first of all, great to be here in Miami. Great to be at the Leerink meeting. So we are very excited to launch Pombiliti Opfolda at the end of last year. We first launched in Europe. We got approval in Europe and the U.K. The label there was in adult late-onset Pompe disease patients, so includes both naïve and ERT-experienced patients. In the U.S., we also got approval. That was in a label that basically was for patients not improving on their current ERT. Importantly, that, there's two aspects to that. One is it's from any ERT, including the traditional standard of care, Lumizyme, as well as Sanofi's new product, Nexviazyme. It also is for people, you know, not improving means either worsening or currently stable on your current ERT. When we have, you know, done market research and talked to physicians here in the U.S. prior to the launch, they'd estimated about 25% of their patients were sort of clearly progressing, 25% seemed to be improving, and about 50% were they perceived generally stable. So that not improving on their current ERT really goes after that 75% of that population in the U.S. Remember, longer term, we also believe some of those patients currently improving might, you know, start to plateau and ultimately start to decline. So we think that's, you know, outside of the U.S., very nice broad label, within the U.S., a label that we're very happy with and, you know, first thing we can go in and ask is, you know, "How is your patient doing? Are they currently improving on their current treatment? Okay, great. And then, how have your conversations on Pombiliti and Opfolda been evolving across different treatment centers and practice settings? Does any particular groups of physicians seem to appreciate the data more than others? Does anyone need you to focus more on them in order to appreciate the profile? It's a market that's been around for a while, and there's, you know, already been a couple options made available, and now you're coming, you know, at this point. So I'm just wondering about the receptivity and how it looks across the marketplace. Yeah. So, you know, we were in the position of having a very broad global phase III program, expanded access program. So we had worked with most of the large Pompe centers around the world and the U.S. through our trials. So obviously, those were people that had experience with the product. You know, first part of launch with them was to help them transition their trial patients over to commercial product. But we've been very excited by the reaction, you know, broader within the Pompe treating base, and we're starting to really see that, you know, base expand. So there it's a little bit of a different conversation 'cause those folks don't have as much familiarity with Pombiliti Opfolda, so there it's really educating them about the product, about the trial outcomes. But, you know, it's really those, you know, two groups of sites, and then it's, you know, more broadly, you know, asking them, what are their patients? How are they doing? Are they stable? Are they improving? And, and that level is a new conversation. Traditionally, there was one treatment option, and physicians didn't really have to think through, you know, exactly how their patients were doing and who should switch to a new treatment. Interesting. And in the U.S., can you talk a little bit more about the breakdown of treatment-experienced patients who are switching to Pombiliti and Opfolda, and what are you seeing, where are you seeing these patients come from? Yeah, great question. In terms of, you know, whether they were on Nexviazyme or Lumizyme? So really, you know, just as a quick reminder, the last time we gave an update on sort of numbers where it was at J.P. Morgan, early January, we'd said there were 120 patients currently on treatment or prescribed to go onto treatment. 105 of them had been from trial transitions. So of the new patients we'd seen then and what we continue to see now this year, interestingly, they really reflect the underlying population within the geographies. So in the U.S., where most patients are on Sanofi's new treatment, Nexviazyme, we're seeing primarily Nexviazyme patients switching to Pombiliti Opfolda. We're still seeing some Lumizyme patients there as well. And I know you didn't ask, but outside in the U.K. and in Germany and Austria, we're actually seeing sort of the opposite. We're seeing more Lumizyme switchers and a smaller percentage in Nexviazyme and also some naïves. So really sort of represents what we're seeing come on to Pombiliti Opfolda really represents sort of the underlying patient dynamics or segments in those different geographies, which I think shows that there's a good value proposition sort of across patients. Okay. What about the expanded access program? Have all of the patients or most of them transitioned onto commercial drug so far? Yeah. So, so really in terms of that program, clinical trial and expanded access, what we said was about 105 patients from the three countries where we'd launched at the beginning of January, involved in that group. Germany and the U.K., all patients are on commercial drug. So the scheduled for treatment group was primarily from the U.S. because the launch was later, and the vast majority of those have now transitioned on to commercial drug. Okay. Then, if we focus in on the switch dynamic a little bit more, what aspects of the efficacy profile seem to resonate the most with physicians in the different geographies based on what you can emphasize on the label? What data is it that seems to be resonating the most? Yeah, you know, when you look back at the, the phase 3 data, you know, the strongest set of data was in the 80% of the enrolled patients that had been on Lumizyme previously, and they'd been on Lumizyme for quite a long time, I think on average, 7 or 8 years. And really, in that group, and we've continued to show some of that data at different medical conferences in many different ways, you know, when you looked across all the endpoints, they either stabilized if they'd been progressing in the patients that were remaining on Lumizyme, or they actually improved as a change from baseline. So in some cases, letting patients, you know, have additional muscle strength or additional ability to do things that they might not have been able to do. So that's probably the most, you know, compelling set of efficacy data, was that in those patients that were generally stable or declining on parameters, that we were able to stabilize them and actually improve some aspects. So that's the core, but, you know, our data in the naive patients, they responded very well. They responded very well in the control group as well. But our phase two data has shown really good durability of effect out to 4+ years. So that complete set of data, I think, is compelling, both in those experienced, where we really have that strong data head-to-head in a randomized, blinded study, the only product to have that data, versus standard of care, and then really naive too. It's a, you know, we show that we can really help those patients as well. I think we're seeing that, you know, in Europe, where naïves are a part of the label, we're seeing, as I mentioned, uptake in the naïves. Yeah. Okay, and then looking ahead, can you remind us what new markets are expected to come online? Yeah, in this year, primarily European markets. So obviously, we have the U.K. and Germany of the Big Five. We would anticipate seeing the other members of the Big Five this year. In fact, in Spain, we've already received reimbursements and just done the first infusion, so that's really exciting. That was kind of ahead of schedule. And then we will expand into other European markets, primarily this year. The list is Belgium, Netherlands, and the Nordic countries in addition to the Big Five. And then we will get to what I call rest of the world markets such as Australia, Japan, and Canada. We'll submit this year, but it'll take obviously a bit longer to get on the market. Okay. And if we take a step back and look at the overall late onset Pompe market, our analysis suggests that the market expanded when Nexviazyme entered. Do you get the sense that this is something that could occur again with Pombiliti and Opfolda? What, what would be the drivers of this dynamic? Yeah, you know, we know Pompe, like a lot of other rare genetic diseases, is significantly underdiagnosed. So we know there's still very strong underlying patient growth through diagnosis. You know, with Nexviazyme coming in, it's still both from Sanofi, so not clear exactly what might have driven some of that growth other than possibly there could have been patients who... You know, there are some patients who had stopped Lumizyme for whatever reason. Maybe some of them came back on to Nexviazyme. But you know, with the second company coming in, like Amicus, we know for sure we typically see the more companies in a space, the better the diagnostic initiatives are. You know, we're certainly interested in continuing to help physicians diagnose Pompe and Fabry, and we'll do what we can there. So, you know, you might actually see additional market expansion now with Amicus coming in, both from a diagnostic perspective, but again, even if there are still patients that might be sitting on the sideline, that maybe they'll come onto treatment now. Okay. And then, thinking about the launch in 2024, how are you thinking about the revenue contributions from different geographies? And then acknowledging that the company's not providing guidance, what do you make of the consensus estimates that are out there? I think it's currently around $100 million for the year and- Yeah. What I would say is as follows: We clearly chose not to give guidance on Pombiliti + Opfolda for this year, unlike Galafold, which is obviously on a trend trajectory and has been for several years, although accelerating in 2023. As far as Pombiliti + Opfolda is concerned, I'm not going to comment on consensus. What I will say to you is we have continued to see an acceleration of new patients in the first part of the year. We'll share what the Q1 numbers are once we get the Q1 earnings in May, and then quarterly thereafter. I think the really important metric for us, however, for this year, is how many patients do we actually have on drug at the end of the year as we enter next year? Because that will set up a more sort of steady state trend for us, is our belief. The variability this year is probably mostly around the fact that in the second half of the year, we have a number of those 10 submitted dossiers where we expect to get pricing and reimbursement.... and it's difficult to know exactly when those will come. They'll come sometime in the second half, we anticipate. But we're also, you know, the reality is, if it takes us a little bit longer or a little bit shorter, depending on how negotiations are going, we try to do what's the right thing for the value for the long term, and that can be in the first year, some of the variability, and hence why we're not giving the guidance. But we will get there eventually, once we have a trend, and we will certainly update you quarter by quarter. Okay. Great. I guess that's a nice segue to Galafold. So, that product continues to launch very nice, despite being on the market for several years. Can you remind us what you saw in 2023 and what's currently driving the growth so far this year? Really, I mean, it's pretty remarkable that patient demand was the highest in 2023, I think, since for the last five years or so. And actually, if you look at the makeup of that, just under 60% was basically naive patients, as opposed to just over 40% being other switch patients. So that's a really good story as we think about the future going forward. We're also. You know, the reality is, as I think we've talked about, Joe, you know, there are 17,000 diagnosed Fabry patients. There are 11,000 of those that are actually treated today. So right there, we've got an opportunity with the 6,000, and most of those, we believe, at this stage, are patients with the amenable variant. So we see that as a big growth opportunity. We anticipate that the market will grow by the end of the decade from about $1.9 billion to about $3 billion by that point in time. And then we look at what, what are the other additional things that can happen. It's one of the largest undiagnosed, so to speak, genetic disorders. Yeah, genetic testing, yeah, really cheap in this day and age, whereas it used to be really expensive. Yeah, newborn diagnosis and screening, you know. You know, the reality is that's not happening everywhere. You find a newborn, an X-linked sort of disease, you know, there are likely to be other patient members, etc. So we see that market continuing to grow pretty much to the end of the decade in high single digits, low double digits. I think it's the, yeah, the small molecule and the only one in that space that helps us too. What are your expectations for sales this year, and what needs to fall into place? So we've clearly said 11%-16% growth, which puts the midpoint at about $440 million. I can say that I think, you know, the trajectory is going, continues to go extremely well. And I think the building blocks are some of those things I was sort of talking about, making sure we're focused on getting to those amenable patients within that sort of diagnosed but untreated group, and then through additional screenings, etc. And maybe you can talk a little bit about where AI plays into this too. Yeah, no, thanks. I think, you know, as, as Simon was talking about, there are Fabry is probably one of the largest genetic diseases where there's still such a lack of diagnostics, which is crazy, given it's been, there's been an approved product for almost two decades. But there, when you look at newborn screening, at-risk screening, there are more people living with Fabry, far more than, that are not diagnosed, than are diagnosed. So lots of things are helping add to that. You know, the newborn screening going on in five or six states, the at-risk screening, the family screening, the low-cost genetic testing. One of the things Amicus is very excited about helping to contribute is using AI and electronic medical records and actually trying to help networks say, "Hey, here are some patients that very likely have Fabry. You know, would you like to have them get tested?" You know, if you could do something like that in, you know, four, five, six different networks, you could find many of the patients and family members that live around the country. So, you know, it's a way that we might be able to add significantly to that already kind of underlying growth in diagnostics. So we're in the middle of piloting our sort of AI electronic medical record approach at a large healthcare system in the East Coast of the U.S., and if that's successful, we look to pilot that other networks. Interesting. It's shocking that only 5 or 6 states, I think I heard you say, do newborn screening? For Fabry, yes. For Fabry? Yeah. It's amazing, but you might be able to find folks on the back end. Yeah, no, you know, what's amazing in the U.S. is what we're seeing is those five or six states. You find a newborn that lives in Missouri. There's a family that lives all around the country. So, you know, you're finding people all around the country, even with newborn screening in a few states or with network, you know, screening of a health system, just a few different networks, you can find everybody or all the families at some point. Interesting. 'Cause it's Fabry is an X-linked dominant disease, so you can just screen families. Okay, great. And I know you, you issued revenue guidance of at least $500 million for 2024, which suggests Pombiliti and Opfolda sales should be... at least $60 million since, I'm gonna- Galafold is, you know, is expected to be- I'm gonna correct. I'm gonna correct. I'm gonna correct. Gonna correct the record. We never issued revenue guidance of $500 million. The intent was to say we have two really important milestones coming up in 2024. First one is we pass the $500 million mark from a revenue perspective as a milestone, which I think is an important milestone for our evolution as a company. Secondly, yeah, the other important milestone is full-year 2024 non-GAAP profitability. And I think you can see that once you get over a certain threshold with Galafold, and you continue to build the sales, you start to see that fall to the bottom line. That was really the intent, not some sort of backhanded way to- I appreciate the clarification. It makes perfect sense. Okay, great. So let's see. Simon, can you remind us of the recent financing deal that you conducted with Blackstone, and how does this change the cost of capital, and what does the cash balance and runway look like now? So the deal we did with Blackstone was back at the beginning of October for $400 million. We had $400 million worth of senior secured debt before that. We essentially refinanced with Blackstone with two objectives. One was to make it slightly cheaper than the previous financing, but I think the more important one was really to match our principal repayments with our cash flows better. So for the first three years or so, we have interest-only payments. We start paying principal back essentially at the very end of 2026, very beginning of 2027, where we anticipate having obviously a lot more profitability and cash flow than we have today. So that was the intent. In terms of sort of how we think about cash, what I would say to you at this stage is we ended last year $286 million worth of cash. Because we are now moving towards full-year non-GAAP profitability, which is a sort of proxy for cash spend within the P&L, there is another important piece, which is the cash we use primarily for inventory purchases for Pombiliti Opfolda that's flowing through the balance sheet. But all of this is building towards a trend to be cash flow sort of positive and sustainable for the future. And so we really use that financing to help match up those timelines better, which I think is... and we have a sort of commitment with the current structure of the business as it is today. Yeah, assuming, obviously, everything goes according to plan, we don't want to have to issue additional equity at this stage in the life cycle. Great. Okay. I guess if we can move back to Pombiliti and Opfolda, I'm thinking of a question that we get from a lot of investors, who wonder whether you might exhaust a bolus of patients who are naturally predisposed to adopt a new ERT, and then you might then move into a steady state of patient switching, which might be, you know, less robust. How do you guys think about... When you look at the market, you probably have a much clearer view of than anyone when you look at this marketplace. So, Yeah, it's a good question. Are there segments of patients that make sense to think about, that you know may have different propensities to adopt a new product? I think for sure there are, you know, some different segments that you can think through ways that they might be more or less to adopt. Clearly, there's the trial access patient, right? That is, represents sort of a starting bolus for us. You know, there could be the people that have been on treatment longer. Clearly, patients that are worsening are high candidates to go onto Pombiliti. Those could be people that had switched to Nexviazyme, that are now worsening as they've been on long enough for physicians to assess, or they could be people that were still on Lumizyme, hadn't switched yet and are worsening. So we view it much more as sort of those patients, regardless of what treatment they were on, you know, that they could be sort of the initial focus of physicians. Then there's the middle group that's stable, and I think there it's kind of defining, are those patients actually stable? When the deeper conversation happens, we think we're starting to hear significant percentage of them are worsening in some aspect of their lives. Yeah, isn't everyone worsening? Is anyone stable? Good, good question. And then even for those that truly are stable and impaired, and remember, these are not normal patients. These are people that are, have significant loss of muscle strength but are generally stable. The data we have from PROPEL shows that those patients could potentially gain back some of that kind of function on different parameters and set a new baseline, have new things they could do in their lives. So we, we think there's a good value proposition across the board, you know, different dynamics here or there, but ultimately, we see this as like a strong, progressive launch. You know, the lumpiness could be there about different geographies coming on board. But really, we sort of see it as we, you know, strong and steady. Maybe, you know, we'll know more as we get farther in the launch, but. Makes sense. So, in the U.S., is there a potential to eventually expand the indication into naïve patients? There is potentially down the line, if you think about the opportunity there, you know, it's in a given year, less than 10% of the patients might be naïve to treatment in a given year. Ultimately, those patients will have been on an ERT for some period of time and might not be improving, and they could ultimately become eligible. So when you look at sort of the number of patients that it could represent, doing a large phase III, phase IV comparative study doesn't necessarily make sense, or we could end up continuing to get data in registries outside of the U.S. As I mentioned, we're seeing naïve patients go into treatment. We'll collect them in our registry. So there could be that real-world evidence that we compile, and ultimately, down the line, could try to get expanded labeling. But from a commercial opportunity, from sort of an unmet need, it, it's not, you know, a huge must-have. And that's only in the U.S., and we have naïves outside of the U.S. Anything to add? I don't have anything to add. I think, yeah, you know, I think from a CFO's perspective, obviously, you would like to see some return if you're gonna do that type of trial, and realistically, it probably doesn't make sense. Right. Okay. And then, back on the switching dynamics, why do you think more patients are switching from Nexviazyme in the U.S. than Lumizyme? I mean, I just think there's more of them. So we know, you know, Nexviazyme launched about 2 years ahead of Pombiliti Opfolda. By the time we launched, they'd gotten to about 60% of the patients, so there's just more of them that are on Nexviazyme in the U.S. As I mentioned, we're seeing kind of both patient groups switch over. You know, we've talked about this a little bit. There could have been that, you know, that Nexviazyme switching group might have been sort of enriched for people that weren't doing well already on Lumizyme, and maybe that group tends to decline more and more likely to switch. I think we'll learn more about that particular dynamic, but really, it just seems to represent that that's the available population in the U.S. As I mentioned, outside of the U.S., where the population has kind of switched, we're actually seeing more Lumizyme patients than Nexviazyme. Is that just because of- We think it's the same, just more of those patients, you know... So it seems like we're drawing somewhat at this point in the launch equally from the existing population geography. Okay. And, I think in the U.S., you previously reported patient referral forms metrics. Can you give us an update on where that number stands now? Well, as we said on our earnings call, you know, we're still averaging around about 90 days from prescription to first infusion. I think where the data is maybe giving us a little bit more information at this point in time is that now we're getting more new patients. Those newer patients are passing through the system faster than actually the clinical trial patients were. And I think part of that is the sort of, if someone has been switched, sense of urgency to get them on drug. Whereas if you're coming off a clinical trial where you're being funded on the drug, you've got to go through things like end of period study, those type of things, that maybe slows it down slightly. But given those newer patients are coming on board, you would expect the number to drop over time. When we launched Galafold, it was about 90 days. Today, it's about 30 days, so we anticipate seeing it sort of trend downwards. I think the other important piece is on, from a formulary point of view, all the major sort of payers now, the UnitedHealthcares, the Aetnas, the Cignas, et cetera, all have us on formulary, so I think that will also help going forward. And Joe, I would say, you know, we expect to update sort of quarterly on sort of patients on drug or, you know, or with a scheduled infusion, aka a PRF in place. So, you know, we're trying to be very disciplined on that and do it sort of quarterly and not interim updates so- Understood. Won't have an update for you today, but other than the fact that we've said since last year, as we've looked, kind of our monthly rate of new patient adds is growing, our prescriber base is expanding, so, and look for kind of updates quarterly. Okay. Understood. Great. Well, I think we're just about out of time, so thank you so much for the update, and keep up with the good work. Thank you. Thank you. Thank you, Joe.