Amicus Therapeutics, Inc.

Good morning, ladies and gentlemen, and welcome to the Amicus Therapeutics Third Quarter 2023 Financial Results Conference Call and Webcast. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session, and instructions will follow at that time. As a reminder, this conference call is being recorded. I would now like to turn the conference over to your host, Mr. Andrew Fonin, Vice President of Investor Relations. You may begin. Good morning.

Thank you for joining our conference call to discuss Amicus Therapeutics' third quarter 2023 financial results and corporate highlights. Leading today's call, we have Bradley Campbell, President and Chief Executive Officer, Sebastian Martel, Chief Business Officer, Simon Harford, Chief Financial Officer, and Dr. Jeff Costelli, Chief Development Officer. Joining for Q&A is Dr. Mitchell Goleman, Chief Medical Officer, Ellen Rosenberg, Chief Legal Officer, and Mike Cavaney, President of U.S. Commercial Business and Head of Global Marketing, As referenced on slide two, we may make forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 relating to our business as well as our plans and prospects. Our forward-looking statements should not be regarded as representation by us that any of our plans will be achieved. Any or all of our forward-looking statements made on this call may turn out to be wrong and can be affected by inaccurate assumptions we might make or by known or unknown risks and uncertainties. We would caution not to place undue reliance on any forward-looking statements which speak only to the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, and we undertake no obligation to revise or update this presentation and conference call to reflect events or circumstances after the date hereof. For a full discussion of such forward-looking statements and the risks and uncertainties that may impact them, we refer you to the forward-looking statements and risk factors section of our annual report on Form 10-K for the year ended December 31st, 2022, and the quarterly report on Form 10-Q for the quarter ended September 30th, 2023 to be filed later today with the Securities and Exchange Commission. At this time, it's my pleasure to turn the call over to Bradley Campbell, President and Chief Executive Officer. Bradley.

Great. Thank you, Andrew, and welcome everyone to our third quarter 2023 conference call. I'm very pleased to highlight the continued progress across our global business through what has been a tremendous third quarter for Amicus. As we did in this morning's press release, let me highlight several key points before I turn it over to the team to give more detail. First, Gallifold continues its strong performance and remains the cornerstone of our success. We are very pleased with the commercial uptake of Gallifold globally, which for the first time has achieved over $100 million in quarterly revenue. Gallifold's performance represents 19% growth from the third quarter last year on a constant currency basis, And on a year-to-date basis, Gallifold revenue growth was 17%, both at constant exchange rates as well as in reported numbers. We continue to observe strong trends across our key performance indicators in all key geographies in the third quarter. This includes continued demand through new patient starts from both the switch and naive populations in all of our leading markets, a steady growth of in-person visits between our field team and Fabry treaters over the same period last year, and sustained patient compliance and adherence rates of over 90%. Growth in the third quarter was driven primarily by patient demand from net new patient starts. Based on Gallifold's strong performance throughout the first nine months, we are increasing again our full year 2023 revenue growth guidance to 16% to 18% at constant exchange rates. Second, Pompility and Opfolda, our novel therapy for late-onset Pompe disease, is now approved and launched in the three largest Pompe markets. Following the recent US FDA approval of Pompility and Opfolda in September, the commercial launch is now well underway in Germany, the UK, and the US, which again are the three largest Pompe markets globally. As Sebastian will cover in more detail in a moment, our team is making tremendous progress in converting individuals from clinical studies and expanded access programs to commercial supply in our reimbursed geographies. We're also already seeing new commercial patients who are switching from both of the available ERTs, and additionally in Europe, patients naive to treatment coming on to commercial drug as well. We're pleased to share that as of early November, more than 60 patients are being treated with commercial product, and multiple additional patients have been scheduled to start their treatments. We're very pleased to see the early days of the launch track ahead of our expectations, And importantly, we're well on track towards our goal of transitioning all clinical trial patients to commercial supply in these three major markets by year end. Beyond that, we'll continue to focus on the broader patient access by expanding into the major European markets as we navigate the country-by-country reimbursement process and focus on additional regulatory submissions outside of Europe as well. By the end of this year, we will have submitted reimbursement dossiers in over a dozen countries With the global launch of Pompility and Upholda, we look forward to providing a real choice to challenging therapeutic expectations for both physicians and those living with Pompe disease. Finally, we've continued to maintain a strong financial position as we execute on the expansion of Gallifold and advance the global launch of Pompility and Upholda. With the launch now well underway, the recent refinancing of our debt under more favorable terms and continued strong growth from Gallifold, we are well on track to achieve non-GAAP profitability in the fourth quarter this year. Ahead on slide four, we're also making great progress towards achieving our key strategic priorities for 2023. First and foremost, continuing to sustain double-digit growth for Gallifold around the world. On the back of our strong performance year to date, we have now raised the expected annual growth rate of Gallifold to 16 to 18% at constant exchange rates, We've now secured regulatory approvals for Pompility.FoldUp by the FDA, EMA, and NHRA, and now are executing successful launches in those key markets. We've continued to judiciously invest in the advancement of our best-in-class next-generation Fabry and Ponte genetic medicines and capabilities, as well as our next-generation chaperone for Fabry disease. And as always, we are maintaining a strong financial position as we carefully manage our expenses. and investments and continue to grow the top line on our path to non-GAAP profitability. With that, let me now hand the call over to Sebastian Martel, our Chief Business Officer, to further highlight our commercial performance. Sebastian?

Thank you, Bradley, and good morning to everyone on the call. I'll start by providing you with more detail on our GalaFold performance for the quarter. As you can see on slide six, for the third quarter 2023, GalaFold reported revenue reached $100.7 million. in revenue. GalaFold growth continues to be driven by strong patient demand, particularly from our leading markets. Turning to slide seven, our results here to date highlight the strengths of our global commercial efforts. The demand for GalaFold globally continues to be strong with patients added in all major markets, delivering operational growth of 17% over the same nine-month period in 2022 at constant exchange rate. From a year-over-year perspective, there's a negligible impact from foreign currencies. As a result, GalaFold reported revenue growth versus the same period last year was also 17%. GalaFold continues to be the fastest growing treatment for Fabry disease globally, with 19% growth this quarter at constant exchange rate. In fact, both growth and net new patient staff have been higher this year than the previous three years. Our leading markets, such as the US, the UK, EU5 countries, and Japan, remain the biggest drivers of patient demand. Throughout the first nine months of 2023, the number of patients coming onto GalaFold has continued to exceed internal expectations, which indicates continued growing demand for GalaFold globally and a healthy return to a more normal post-COVID environment. We ended the third quarter with about 60% of the global market share of treated amenable patients. And within the global mix, we're seeing stronger uptake in naive populations. So we continue to achieve high market shares in country where we've been approved the longest. And there's still plenty of opportunity for patients to continue to switch and to continue to grow the market as we penetrate into the diagnosed and treated and among people naive to treatment. All of that is underpinned by impressive compliance and adherence rates that continue to exceed 90%, reiterating our belief that those patients who go on Galafold predominantly stay on Galafold. As mentioned on past calls, due to a variety of factors, including uneven ordering patterns and FX fluctuations, the rate of growth within the year is typically non-near, and we expect that to continue into 2024. On slide eight, We know there's a significant demand for GalaFold and that the segment of the global fabric market made of patients with the medical mutations has the potential to reach $1 billion in annual revenue in around five years. We anticipate sustained growth throughout the end of 2023 and into 2024 to be driven by several key growth drivers. First, continuing to penetrate existing markets, further uptake into the naive populations and the diagnosed untreated population, expanding into new geographies and label extensions. As we just mentioned, all of these efforts are supported by solid compliance and adherence rates, positive reimbursement and access mechanisms around the world, and increasing diagnosis globally. I'm pleased to share that we continue to make progress on expanding GalaFold into new markets and extending the labels. Just to name a few examples, we've recently received positive reimbursement for GalaFold in Taiwan, as first-line treatments for naive and eligible amenable patients. We've also received reimbursement in Lithuania on a named patient basis. Additionally, we've received approval in New Zealand and are engaged as we speak in pricing and reimbursement negotiations for GalaFold in Hong Kong, Turkey, and Singapore. In the longer term, we continue to see significant growth in the Fabry market globally, driven by diagnosing new patients through a variety of measures, including high-risk screening, newborn screening, and other diagnostic initiatives, which we continue to support. Also important to note here, we have often exclusivity in the U.S. and in Europe, and in addition to our now 54 orange book-listed patents, including 10 composition of matter patents, that gives us IP coverage into the late 2030s. This provides us with the opportunity to provide access to GalaFold globally for a long time to come. We intend to continue to protect and enforce our broad intellectual property rights. And looking ahead, we expect steady double-digit growth for GalaFold through the end of this year and into 2024. And we remain confident that without strong IP protection, GalaFold has a long runway well into the next decade. Let's turn now to Pompility and Upholder on slide 10. we're incredibly excited to have Pompiditi and Opolda approved and launching in the EU, the UK, and the US. Those three regulatory approvals are really a turning point for Amicus, placing us in the rare territory of biotech companies with multiple products in the market and on the verge of achieving non-GAAP profitability. On slide seven, we outline our global launch progress with Pompiditi and Opolda, which is being led by a world-class commercial and medical organization, This launch leverages our highly experienced cross-functional teams to quickly transition all clinical trial and expanded access program patients to commercial supply, and in parallel, ensure that treating physicians have the information they need to identify those patients who would benefit from starting on or switching to POMBILITY and or Folder in each respective launch country. The process of switching clinical trial and expanded access patients in these first three geographies started right after approval and will be complete by year end. The significant overlap of treatment centers, hospitals, physicians between Fabry and Pompe disease has allowed us to optimize our business infrastructure to support a seamless transition for patients. Within the first 30 days of approval, all core treating centers have been engaged with and we've had very positive feedback from HCPs and other stakeholders as to our business approach, our support, and our patient focus. As of early November, as Bradley said, more than 60 patients are being treated with commercial products, and multiple additional patients are scheduled to start their treatment. Additionally, we've also started to see patients from both of the other approved therapies switch over to POMBILITY and OPFOLDA. We expect POMBILITY and OPFOLDA revenue to come in around $10 million for the full year 2023, which is right in line with consensus expeditions. We're working in partnership with physicians to ensure that they have all the information they need on Pompility and Opfolda for their patients, and we believe our two-component therapy is poised to have a significant commercial opportunity. Based on early interactions with Pompe experts, we're pleased with the positive feedback from physicians regarding patient experience and their engagement with the amicus field team. Finally, within these early days, we find an important metric to track is our progress within access and reimbursement. We have a highly experienced team who are engaging in positive conversations with payers to demonstrate the value of mobility in our product. Today, as you know, we're launched in Germany, in the UK, in the US, and Austria. We're also active in pricing and reimbursement discussions with additional major European markets as we focus on securing broad patient access throughout the EU. By the end of this year, we'll have submitted reimbursement dossier in over a dozen countries. On slide 12, I'm pleased to provide additional color on the even launch progress of POMBILITY and OPFOLDA by country. Maybe first with Germany, I'm pleased to report that all expanded access in clinical trial patients have now been transitioned to commercial product. Additionally, individuals are now starting to switch from other therapies to POMBILITY and OPFOLDA in addition to the sorry, to those naive to treatment. We've also received very positive feedback from HCPs and pharmacists on their engagement with the Amicus team, whose attentiveness has been critical in ensuring a straightforward transition process. In the UK, we're seeing a very quick conversion of IMS patients to commercial supply, as well as switches from other therapies. As a matter of fact, these conversions are occurring ahead of schedule, with now 100% of IMSS patients converted as of yesterday. In addition, our field team has been quick to engage with all treating centers and HTPs in the UK to help facilitate a prompt conversion process. And in the US, all launch activities are underway with first conversions progressing as planned. In fact, 66% of patients in clinical trials have already PRF submitted with their physicians and they're on track and we're on track to transition all clinical trial patients by year-end. Importantly, thanks to the launch readiness of our team, our multi-channel programs launched within the first few days of approval, and the field team has made positive headway with both prescribers and payers. So in summary, we're very pleased with the launches of POMBILITY and APOLDA across all the first wave of countries. The strength of our clinical data, the in-depth experience of therapy effectiveness through EAP programs, and the depth of talent we have at Amicus gives us great confidence in our ability to make a real difference to people living with Pompe disease. We believe Amicus is in a great position for a second successful launch, and with that, I will hand the call over to Jeff Catteli, our Chief Development Officer, to discuss the ongoing clinical studies and regulatory timelines. Jeff?

Thank you, Sebastian, and good morning, everyone. On slide 13, we remind folks that we continue to build the body of clinical evidence for palmbility and alfolda through our ongoing clinical studies as we execute on expanding commercial access through regulatory submissions. As we enter the second phase of launch, in addition to the various reimbursement dossiers that Sebastian just noted, we are in the process of submitting, we also have multiple ongoing or planned regulatory submissions for marking approval in new geographies throughout 2024. Importantly, for the younger Pompe community, we continue to enroll the ongoing open-label ZIP study for children living with late-onset Pompe disease and the ongoing open-label Rosella study for children living with infantile-onset Pompe disease. And through ongoing clinical studies and the anarchist Pompe registry, we expect to continue generating evidence on the differentiated mechanism of action and the long-term impact of Pumbility and Uphold across endpoints and patient populations. Importantly, experience with Pompility and Opthalda is quite broad with approximately 75 centers having participated in clinical trials in various access programs globally. Finally, as highlighted in the pipeline slide in the appendix, for our earlier stage pipeline, we continue to focus on novel approaches for Fabry and Pompe, including gene therapy to deliver our engineered GLA and GAA transgenes, and a next-generation Fabry chaperone. With that, I would like to now turn the call over to Simon Harford, our Chief Financial Officer, to review our financial results, guidance, and outlook. Simon?

Simon Harford Thank you, Jeff. Our financial overview begins on slide 15 with our income statement for the third quarter ending September 30, 2023. For the third quarter, we achieved total revenue of $103.5 million, which is a 27% increase over the same period in 2022. At constant exchange rates, revenue grew 22%. The global geographic breakdown of total revenue during the quarter consisted of 66 million, or 63% of revenue generated outside of the United States and the remaining 38 million or 37% coming from within the US. Cost of goods sold as a percentage of net sales was 9.6% in the third quarter 2023 as compared to 16.4% for the prior year period. Total gap operating expenses increased to 111 million for the third quarter of this year as compared to $102 million in the third quarter of last year, an increase of 8%. On a non-GAAP basis, total operating expenses increased to $19 million for the third quarter of 2023, as compared to $85 million in the third quarter of 2022, an increase of 5%. We define non-GAAP operating expense as research and development and SG&A expenses excluding stock-based compensation expense, loss on impairments of assets, changes in fair value of contingent consideration, and depreciation and amortization. Net loss for the third quarter 2023 reduced to $22 million, or 7 cents per share, as compared to a net loss of $33 million, or 12 cents per share, for the prior year period. Driven by the revenue growth of Garlefold and careful expense management, we continue to make progress towards our path to non-GAAP profitability in the fourth quarter of this year. Cash, cash equivalents, and marketable securities were 280 million at September the 30th, 2023, compared to 294 million at December 31, 2022. Turning now to slide 16, I am pleased to share we have revised our revenue guidance for the year. We are increasing our full-year GalaFold revenue growth guidance to 16 to 18% at constant exchange rates driven by strong patient demand. Our full-year 2023 non-GAAP operating expense guidance remains at $330 to $350 million. In October, we were pleased to announce the $430 million refinancing collaboration with Blackstone. Under the terms of the agreement, Blackstone will provide amicus with $400 million in senior secured term loan to facilitate a refinancing that we have just done of our existing debt under more favorable terms, plus a $30 million investment in amicus common stock. This strategic agreement allows us to better align our borrowing and anticipated cash flows as we continue to grow revenue for the long term. And with that, let me turn the call back over to Bradley for our closing comments.

Great. Thank you, Simon, Jeff, Sebastian, as well as a big thanks to all of our employees around the world who work tirelessly for people living with rare diseases. Entering this next phase of the company, I am confident Amicus can continue to drive sustainable long-term value and deliver life-changing therapies to more people in need. And with that, operator, we can now open the call to questions.

Thank you. Ladies and gentlemen, if you have a question, please press star 1 1 on your touchtone telephone. Again, that's star 1 1 on your touchtone telephone to ask a question. At this time, we request that you ask only one question. If you have any additional questions, please enter back into the queue. Thank you. Please stand by while we compile our Q&A roster.

Thank you for standing by.

Our first question comes from the line of Tazeen Ahmad of Bank of America Securities.

Hi, guys. Good morning. Thank you so much for taking my question. Maybe, Brad, can you give us just a little bit more color on how you're thinking about the cadence of this launch? So, you know, you got approved at the tail end of the quarter. Should we expect any sort of seasonality as we continue to build out your relationships with the appropriate physicians And at least near term, how should we think about the proportion of new patients that are going to be added versus those that you continue to convert from EAP? Thank you.

Great. Thanks, Suzanne, for the call. Very much appreciate it. And as we said, I think overall we're super pleased with where we are right now with the launch. I think you asked a few questions there, kind of cadence of new patients, distribution of conversion versus new patient starts, and then is there any kind of seasonality changes So I'll take the first one first. So Cadence, what we've said is our goal this year is really to first and foremost convert the existing patients, both compassionate use or expanded access, excuse me, and then also clinical trial patients. But as I think Sebastian highlighted in the call, we're making great progress there with significant, you know, all the patients converted in Germany, the majority of patients converted in the U.K., and two-thirds of the patients having prescriptions and now working through that process in the United States. So I would say the majority of new patients this year will come from those conversions. But what we're really pleased with as well, and I think we talked about this, is we're already seeing patients switching from both existing ERTs in each of the markets. And in Europe, we're seeing new patients starts as well. So I think if you look at all those KPIs, we're really pleased with how that's going. Once we get through that conversion process, which we're on track to do this year, then next year, obviously, the majority of patients are going to come from switching from existing therapies and then starting new patients as well in Europe and other markets. So really pleased with the progress so far. In terms of seasonality, You know, I think just based on kind of the flow we've seen with Gallifold, I wouldn't be surprised if we see a similar nonlinear kind of pattern as we go through the year. But we'll know a lot more as we progress through next year. And we can provide that color as we observe it so that you guys can, I think, model out the progression. I think clearly next year will be a significant contribution of revenue from Pompability on Folda in particular as we maximize the run rate going into the next year.

Okay. Thanks, Brett.

Thanks, Suzanne.

Thank you. Our next question comes from the line of Anupam Rama of JP Morgan.

Hey, guys. Thanks so much for taking the question, and congrats on the quarter. In the slides you noted related to plumbability and up-folder that you're expecting to have multiple regulatory submissions in 2024 for the product, So what are the key regions that we should be thinking about here, and when could they be contributing to the top line? Thanks so much.

Yeah, thanks, Anupam. Good question. I think there's two things that are going on here. First is regulatory submissions, and then the other, of course, is the reimbursement process that's playing out in the rest of the major geographies in Europe. As I alluded to on the call, we'll have more than a dozen reimbursement dossier submitted by the end of the year. So I think you could start to see revenue from the European markets play out, you know, probably towards the back half of the year. We were really faster than average getting through the reimbursement process with Gallifold. And I think you'll see, you know, based on the value proposition and our pricing philosophy, I think you'll see similar fast-paced, and I think as we go into next year, we can give a little bit more tight direction in terms of when we might see that additional revenue come on. Jeff, do you want to talk a little bit about the key regulatory submissions for next year and kind of how that should play out?

Yeah, thanks, Brad, and thanks for the question, Anupam. So, you know, we have ongoing submissions we're working on, others that we have planned, you know, in the other sort of major markets outside of U.S., U.K., Europe. for next year. I don't think we're going to list specifically which countries, what dates yet at this point, but you can expect, you know, after those submissions next year in this kind of Tier 2 markets that, similarly to the other Tier 1 markets, we'll have reimbursement negotiations. So, unlikely that those new submissions next year, you know, significantly contribute to revenue next year. It would more be a 2025 revenue boost from the second wave of submissions. Thanks so much for taking our questions.

Thank you. Our next question comes from the line of Ritu Baral of TD Cohen.

Hi, guys. Thanks for taking the question, and good morning. Brad, I wanted to ask about slide 12 and the 66% patients received PRFs. Can you clarify what the PRFs are? Are those start forms? Are they filled out start forms? I just haven't encountered that term before. And as you look at the profile of the maybe, you know, handful of commercial patients that you have that aren't transferred and the start forms that you may be getting, how are you thinking of that split between a myosin converter, the myosin converters versus the next viazine converters? And I think we're all really curious about what those next viazine converters look like, like how long do doctors give before they're like, nope, this doesn't work. Let's try something else.

Thanks. Sure. Thanks, Ritu. Great questions. Maybe, Mike, you can just talk a little bit about the progress we're making and remind Ritu about the PRF prescription or patient referral form, excuse me, and also kind of the reimbursement progress we're making, and then I'll take the call or, sorry, the question around kind of the mix of patients from the different therapies.

Sure. Thanks, Brad. Excuse me. The PRF is a patient referral form. It's essentially our prescription. And the 66% is the percentage of those that have been sent into our hub from our clinical trial physicians. So we have approximately 40 clinical trial patients, and about 66% of those have already come in. So we're working on a reimbursement for those. We're doing all the benefits investigations, figuring out what each payer's prior authorization form looks like and moving that with the physician to have the physician fill that out to move forward to commercial product. And reimbursement so far is going well. We have more than a handful of patients who have received full approval to begin therapy. We're in the process of setting up that therapy now. As you know, different from Gallifold, which was an oral, this has to be set up every two weeks. So we have to plan out with the with the patient and with the provider when their last dose of the clinical trial product will be and when their first dose of commercial product will be. So that's going extremely well. We haven't really had any issues thus far with payers in terms of moving forward with our clinical trial patients. And Brad, about half of our non-clinical trial patients have been Lumazine, half have been Nexviazine. But Brad, if you want to move forward on that.

Yeah. Yeah. So great, as Mike said, great distribution. And I think, you know, from a targeting perspective, based on the label, any patient is an eligible switch patient. So we don't really differentiate between, you know, what we're, what we're talking to with, with physicians and patients around Pompility and Uphold, regardless of which therapy they're on in the United States. And so far, as Mike said, it's about half and half. And the kinds of things that we've, talked about before, Ritu, is really focusing on that improvement language. So that just gives us such an important differentiating aspect to say, look, if your patient is not improving on their existing therapy, they should consider switching to pumpability on Fulda. And we're already seeing great, great traction there. What we estimate, we have kind of two data sources in terms of how long we think a patient might need to be on Nexvizime initially before they consider a switch. From patients, they say they'd be interested in considering that as early as six months. From physicians, they say they'd consider six to 12 months roughly in that time period. And if you think about the approval timelines, a significant number of patients who had switched from myosin are already in that kind of six to 12 month window and you're seeing that play out. So all the metrics we're tracking look great so far and we're really eager now to begin the commercial switch process as well.

Awesome. Brad and Mike, are PRFs, the number of PRFs, something that you would consider reporting going forward?

Yeah, that's something we did with Gallifold, Ritu, you might remember. And so I think that it's a key leading metric in the U.S. where you go through that PRF process. So I do think we'll likely provide color on that in arrears, so looking backwards. We did it for an initial period, and then we focused more on patients. Once you get into kind of the rhythm, it's really patients on drugs. That's more important. So stay tuned for that.

Awesome. Thank you. That will be very helpful.

Thank you.

Please stand by for our next question. Our next question comes from the line of Joseph Schwartz of LeeRank Partners.

Thanks very much, and congrats on all the progress. Based on the figures you provided, it looks like you've already seen around 33 PRFs since launch in the United States. I was wondering if you could give us any insight into How many of those are de novo versus expanded access patients? And are you still anticipating being able to convert all expanded access patients to commercial therapy by the end of the year? I think there were around 50 total. And how long do you think it might take to move patients from a PRF to commercial therapy? And then in the US, are you seeing any demand outside of the EAP that you can quantify for us, and how much lumpiness do you think there might be once you work through the initial EAP bolus, if you will?

Thank you. Yeah. Thanks, Joel. Good question. So, Mike, maybe talk a little bit about the sort of initial time from PRF to infusion, and then kind of what we see it from a Gallifold perspective, kind of more the steady-state process. And then talk a little bit about, provide a little bit more color on the distribution of clinical trial conversions versus new patients, new switch patients. I think that covers most of what you asked, Joe.

Sure. When we look back on Gallifold PRF to shipment times at launch, it was about 60 to 90 days because it's a new product. Payers need to sort of go through their process, get it on formulary. So in general, it's about 60 to 90 days. Uh, we do, we do as we, and we have here, we do get authorization sometimes more quickly than that, but we put in on average, we're looking at the 60 to 90 day window for any really new rare disease product, um, to get through the payer system. Over time with Gallifold, we're a little over five years out now with Gallifold. it's down below 30 days and we would expect that trend to continue with pumpability not full to overtime. And so we don't really have a specific number yet on PRF to shipment time because we're just starting out, but we're anticipating the 60 to 90 day window with some coming before. We already have more than a handful of approvals from payers. And we just got some of those PRFs in the mid October timeframe. So we've already seen that, um, go well in a couple of cases, but again, it, it will take payers a little bit of time to go through the product. Um, the second question was the mix of, of clinical trial conversions and then new patients. Sure. The vast majority right now have been clinical trial. Um, we've got a handful, a little bit more than a handful of patients who weren't in the clinical trial that we received PRS for. And as I said, some of those are switches from Lumazine. Some of those are switches from Nexviazyme.

Yeah, so I think, Joe, as maybe I mentioned in answer to another question, the vast majority of patients this year will be conversion patients in each of the markets. But we're really thrilled that in the UK and in Germany and the US, we've already seen multiple new commercial prescriptions come in who are not conversions. And so I think this year, if you kind of project out to the end of the year, the majority will come from conversions, but our goal is to maximize the number of new commercial starts as well over the course of this year. And then keeping in mind the timeframe that Mike suggested and looking at the stats in the other markets, our goal also is to convert all of the patients this year. And so next year, the vast, vast majority of demand is going to come from new commercial patients. Very helpful, thank you.

Thank you. Our next question comes from the line of Ellie Merle of UBS.

Hi, this is Sarah on for Ellie. Thanks so much for taking our question. A few quick ones from us. I guess, can you give us a sense from speaking with physicians, any feedback that you're hearing either on the number or the percent of their patients that are declining or not improving on standard of care, and also how physicians are deciding between your product and Nexviazyme in terms of switching a patient to a new therapy. And then earlier when you mentioned that 50-50 split between Myozyme and Nexviazyme, is that something that you think continues to play out longer term, or how do you see that looking? Thanks.

So maybe I'll take the second two questions and then Jeff, maybe you can talk to the first one in terms of how physicians are evaluating a patient's response to therapy. So, you know, over time, I think it depends on which market you're talking about, right? So in the United States, it's I think north of 50% of patients now have been reported to have come on to Nexvizime, and so our anticipation is that you'll draw probably relatively equally from both of those segments because they're roughly equally weighted, maybe a handful more Nexvizime patients. In other markets, you have a smaller penetration of Nexvizime, so still the majority of patients are on Meizime, and I think there you'll see kind of relatively equally weighted distribution. And so I think, you know, it'll be kind of a market-by-market conversion rate. The most important thing is that the label, and we talked about this, and this is why it's so important, some of these key elements of label, that it is agnostic to antireplacement therapy. So it doesn't matter whether the patient's on myosin or nexbizine, the physician and the patient are going to focus on the data. And we would remind people that we're the only product that has in a well-controlled study looked at patients switching from an active comparator to our product and we've shown improvement at six minute walk and stability enforced vital capacity so that's really the differentiated data set that we have that we are using to go talk with physicians around options for therapy so Jeff do you want to talk a little bit about kind of um improvement and why that's so important and why it captures such a broad opportunity for us to differentiate?

Sure, Brad, and thanks for the question, Sarah. So, you know, we have done some market research and conversations, you know, with physicians and based on what they're telling us, it's 75% approximately of their patients are not improving and that means they're either worsening or, you know, stable. And based on the data we have and, you know, the data that suggests there is a possibility for actually improvement in both naive and switch patients, that really seems to be the main driver of a decision. You know, a big one we've also seen, and remember this is early days, majority of the current commercial switches are from our trial access patients, so it's a small end, but, you know, it's really that potential for improvement in sort of the experience that either physicians or patients have had. And, you know, we think that those anecdotal reports of how patients are doing as that spreads throughout both the physician and patient community is going to be a big driver as well. But still early days and we'll continue to listen to hear the specific reasons different patients are deciding to switch or physicians are deciding to have their patients switch. But we think it's going to be driven by efficacy and patient experience.

One place that you might look, Sarah, as we have talked about this before, there was an independent poster that was published at the World Congress that talked about individual, of course, case studies, but it was the center itself reporting on individual patients' response to therapy and how the switch process went. And I'll say that's a piece that is never going to show up in a data. It's not going to be something that a physician kind of promotes on, of course. But we've heard over and over again that the experience team we have, both the sales reps themselves, the MSLs and medical affairs team in the United States, our patient hub, which helps people work through the reimbursement process, I think we've really established ourselves as trusted, incredible partners. And that really makes a difference too, right? I mean, these are life-threatening diseases. These are big decisions for people to make. And I think Amicus has established ourselves as really trusted partners in this field. And I think that goes a long way towards physicians and patients wanting to take a different tack and trying Pompili-Naprola.

Great, thanks. Thank you.

Our next question comes from the line of Kristen Kluska of Kanner Fitzgerald. Please go ahead, Kristen.

Hi, good morning, everybody. You've obviously reported on a number of endpoints, but I'm curious in a real-world setting, what are the biggest drivers and what feedback they're looking to get from patients to determine whether or not their current therapies are suitable for them?

Yeah, it's a great question, Kristen. Thank you. And you're right. So clearly the, you know, the primary registration endpoint was, were six minute walk and force vital capacity. And those are still very important from a physician perspective. But Jeff, maybe talk about the, the importance of those other endpoints and, and how, you know, patients might be feeling when they, when they transition and how important that can be as well.

Yeah, thanks, Kristen, for the question. So, you know, as Brad said, there's a number of different measures that physicians and patients use to sort of assess how they're doing. Some of those do include when they come in every six months, they do get this sort of battery of more standard assessments. Many of those are similar to the trial assessments, like a six-minute walk or an FEC. But it is, you know, there definitely is variability across physicians on sort of what measures they use. A big part of it is also just sort of their questions to the patient about how are you doing in your daily life on doing different tasks, you know, walking upstairs, are you having falls, et cetera. And then also, you know, some of the physicians will look at biomarkers. So it's really that totality of sort of assessments of how patients are doing. You know, there could be opportunities within those six months more rigorous kind of assessments to also have check-ins with their physicians. But it's really sort of that combination of parameters that are looked at. And importantly, as you know, we look at the U.S. and sort of the not improving aspect of the label. That is, you know, not specific to any endpoint or parameter. It's more sort of left to the judgment of the physician, the patient, to sort of holistically assess if that patient is actually not improving or not.

Thank you. Thank you.

Please stand by for our next question. Our next question comes from the line of Dai Ganha of Stifel.

Hey, good morning, guys. Thanks for taking my question. One question on ATGA, Pumbility of Folda. The remark you made about the naive patient experience in Europe, I'm pretty curious, what are you seeing there? What was the sort of cadence of events that led to that naive patient coming on therapy? And obviously, how do you see this kind of panning out going forward? Is this going to be a spread of the word and kind of ballooning from there to go after the naive segment? And then second for Jeff, as you think about the next-gen, obviously the non-GAAP profitability is well intact, but how are you thinking about the next-gen molecules? We've seen some disappointments on the gene therapy front for Fabry and Pompei and obviously next-gen chaperone. Just kind of curious how you're thinking about sort of the patient segment you're going to go after. Thanks so much.

Thanks, Dagon, for the questions. Yeah, so the naive segment in Europe, of course, it's early days, but we are pleased to already be seeing, you know, newly diagnosed patients or diagnosed untreated patients come on to therapy. That's a really important segment. Pompe is not quite as underdiagnosed as Fabry disease, but if you look at all the literature, as we've done newborn screening, as we've done high risk population screening, and as other manufacturers have focused on those segments as well, you're still seeing a healthy diagnosis rate. And so we continue to expect there to be, you know, newly diagnosed patients fueling the market, uh, for, for many years to come. And of course, just as we've done in February, we'll invest in those as well. And I think, look, if you look at the literature, if you look at some of the work that Dr. Kishnani and others are starting to do, it is clear that number one, patients are slipping through the cracks and are being diagnosed later in life, well after they've exhibited symptoms that should warrant a treatment. But we're also looking much more closely at patients who maybe historically would have been seen as quote unquote stable, who are newly diagnosed. And if you look closely, this is a progressive genetic disease. And I think there's a growing body of evidence and support from physicians to treat those patients earlier. So I think that will continue to happen throughout the Pompe community. Jeff, do you want to talk a little bit about kind of how we're thinking about the chaperone? And I think that, you know, the top line that I'll provide is that We'll talk more about our pipeline as we go into next year. As you said, Dagon is a judicious investment at this point. We're focused on profitability and using a little bit of resources to keep those programs going, but the main focus is Gallifold and Pompiliotifolda. But do you want to talk a little bit about how we're thinking about the chaff-grown program, Jeff?

Yeah, thanks, Brad. And I'll start Dagon with the gene therapy programs briefly. You know, there we have seen some challenges in the field, you know, for some other gene therapy programs, you know, continued challenges around durability and some of the safety. And we know that manufacturing is a challenge in terms of costs. And, you know, regulators are wanting to see in some cases that the gene therapies bring some aspect of superiority to sort of justify some of the inherent risks of gene therapy. So I think you're going to see people focusing more on sort of the patient segments that are not doing well in stereotyped care where you might be able to best show some aspects of kind of benefit over approved therapies. You know, given that and our judicious investment in the pipeline, we think our trans genes are best in class, you know, more potent than well-type, but we're really looking at trying to solve some of the challenges around delivery and safety so that, you know, when we are able to, you know, more rapidly bring those forward, what we're bringing forward is something that really could deliver on that benefit over existing treatments. And in terms of the next-gen chaperone, you know, really they're still early days, but we're trying to see if we can expand sort of the number of amenable mutations, as well as potentially improve upon, you know, Gallifold in terms of efficacy. It's at a high bar. So, you know, challenging to kind of improve upon the response of amenable mutations, but we think that would be great down the line, you know, in the future, you know, when potentially Gallifold may go generic to have something that could be, you know, incrementally better. Importantly, to extend amenable mutations, you know, we know it's clear that there's a preference for oral administration of therapies where possible. So if we could expand that list of amenable patients, we think that would be a big impact. Great.

Thanks so much, and congrats on the progress.

Thank you. Our next question comes from the line of Gil Blum of Needham & Company.

Hey, good morning, everyone. Let me add my congrats to the progress. Maybe kind of looking more forward here to 2024, you know, currently the majority of revenues are being recognized outside of the U.S. Do you think this dynamic may change now that you've launched in Pompeii? Thank you.

Yeah, thanks, Gil. In the Fabry markets, just based on the pricing dynamics, you know, you've kind of historically seen a 70 to 30 distribution between ex-U.S. and U.S., As you saw in our reported numbers, that's drifting a little bit more towards 60-40 at this point for us. And I think with Pompeii, you'll probably continue to see that slightly larger ratio of U.S. revenues versus ex-U.S. revenues. I think if you look at the existing Pompeii market, it is more close to that kind of 60-40 split. So, yeah, I think that's a reasonable sort of long-term expectation as the balance of our revenue comes from both Pompeii and February. We'll, of course, continue to report on that distribution of revenue, and if there's changes and trends there, we'll guide people that way. But I think that's kind of a reasonable expectation for the next few years.

Thank you. Our next question comes from the line of Jeff Hung of Morgan Stanley.

Thanks for taking my question. For Pompability and Upholda, can you just talk about the impact you've seen from KOL implementation outreach in Europe, and how does that set your expectations for the pace and the impact of your research outreach efforts in the U.S.? You know, is there anything that you might see that'd be different in the geographies that you could highlight? Thanks.

Probably the biggest difference between Europe and the United States is, you know, outside of the United States, there's no real opportunity to interact directly with patients, whereas in the U.S., you do have some medical education that can go towards the patient community, so there's a little bit more of a direct interaction there. We also have a team of patient education liaisons who are in the field who are helping with the infusion process. You know, many of these patients do home infusions, and so that's a slightly different dynamic as well. But by and large, you have a very active, very aware physician community and likewise, very active, very aware patient community. And so right now, the focus from Jeff and his team and from the commercial organization is on educating physicians, the availability, talking about the data, et cetera, and generating new evidence, which we're, you know, you will continue to generate new publications and presence of medical congresses. But I think also you'll see a growing kind of word of mouth as more and more patients have experience with Pompability Not Folded directly. I think you'll see that start to really play a part as well where, you know, either a family member or somebody through the community talks about their experience and encourages others to think about that experience as well. So I think that dynamic will continue to grow as more and more new patients have access to Pompability Not Folded.

Great.

Thank you. Thank you. Our next question comes from the line of Salveen Richter of Goldman Sachs. Please go ahead, Salveen.

Hi, team. This is Srinath Rao for Salveen. Congratulations on the quarter. A couple of questions from us. Of the 75 treatment centers worldwide that have participated in the clinical trials and expanded access programs, what percentage of the patient population is covered through these 75 treatment centers? And the second question is that you mentioned that patients are already switching from existing ERTs. We understand that the numbers are small, but is there any insight you can provide on how those patients are doing once they've switched over? to vulnerability and upholder.

Sebastian, do you want to talk about the kind of what percentage those top KOLs, what percentage of patients either flow through them or prescriptions flow through them? And then I'll take the second question.

Yeah. So, you know, Pompe disease is you know, treated with a fairly concentrated HCP group on a global basis. You've got, you know, differences on a country by country basis with some markets being very concentrated. The UK, for example, has six main reference centers for those isosomal storage disease. And you've got, you know, Germany at the other end of the spectrum, which is a lot more fragmented. And so, it really varies by country. In some, you essentially deal with a very small number of key accounts in some way, and in others, you have to expand to a larger group. Although, like you would see typically for any rare disease, We're not talking very broad number of physicians in the grand scheme of things. It's still somewhat concentrated.

Yeah, thanks, Sebastian. So I think those 75 KOLs globally, they probably influence in some way the vast majority of treatment decisions, so 75%, 80%. whether in the end they actually end up being the treaters themselves. You've got home infusions. You've got, as Sebastian articulated, both Germany and the United States. You have infusion clinics or more community-based physicians that are doing the infusions. But I think those top KOLs influence the vast majority of treatment thoughts and decision-making, which is important. In terms of the second one, how are patients doing? I think you know, too early to know how the initial switch patient, if it's first handful of weeks, we are getting very positive feedback, again, word of mouth from physicians and patients on the switch process and how they're feeling in the initial days. And so I think early signals are that it's very positive. I would though, you know, say in terms of a date from a data perspective, you're starting to see us present on the long-term outcomes of patients from the, um, from the Propel study and from our other boluses of patients. And I think that's where we see, you know, we're very confident in that long-term data being durable and consistent across patients.

Thank you. That was your last question. This concludes today's conference call. Have a great day.