Amicus Therapeutics, Inc.

Good morning, ladies and gentlemen, and welcome to the Amicus Therapeutics 4-Year 2021 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. If anyone should require assistance during the conference, please press star then 1 on your touch-tone telephone. As a reminder, this conference call is being recorded. I would now like to turn the conference over to your host, Mr. Andrew Farnan, Executive Director of Investor Relations. You may begin.

Thank you. Good morning, everyone. Thank you for joining our conference call to discuss Amicus Therapeutics' full year 2021 financial results and corporate highlights. Speaking on today's call, we have John Crowley, Chairman and Chief Executive Officer, Bradley Campbell, President and Chief Operating Officer, Daphne Creamy, Chief Financial Officer, and Dr. Jeff Costelli, Chief Development Officer. Joining for Q&A will have Dr. Mitchell Goleman, Chief Medical Officer, and Sebastian Martel, Chief Business Officer. 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 the 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. Your 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 full year ended December 31st, 2021, to be filed later today with the Securities and Exchange Commission. At this time, it is my pleasure to turn the call over to John Crowley, Chairman and Chief Executive Officer.

John? Great. Thank you, Andrew, and welcome, everyone, to our full year 2021 results conference call. I am pleased to highlight the progress that we've made at Amicus throughout 2021 and now into the start of 2022. a reflection of the broad execution across our business. As we did in this morning's press release, I'd like to highlight several key points. First, Gallifold continues its strong performance and is the cornerstone of our success. For the full year 2021, Gallifold revenue is $306 million and in line with our full year revenue guidance. We are very pleased with the execution of Gallifold globally which was largely driven by new patient accruals from both the switch and naive populations, as well as sustained patient compliance and adherence rates. We expect significant growth for Gallifold in 2022, and we believe that Gallifold has the potential to be a $1 billion medicine at peak revenue. Second, we continue to make great progress on our global regulatory filings for ATGAA, our novel next-generation therapy for Pompe disease. The U.S. and EU regulatory reviews are progressing very well, and we are extremely pleased with the level of engagement from the regulatory agencies. We recently completed the mid-cycle review with the FDA, and we remain confident in ATGAA's approvability and its potential to become the next standard of care in Pompe disease. As a reminder, the FDA has set a PDUFA action date of May 29, 2022 for the NDA related to the enzyme stabilizer, and July 29, 2022 for the VLA of the biologic. In the EU, the marketing authorization applications for ATGAA were submitted to the European Medicines Agency in the fourth quarter of 2021, and we are actively engaged in the EMA reviews, and we expect the CHMP opinion later this year. Our global launch plans continue to accelerate for APGAA, including targeted investments in additional personnel to support the launch and significant investments in launch inventory preparations. We are now closer to having another potential treatment for people living with Pompe disease, both in the United States and in Europe, with further regulatory applications planned in the months ahead. And third, and importantly, Amicus has maintained our strong financial position and remains committed to achieving profitability in 2023 as we continue to execute on the global expansion of Gallifold and prepare for the global launch of ATGAA. We have no need for any equity or equity-linked financings to achieve profitability. Turning to slide five, as announced today and highlighted on this slide, we have made the strategic decision not to spin off our gene therapy programs and technologies. The decision here results from the current unfavorable market conditions affecting the biotech sector broadly, as well as an increasingly challenging environment for standalone gene therapy companies. Again, Amicus remains strongly committed to achieving profitability in 2023 without the need for any further dilutive equity or equity-related financings. In order to accomplish this, we will concentrate the vast majority of our efforts and investments in our priority growth franchises in Febre disease and Pompe disease. We will do this through, one, the continued global growth and commercialization of Gallifold, two, by advancing the activities to secure global regulatory approvals and commercial launch for ATGAA, and thirdly, by making judicious strategic investments in next-generation therapies in Febre and Pompei, and in core science and platform technologies in the field of genetic medicine. This strategic prioritization of our pipeline, as well as the reorganization of our internal R&D team, is expected to result in approximately $400 million in net cost savings through 2026. This is a similar amount in savings associated with the previously announced spinoff. This decision to streamline and prioritize our gene therapy pipeline portfolio and overall R&D operations is designed to create a more efficient organization that is highly focused on delivering for patients and for shareholders. We are able to achieve this $400 million in cost savings ahead by taking three principal actions with respect to our R&D. First, we are prioritizing our pipeline portfolio including the decision to focus on core platform and enabling technologies. As such, we will not be moving multiple gene therapy programs into the clinic in the years ahead. This prioritization will significantly reduce R&D-associated expenses in clinical operations, manufacturing, and supporting activities. Second, we are maintaining overall amicus employee count flat at about 500 employees for the next several years. To achieve this, we today are reducing our overall workforce by 7%, about 35 individuals, mostly all in our R&D organization. This will allow us to continue to hire key personnel for the global growth of Gallifold and the coming launches of ATGAA, again, while keeping overall headcount at Amicus flat at about 500 employees globally. And third, we will suspend indefinitely our plans to build an internal gene therapy manufacturing organization and facility. These portfolio and organizational changes will strengthen amicus by sharpening our focus, investing appropriately and very judiciously in our pipeline, and ensuring our continued financial strength. We at amicus are rapidly approaching two pivotal inflection points. First, the global launch of a second rare disease medicine in ATGAA. And secondly, profitability. A second product in profitability. These are rare feats that we believe will enable amicus to truly enter the upper echelon of biotechnology. Turning now to slide six, key strategic priorities for 2022. Here, as we laid out last month, we are focusing on achieving our key strategic priorities for this year. These include One, we will continue to drive Gallifold to more people living with febrile disease with amenable variants in existing and in new markets. We look to achieve double-digit global product revenue growth of 15 to 20 percent with revenue of $350 to $365 million for the year. This growth reflects the strong momentum and demand behind this precision medicine globally. Second, we remain steadfast in our commitment to advancing ATGAA regulatory filing and initiating the anticipated launches of ATGAA in the United States. Leveraging our seasoned global commercial team and experience across all areas needed for an effective drug launch, we are fully prepared and anticipate another successful launch with ATGAA. Third, we are strategically advancing our best-in-class next generation genetic medicines and capabilities. Four, again, we will continue to maintain a strong financial position as we carefully manage our expenses and investments, and we remain fully funded through all major milestones. Before I hand the call over, I'd like to provide an update to our previously announced leadership transition. Again, as we previously announced in September 2021, Brad Campbell will be succeeding me as Chief Executive Officer. With that transition now taking place effective August 1, 2022, I will also now become at that time the full-time executive chairman of amicus for a two-year term and expect to continue as the non-executive chairman of the board at amicus thereafter. This transition will enable Bradley and I to continue our tremendous long-term partnership in very clearly defined roles ahead. As I've highlighted on past calls, there is no one more capable to succeed in this role And both Bradley and I remain steadfast in our drive to achieve our strategic goals and priorities laid out here today and our mutual vision for Amicus for years ahead. So with that, Bradley, I'll turn the call over to you.

Great. Thanks, John. And thanks again to you and the board for your confidence in me beginning in August to continue the inspiring work that you've done here at Amicus in building and leading this amazing organization. I really look forward to our ongoing partnership. and to leading amicus in our mission to deliver value for patients and for shareholders. And now, good morning, everyone. As John mentioned, I'll start by walking you through in more detail our Gallifold performance for the year. On slide eight, we give our global snapshot of Gallifold commercial progress. As John mentioned, for the full year 2021, total product revenue was $306 million globally, largely driven by strong new patient accruals and sustained patient compliance and adherence rates. Geographic breakdown of revenue during the full quarter was $210 million, or 69% of revenue generated outside the United States, and the remaining $95 million, or 31%, coming from within the United States. As we've mentioned previously, this is in line with the roughly 70-30 split that we expect as we continue to grow both parts of the business for many years to come. Turning now to slide 9, Q4 and our full-year financial results highlight the strength of our global commercial efforts and executions. The business continues to be incredibly resilient with patients added in all of our major markets and many new markets as well. In fourth quarter, revenue reflected increased patient demand and also benefited from continued foreign exchange headwinds, excuse me, tailwinds benefit. As mentioned on past calls, due to a variety of factors, including timing of orders as well as payer reauthorizations in the United States, the rate of growth within the year is typically nonlinear. Usually, in a given year, we see stronger quarter-to-quarter growth in second quarter and fourth quarter versus first quarter and third quarter, and that pattern has continued. And so we've provided now for the first time in the table on the right-hand side of the slide a three-year historical snapshot of the percent of Gallifold sales that occur each quarter during a given year. We would expect a similar trend to occur this year in 2022. The good news is, even with the COVID dynamics that we discussed earlier this year in JP Morgan and at the end of the year last year, that have continued into the early part of 2022, as we pass the midpoint of the quarter, we're trending on or even slightly ahead of our budget. So we're off to a good start for the year. And again, this is driven by strong global patient demand for Gallifold for many patients at key markets around the world. On slide 10, we've called out several of the drivers and metrics which will lay the foundation for growth this year and beyond. We ended 2021 with more than 1,750 patients on Gallifold globally, which is a little under half of the global market share of treated amenable patients. And while the global mix remains about 55% switch patients and 45% naive patients, in many geographies we're starting to see stronger uptake in naive populations, just as we anticipated. So we're achieving higher market shares in countries where we've been approved the longest, but there's still plenty of opportunity to continue to switch patients over to Gallifold and continue to grow the market as we penetrate into the diagnosed, untreated, and newly diagnosed segments. Within our core business, the EU5, U.S., and Japan, we continue to see strong growth coming out of these markets, and in fact, in Europe, where we've been approved the longest, we're now at about an 80% to 90% market share of switch patients, so the growth is largely driven by bringing on new patients to Gallifold. Whereas in markets like Japan and the United States, we're still at about 50-50 switch in naive in terms of new patient starts from launch. And on the other hand, if you look at the newer markets coming on, such as Latin America countries like Brazil, Chile, Argentina, Colombia, Asia Pacific countries outside of Japan, the Gulf states, as well as countries in the Middle East and North Africa like Turkey, where we're hoping to get approval later this year. We're now seeing greater traction coming into 2022, and we expect that to continue to be a major growth driver throughout the next several years. All of that is underpinned by the impressive compliance and adherence rates that continue to exceed 90%, reiterating our belief that those patients who go on Gallifold generally stay on Gallifold. Importantly, the value of Gallifold also continues to be recognized by payers around the world. with a vast majority of insurance reauthorizations granted in 2022 by U.S. payers and a very strong track record of successfully negotiating and renegotiating reimbursement outside the United States. Our relentless focus remains on ensuring access to Gallifold for anyone who needs it. Moving now to slide 11, with several years of performance and a successful track record, Behind us, we know that Gallifold has the potential to surpass $500 million in annual revenue over the next couple of years through several key growth drivers, continuing to penetrate into existing markets, expansion into new geographies, and broadening the labels. In the longer term, we remain confident in that billion-dollar peak revenue opportunity as we continue to see significant growth in the Fabry market globally, driven by diagnosis from high-risk screening, newborn screening, and other diagnostic initiatives, which we continue to support and invest in as well. Finally, we have orphan exclusivity in the United States and Europe, in addition to our 27 Orange Book-listed patents that give us IP coverage into the late 2030s, 13 of which provide protection through 2038. So plenty of opportunity to provide access to Gallifold globally for many years to come. Finally in slide 12, this just highlights our experienced rare disease commercial medical organization that supports Gallifold across the world. We're present now in 43 countries either directly or through distributors as is outlined on the slide. And really what's critical here is that this is the same team that will launch ATGA globally. There will be very few incremental additions to the team, with less than a dozen new FTEs anticipated globally to support the launch. We have assembled a highly successful, capable group of passionate entrepreneurs who are eager not only to continue to grow Gallifold, but also now with great anticipation of what we plan to be our second approval with ATGA. With that, let me now hand the call over to Dr. Jeff Costelli, our Chief Development Officer, to highlight our ATGA program.

Jeff? Thanks, Bradley, and good morning, everyone. On slide 14, we'll start with ATGA, our novel next-generation therapy for Pompe disease. First, it's important to recognize that Pompe continues to pose a range of health challenges for people affected by the disease, and having therapeutic choices is crucial. Pompe is a severe and fatal neuromuscular disease and one of the most prevalent lysosomal disorders. In addition to the individual human tragedies, we've now seen multiple publications and natural history studies of Pompe patients that highlight the initial benefits of treatment being followed by continued long-term decline on key measures of disease for many individuals. Moving on to slide 15, here we present a summary of the primary, key secondary, and biomarker endpoints from our phase three study As a reminder, PROPEL was a double-blind, randomized study assessing the efficacy and safety of ATGAA in adult treatment naive and ERT-experienced patients against the approved therapy, Alglucosidase-alpha. PROPEL is the only controlled clinical trial to date that included ERT-experienced patients, which represent one of the greatest set of patients with unmet needs. Here on the slide, grouping these endpoints into domains of motor function, muscle strength, pulmonary function, patient-reported outcomes and biomarkers, you can see that the majority of endpoints across all of these key domains favor ATGAA over Alklycosidase-alpha in both the overall and the ERT experience populations. We believe this consistency of effect across the key disease manifestations of Pompe illustrates the potential impact of ATGAA for patients. Moving on to slide 16, we have highlighted key updates on the ATGAA program. First, on the regulatory progress, the U.S. FDA has accepted for review the BLA for cipoglucosidase-alpha and the NDA for miglostat, the two components of ATGA. The FDA has set a PDUFA action date of May 29, 2022 for the NDA and July 29, 2022 for the BLA. As John mentioned, these filings will be reviewed together. We've also shared that the MAA has been submitted to the European Medicines Agency and is under review. and we expect CHMB opinion later in 2022. We now also have multiple early access mechanisms in place, including in the UK, Germany, Japan, and other countries. This includes the EAMS framework that we announced in June, in which ATGA was granted a positive scientific opinion through the Early Access to Medicine Scheme, or EAMS, by the UK's MHRA. This positive opinion recognizes the high unmet medical need faced by the Pompe community and permits eligible adults living with late onset Pompe disease who have received Alkocasidase Alpha for at least two years to switch and have access to ATGA prior to marketing authorization in the UK. And we are seeing significant enthusiasm for ATGA under this EANS mechanism with multiple physicians having requested access across all of the leading Pompe centers in the UK and now with multiple patients receiving infusions. Since the positive scientific opinion in June, interest and momentum for ATGA has grown, and we are pleased to be able to provide access to those who are eligible. At this point, we're happy to report that more than 150 patients worldwide are being treated with ATGA across our clinical extension studies and these early access programs. And for the younger Pompe community, we continue to enroll the ongoing open-label study in children up to 18 years of age living with late-onset Pompe disease and look to expand into patients with infantile-onset Pompe disease as soon as possible. And finally, in response to the many requests for expanded access that we received for children living with infantile-onset Pompe, our expanded access programs for both those living with infantile-onset and late-onset Pompe continue to expand for multiple individuals. With that, let me hand the call back over to Bradley to discuss our launch preparations for ATGA. Brad?

Great. Thanks, Jeff. And on slide 17, we outline, again, the launch preparations for ATGA as we're poised for another anticipated successful product launch. You know, unlike when we launched Gallifold, when we were hiring the commercial organization and supportive infrastructure from scratch, As I mentioned before, we have a presence now in nearly 43 countries around the world, including all of the major markets, and that team will largely be the same that will launch ATGA. We have experience across all areas that are needed for successful drug launch, regulatory, commercial, supply chain, medical affairs. We have experience with payers and reimbursement and access, patient advocacy, and most importantly, the key relationships with rare disease and patient communities. we're very confident in our world-class organization that we can lever for their experience and relationships to deliver ATGAA to people living with Pompe disease around the world. From the team, the medical education, the published phase three data, and the highly regarded Lancet neurology, our experience with reimbursement and access around the world, and again, all the strategic planning that we're doing together with building inventory with our partners in Wuxi Biologics, we believe we're in a very strong position for a second rapid and successful launch for Amicus. With that, let me turn the call over now to Daphne Queeney, our Chief Financial Officer, to review our financial results, guidance, and outlook. Daphne?

Thank you, Bradley, and good morning, everyone. Our financial overview begins on slide 19 with our income statement for the full year ending December 31, 2021. For the full year, we achieved Gallifold revenue of $305.5 million, which is a 17% increase over 2020. This includes a year-over-year operational revenue growth measured at constant currency exchange rates of 14%, further benefited by a positive currency impact of 3%. Cost of goods sold as a percent to net sales was 11.3% in the year as compared to 11.9% in the prior year period. Total GAAP operating expenses were $477.5 million in 2021, relatively stable as compared to $476.8 million in 2020. On a non-GAAP basis, total operating expenses were $406.9 million in 2021, as compared to $415.7 million in 2020. The decrease reflected the timing of investments in our pipeline, partially offset by third-party costs. We define non-GAAP operating expense as research and development and SG&A expenses excluding share-based compensation expense, changes in fair value of contingent consideration and depreciation. Net loss for the full year 2021 was $250.5 million, or 92 cents per share, as compared to a net loss of $276.9 million, or $1.07 per share, for the prior year period. As of December 31, 2021, we had approximately 279 million shares outstanding. This year, we expect total non-GAAP operating expense to be within the range of $470 million to $485 million, driven by continued investment in the global Gallifold launch, ATGAA clinical studies, and prelaunch activities. Let me emphasize that this guidance also includes approximately $70 million related to certain non-recurring costs for the manufacturing of ATGAA to support the global launch as well as committed obligations for the gene therapy portfolio. Importantly, in 2023 and beyond, we would expect non-GAAP operating expense levels from 2022 to decline to a similar level as in 2021. Turning now to slide 21, we continue to operate from a position of financial strength and remain on track to be self-sustainable without the need for any future dilutive financing. and expect to achieve profitability in 2023 as we defined in our press release. Following the termination of the business combination agreement and strategic portfolio alignment, we will focus the majority of our investments on our core value driving franchises in Fabry disease and Pompe disease. This also includes continuing to deliver on the global growth of Gallifold, securing approvals and launching ATGAA globally, as well as driving efficiencies cost savings, and careful expense management. Importantly, strategically prioritizing our pipeline and aligning our internal R&D organization results in $400 million in net savings over the next four years, approximately the same amount in R&D OPEX associated with the previous Caritas spin-out. A few comments about our cash position and 2022 financial guidance. Cash, cash equivalents, and marketable securities were $482.5 million at December 31, 2021, compared to $483.3 million at December 31, 2020. We are issuing our full-year Gallifold revenue guidance of $350 million to $365 million, in addition to our non-GAAP operating expense guidance of $470 million to $485 million. And with that, let me turn the call back to John for closing comments.

Great. Thanks, Daphne and Jeff and Bradley as well. So as you can see, we have been relentlessly focused on performance across the business, driven again by our global team of passionate entrepreneurs who have led and will continue to lead us on our patient-focused meeting. And I'll also state that we also firmly believe that those companies that respond to changes decisively and boldly, we believe thrive best. And we are incredibly enthusiastic about the future of Amicus, again, looking forward to to launching yet a second global rare disease medicine with the ability to change people's lives, we believe, and also have a billion dollars in revenue potential, together with our turn to profitability in 2023. And let me also, operator, before we turn the call to questions, just say that as we look at global events, too, our thoughts and prayers remain with the people in the Ukraine. So, operator, I'm happy to take any questions.

Thank you. Ladies and gentlemen, if you have questions, please press star, then the number one key on your touch-tone telephone. At this time, we ask that you only ask one question. If you have any additional questions, please enter back into the queue. If your question has been answered or you wish to remove yourself from the queue, please press the pound key. Thank you. Our first question comes from the line of Ritu Barrel with Cohen. Your line is open.

Hi, guys. Good morning. Thanks for the question. Hi. So I just wanted to ask about the mid-cycle review. Were there any new topics not in the Day 74 letter? Were there any indications about what are going to be expected for inspections, including of WUSHI and any additional indications of potential advisory committees?

Yeah, I don't want to give too much color to it, too. I'll just say I think we're going to be in a really good place. You know, I think it was an excellent mid-cycle review meeting. We didn't see any surprises. Again, the team has been fully prepared. As is typical, it's, you know, a series of information requests leading up to the mid-cycle review. Again, we've responded to those. Very, very pleased with the level of engagement at FDA. With respect to the inspections, yes, we've always known that they will need to inspect the WUSHI facility, and we're engaged with the FDA to work on those inspections as well. And again, I'll reiterate our belief in the approvability of ATGAA, and we continue to make significant investments in the launch preparations for ATGAA, including a significant inventory build to meet what we think has the potential to be extraordinary demand for ATGAA. So I think we'll continue to be in a good place. And, again, remind everybody the PDUFA date. Yeah, I would target the PDUFA date, as we've said, for some time. You know, it's kind of unique with the two different PDUFA dates. There's really no precedent for that. We continue to guide people toward the latter of those dates, the July 29th date, for the approvability of this novel regimen in full. So I think we're in a good place. Great. Thank you.

Could you just quickly review for us? Could you just quickly review the inventory situation?

I knew you'd get a second one, but go ahead.

Yeah, sorry, the inventory situation. That's all right. I've just been fielding a lot of calls about the inventory situation with Wuxi and how much product is where and the supply you have. And then I'll stop, I promise.

No, that's okay. That's an excellent question. We're in a really good place. We have always been very focused on building inventory. If you remember, we wouldn't go into the pivotal study, in fact, any of our clinical studies, until we had at least a year of inventory available. in hand for any patient coming into a clinical study. So that philosophy has carried through. And maybe, Bradley, do you want to talk about general inventory, build, supplies, but also how we're managing the supply chain globally, including maybe the building also of the Ireland facility? Bradley, go ahead.

Yeah, sure. Thanks for two. So, yeah, as John mentioned, we have been laser-focused on ensuring an intact supply chain, and we talked a lot about that as we were conducting the Pell study that we were able to move products successfully out of China into different markets during what was certainly a challenging time for moving product around the world. So we know we can do that effectively. The Wuxi facility and the inventory that we're building there is sufficient to support both the launches here in the US and in Europe. And then, as John mentioned, the Ireland facility, which she invested in long ago as part of our global supply chain plan, is expected to come on to support clinical use this year and then commercial use next year. So we feel like we're in a really good place to support the global supply and all the anticipated demand that we have for both of those launches.

I'll just add further with respect – no, thank you, Ritu. I'll just add further with respect to managing the supply chain. Not only do we always maintain significant inventory – and are building very significant inventory for the launch, expecting the demand. We also make sure that material continues to move out as it completed its bioreactor runs. It moves out of China to various points around the world, including to Europe and then the United States. So significant inventory is also being held outside of China.

Thank you. Our next question comes from the line of Anupam Rama with JP Morgan. Your line is open.

Hey, guys. Thanks so much for taking the question. At the conference last month, you kind of talked about, like, a patient queue for Gallifold building in the latter part of the fourth quarter, but given COVID, it was hard to get patients to actually initiate therapy. What are some of the trends that you've seen over the last six weeks or so on this? Thanks so much.

Yeah, again, I'll turn it to Brad for more color, but we're more than halfway through this quarter and we're trending just slightly above our budget projections. So I think you're starting to see some of that ease up, but again, driven by fundamental demand and continued compliance adherence. Still COVID headwinds for sure. Bradley, do you want to comment on that?

Yeah, thanks, John. I think you hit some of the key points just to your specific question on APOM in terms of some of those larger orders that we saw placed at the end of the year last year. Those are starting to work through the system, which is great. So that will help us in Q1. And we did see, in particular in January, a pretty similar environment that we saw towards the end of the year last year, but still able to add patients in. In all of our major markets, it's just, again, those disruptions between physicians and patients doing their baseline diagnostics as we start therapy or even potentially identifying new patients just slow things a little bit towards the end of the year. But as John said, I think in February in particular, we've started to see some of those trends ease. We are starting to work through some of those cues. I think the World Conference was a great bellwether. There were over 900 live attendees at the meeting. We had a great presence there, both for Gallifold and for Pompeii. And we think that reflects what we're all anticipating and starting to see, which is an increasing return to normalcy. I think with more and more in-person interactions between patients, physicians, and our commercial and medical organizations. So, So far, the trends look great. As John said, we're slightly ahead of budget, and we're very much looking forward to another successful year for growing Galfold.

Thanks so much for taking the question. Great. Thank you, Anupam.

Thank you. Our next question comes from the line of Joseph Schwartz with SVB Lerink. Your line is open.

Hi. Thanks very much. Given we've seen minimal uptake from NeoGA now that it's approved, and that contrasts with your expectations for ATGA, I was wondering if you could give us your thoughts on where you expect to get the greatest uptake. Do you think that physicians and patients are just waiting to make switches until ATGA is available, and do you think that the limited usage of NeoGA is just because of minimal use in incident patients, or are there other dynamics that you could walk us through?

Yeah, thank you, Joe. You know, I think the Pompe community, patients, parents of children, are incredibly sophisticated, as are the physician scientists who treat these patients, and they're all looking at the data. And again, I think our expectations are built on, you know, if you look at the thousands of patients today who are diagnosed with Pompe, the vast majority of them in the developed world are on an approved therapy. They're on myozyme, lumozyme. So they're looking, you know, and as we know, after a couple of years of benefit, almost universally, they begin to decline again. Children, adults, all patients living with Pompe. So when we did our PROPEL study, again, nearly 80% of the patients in that study were switch patients. And again, the most compelling data where we achieved the statistical significance in improvements in both forced vital capacity and six-minute walk and on virtually all secondary markers were in that switch population. So I think as we've talked to physicians, as we've looked at the data, we think given that virtually all patients in the first several years are going to be switch patients, You know, I think our data in the switch is quite robust and quite compelling, and I think that contrasts with other studies that have been done. So I think that's what gives us our enthusiasm as well, and also based on experience. As Jeff indicated, more than 150 patients, ranging from infants through adults, are on ATGAA. The vast majority of them had switched from standard of care. And what we see is when patients switch to ATGAA, that they stay on ATGIA. And so I think all of that experience has caused us to make significant investment, both in our people and infrastructure around the world to support the launch, but also in the significant inventory build. So, Bradley, do you want to comment on anything else in the market dynamics as well?

No, I think you captured it, John. Thank you.

Great. Thank you, Jeff.

Thank you. Our next question comes from the line of Dago Horn with Staple. Your line is open.

Great. Good morning. Thanks for taking our questions. I'll also stick with one. If we think about the gene therapy endeavors, you mentioned core focus being Fabry and Pompe. I totally get that. I guess Fabry has been ballooning in terms of programs in the gene therapy arena. So can you maybe talk us through sort of your strategies? I know you previously talked about cardiomyocyte targeting. We also know 4D has also cardiomyocyte targeting vector. How can we think about, or how should we think about the differentiation there? And if we think about AGA levels, is that still the key endpoint when it comes to gene therapy for Fabry, or should there be something else that we should focus on? Thank you very much.

Yeah, no, thanks, Dagan. Again, let me again reiterate that, you know, we don't expect gene therapy programs at Amicus in the next several years to be moving into the clinic. We think there's much more core science in Febre, Pompe, and other diseases broadly that needs to be solved. You know, what we've talked about before, these persistent challenges of durability, of targeting, of safety, of manufacturability, against an incredibly challenging, not only biotech environment, but regulatory environment in gene therapy, particularly in the United States. So all of that together is what's led us to really focus on core science. Again, our R&D effort, very sharply focused to support our core franchises in Febre and Pompeii. But even there with gene therapy for Febre, for instance, we think it's going to be a very long road for anybody developing a Febre gene therapy program. We don't believe that you would see approval based on accelerated approval or biomarker endpoints. We think it will be full clinical studies. We think you'll need approved drugs as comparators. It's many, many years of work. So there have been programs that have been in the clinic. There have been programs, as we've seen very recently, that were in the clinic that have stopped, and I think that's recognizing the reality of the challenges broadly and of gene therapy but specifically in February you have approved therapies and again very specifically for the amenable population that we think is very well served with Gala fold we think the benefit risk assessment for gene therapy is going to be very very different so again we think for us for the field there's more core technology and science work that needs to be done before we really see these having the potential to become standard of care, a lot of work ahead. Jeff, I don't know if you want to comment on differentiation. Again, we focus on the transgene. We think we've developed a terrific transgene. We do think that there are still challenges with AAV delivery broadly. But, Jeff, go ahead.

Yeah, thanks, John. Thanks for the question. There's really two main aspects in which our gene therapy program in February is differentiated. One is the use of a ubiquitous capsid and promoter. So not trying to transduce only kidney or only heart, but trying to transduce kidney, heart, skeletal muscle, as many places as possible to produce and secrete the alpha-gal enzyme. And then importantly, as John mentioned, we engineered the alpha-gal in our transgene to actually be a more stable, more active enzyme. So at a given dose of AAV, we see much more robust clearance of substrate with the enzyme produced by our transgene. And in mouse studies, you know, that approach looks to be very effective. You know, when we translate, as you translate to the clinic, you know, I think it's important to look, you know, levels of enzyme in the blood is one way to assess, you know, whether the gene therapy is doing what it should and producing the enzymes. But it's really important to look at then the resulting substrate reduction, and not just in plasma, but importantly in key cells and tissues, and then ultimately on clinical parameters. You know, we know from our animal studies that it requires quite a bit of enzyme in the blood to get good substrate reduction in those deeper tissues, and that's something we're working towards.

Great. Thank you very much. Great. Thank you, Dagan.

Thank you. Our next question comes from the line of Kazeen Ahmed of Bank of America. Your line is open.

Hi. Good morning, guys. Thanks for taking my question. For me, I just want to ask about Dallas Falls. Maybe this is most appropriate for Brad. You know, Brad, you talked about that billion-dollar target for peak sales for quite some time. Can you just walk us through kind of where you are now relative to where you thought you would be before the pandemic, if the pandemic has had any meaningful slowdown of that pick up in market share. And as this launch is maturing, where do you think most of the upside is going to come from, from new patient ads? Or is it just making sure that more doctors are aware of the benefits and trying to, I guess, increase penetration within already prescribing doctors? Or is it expanding to more doctors? And sorry, it sounds like a lot of questions and one in there.

No, they're all good questions, Dazeem. Thank you. I'm happy to address them. So, again, we remain really confident in the overall growth opportunity for Galfold. And as we said before, there's a couple key drivers which I think are embedded in your question. So, first of all, you know, this year we just passed $300 million in global sales. And that's roughly a little under a 50% share of treated amenable. So as we continue our geographic expansion, as we continue to penetrate just in the markets we're in, if you assume we can get to 90 plus percent market share, that's already almost double the revenue potential from our current business, just within the current markets. and anticipated launch markets. So lots of opportunity just to continue to switch patients. So that's one key growth driver. The second one, to your point, we will continue to see uptake both in the diagnosed untreated and the newly diagnosed markets. You know, on the one hand, on the diagnosed untreated, when we launched, we anticipated that there was roughly the same amount of diagnosed untreated patients as diagnosed treated patients. And I think we shared in JPMorgan that we've already grown the market significantly by penetrating into that space. And I think that's something you see with an effective oral treatment launched into an injectable space. There are lots of other comparables that we've talked about before there. So that's one key focus. But the reality is this is a robustly growing market from a diagnosis perspective. And we believe that there are many, many more patients who are undiagnosed out there. And so the efforts that many manufacturers in the Fabry space have put towards finding new Fabry patients, those efforts that we've started to talk about as well in terms of screening populations, partnering with Vitae, looking in high-risk populations like MS and pain, you know, we'll continue to see many, many more Fabry patients diagnosed for the years to come. And I think what's important about that population in particular, those tend to be late-onset patients who are undiagnosed, and those patients tend to have a much higher amenability rate. So you can see how, you know, as the market evolves, to your latter question, I do think that a large part of the Gallifold opportunity will actually come from growing the market, bringing on previously untreated patients to treatment. And just to your last point in terms of timing, you know, we talked a little bit about this before. The underlying Fabry business remains strong. The Galfold business remains strong. But I do think what you saw is maybe a shifting from, you know, maybe a year or so from our original anticipation of passing that $500 million waypoint onto that billion-dollar opportunity. But now I think what you're seeing is a very strong recovery, and we're confident we'll continue to sustain that double-digit growth rate for many years to come and confident that those growth drivers will get us upwards to that billion-dollar opportunity.

Okay, thanks, Brad. And then ultimately, what percent of the mutations did you end up deeming amenable for Gallifold?

Yeah, so when we first launched in terms of the diagnosed patients, we estimated between one-third and one-half of patients. We've never really found a market where the amenability rate was less than a third. But we do have many markets where the amenability is at 50% or even greater, and oftentimes that's driven by, for example, many cardiac mutations which tend to be amenable to Gallifold. And so that's the range of the current diagnosed market. That being said, if you look at the epidemiology, in particular some of the newborn screening studies that showed that well over 80 or 90% of the mutations found in those newborn screening studies were amenable to Gallifold. I think that's where you see in the long term, those patients will have a higher percentage of amenability, and we think there's lots of opportunity for Gallifold to help those patients.

Okay, thank you.

Great, thank you, Tezi.

Thank you. Our next question comes from the line of Christine Kluska with Canada Fitzgerald. Your line is open.

Hi, good morning, everybody. Thanks for taking my question. I saw at World recently that you shared some subgroup analyses from the Propel trials. So I wanted to ask if you could discuss your strategy with some of these particular data sets and how this might help you aid in conversations if commercialized outside of already having the advantage of having the clinical experience in both the ERT switch and naive patients.

Great. Thanks, Kristen. Good to hear from you. Jeff, maybe do you want to just summarize something? for everybody some of the Propel subgroup data that we had shown, and then maybe, Bradley, if you'd comment on how we see that supporting the launches.

Sure, John, and thanks, Kristen, for the question. So the main new subgroup analyses we presented show, you know, across different levels of baseline severity on six-minute walk and on FEC that we saw ATGA had improvement versus IWCA across the different ranges of severity. So really important to see that You know, whether those patients are more preserved or more impaired at baseline, we're seeing a benefit of switching or going on to ATGA. So, Brad, you know, in terms of other key data we have that we'll continue to look into besides those subgroup analyses, of course, this year we're going to continue to look at our long-term data from both Phase I-II and the Rappel extension, and we think that that will be really impactful new data coming out. And we'll continue to report more of the secondary analyses from Propel, some of the patient-reported outcomes in particular, which we've not yet fully presented anywhere. But Brad, maybe over to you for implications on specific how we use that data in launch. Sure.

Look, I think first, as John mentioned, this is an incredibly sophisticated patient and physician community, and they will be data-driven to understand which product may be most appropriate for their patients. And we continue to believe ATGA has the most robust data set. And as John mentioned, we're the only company to have sponsored in a well-controlled study both switch and naive patients. As you get down into those different subsets of patients, I think what we want to see and what we are seeing is that ATGA has a strong impact in that study as you look across, as Jeff mentioned, baseline severity, age, et cetera. And so, you know, I think what that means is what we believe, which is ATGA can have a strong impact on all Pompe patients, whether they're switch or naive or different levels of severity. I would also mention that we have, you know, from the Phase 1-2 data, we showed strong impact on ambulatory patients, which is a significant area of unmet need. And as we get into those secondary PROs, as Jeff said, of course, pulmonary function and mobility are critical endpoints, both for patients and physicians. But there are a number of other factors that I think patients would point to that are important for their quality of life. And I think as we continue to mine that really robust data set, Further support across those other endpoints, I think, will just be more support for the interest and the impact for ATGA in this population.

Thank you.

Thanks, Kristen.

Thank you. Our next question comes from the line of Yong Zong with BTIG. Your line is open.

Hi. Good morning. Thanks very much for taking the question. I have a follow-up question on ERT switch patient Pompe for ATGA. So one piece of input that we have heard from physicians is that if patients are stable on existing ERT, they would like to keep those patients on their current therapy. So I don't know. So do you think that those patients who are starting to show loss of response to existing myosin or lumizine could be probably the easier patient population to target. And for those patients who are stable on existing ERT, what do you believe would be the strongest evidence to convince those physicians that maybe switch is a good idea?

Yeah, thank you, Yun. Yeah, absolutely. And that's what we expect. We think the greatest opportunity in the next several years is within the ERT switch population. And within that population, we think certainly those people who have already shown decline, sometimes dramatically, we think those would be the ones most eager to switch, of course. Those just beginning to plateau or even subtly declining, we think would be kind of the next tier of people most open to switch. And for those patients who are currently stable on ERT, I think they're going to want to see how those switches go when we start to get into the many hundreds of patients I think you could have a mindset where people say, well, why would I wait to decline on standard of care before switching? And I think, too, this is where our data would be very helpful. Again, when we went into the clinic, our goal was initially to just stabilize patients, to stop the decline for switch patients. And, again, what we've seen is that in many patients on key measures of disease, pulmonary muscle strength, that we can actually not only stabilize them but improve them. And I think, again, in a data-driven world for patients and physicians and scientists, that's what's going to drive the day as it should. So I think over time, as we continue to build the body of evidence, I think all patients on ERT standard of care will ultimately consider a switch to ATGIA. Thank you. Sure. Thank you.

Thank you. Our next question comes from the line of Ellie Merle with UBS. Your line is open.

Hey, guys. This is Johnny off for Ellie. Thanks for taking the question. On CLN6, what are your theories that led to the loss of durability? Is it disease-related or aspects of the gene therapy construct? And what are kind of the learnings you had from this?

Yeah, again, to remind everybody, for CLN6, we had previously announced that, again, with that a very, very small disease, but tragic disease in these children that over time, while we saw an initial stabilization, particularly in the younger children, that didn't have a durable effect in all patients. When we looked at the long-term data toward the end of 2021, we saw that decline. We don't know exactly why. We know it was a low dose that was given first. Secondly, it was given intrathecally. We've done some follow-on experiments that show that Delivering it into the inter-cisterna magna is probably more optimal, so it could also be a route of delivery. And yes, I also think it's the nature of the disease, again, with a lack of the ability to see cross-correction. Given the biology in CLN6, it makes this incredibly challenging, and we knew that when we acquired the programs from Nationwide several years ago. So it's probably a combination of all of that dose, route of administration, and and just some incredibly difficult biology unique to CLN6.

Got it. Thank you.

Sure. Thank you, Jen.

Thank you. Our next question comes from the line of Gil Bloom with Needham & Company. Your line is open.

Good morning, everyone, and thank you for taking our question. Considering the fact that you might have a little bit more flexibility Would Amicus consider in licensing some new program that fits well with the core strategy around Subray and Pompei? Thank you.

Yeah, thank you, Gil. You hit on an important point with the cost savings that we have in R&D here now, again, over $400 million over the next four years. That will take us to profitability. We will continue to have a pipeline. Again, our core focus will be advancing our programs and research and development in our core franchises of Febre and Pompei. We will also continue to do research and development in core platform technologies broadly in genetic medicine, including in the fields of gene therapy and looking particularly at next generation technologies. We are developing and have developed some, we think, very promising core technologies that will address Problems like durability and targeting and safety, those need to mature more in our science labs with a refocused team here at Amicus. With that, we have been looking at technologies. I think over the next year or two, we would look at complementary technologies, for instance, maybe in the field of immune modulation in the delivery of genetic medicines. So we'll look at that, but you bring up an important point that By the restructure that we've done and the refocusing of our prioritization here at the pipeline, it gives us the organizational and financial bandwidth in the years ahead to look at other technologies, potentially outside of the AAV field, potentially non-viral mediated delivery of genetic material, again, focused in Febre, Pompeii, but in other areas as well where we think it could be applicable. So, yes, we will look at technologies first, I think products second, The other area, when we're fully profitable, we think with another great advantage that we have at Amicus, we've invested substantially over the last six and a half years to build a world-class global commercial organization. All Amicus medicines are delivered by Amicus teams now around the world. We have substantial operating leverage as we've moved to the ATGAA launch, so for minimal further investment in commercial globally. We can launch a medicine with a billion-dollar potential. That's just tremendous operating leverage and execution. So we think, again, once we achieve full profitability, we can very carefully look at other products that we could deliver through our commercial organization around the world. So I wouldn't foresee that in the next year or two, but beyond I think we could potentially be a partner of choice. So, again, this gives us a lot of flexibility both organizationally and financially in the years ahead to build our pipelines.

Thank you for taking our question.

Thank you, Gil.

Thank you. Our next question comes from the line of Debjit Chattopadhyay with Guggenheim. Your line is open.

Hi, good morning, team, and thanks for taking our question. This is Robert Fink on Debjit. What is the plausible explanation for the underperformance of ATGAA in naive patients, and what would you expect the label to indicate in terms of this? And tied into that, how would you characterize the commercial opportunity, both in terms of addressable patients and likely market share from Sanofi? Thanks.

Yeah, so there's a lot of questions there, Robert. Let me unpack it again to remind everybody. Our pivotal study, the PROPEL study, was about 120 patients, and it was randomized two to one. So for every two patients coming on to ATGAA, one remained on or went to ERT standard of care, myozyme, lumozyme. About almost 80% of the patients in that study were switch patients. And again, in that population, we showed pre-specified in our statistical analysis plan, we showed superiority to standard of care, statistical superiority on forced vital capacity, on six-minute walk. We showed superiority often with statistical significance in multiple other secondary endpoints. So an incredibly strong data set in the switch population. In the treatment-naive population, again, a much smaller study subgroup, for those patients coming on ATGAA, we saw significant improvements. We saw improvements, again, pulmonary function. We saw a six-minute walk across the board. What was confounding in that study, to remind everybody, there were only seven patients who were randomized treatment-naive patients to go on to ERT standard of care, myozyme, lumozyme. And for the first time in any study anywhere, they overperformed expectations. We don't know why, but they did. So it was just in comparison to that relative comparison to that particular control group of seven patients, again, a very small N, where we didn't look favorable to standard of care. But when you look at everything that's known about standard of care, everything published, you look at the comet pivotal study for NEO, we look very favorable there. The biology is very straightforward. You know, if this works in, frankly, some of the more difficult to treat patients in the switch population, we believe very strongly it's working just as well in the treatment-naive patients. Again, as a reminder, also in our Phase II study, we saw five patients in the cohort who were put on ATGAA having been treatment-naive. All five out of five showed dramatic improvements in strength. So, Our strategy has been in all geographies to seek approval for both a switch population as well as a treatment-naive population. With respect to the market, you know, we think in the next several years, 90-plus percent of the opportunity is in the switch population. So from a commercial standpoint, in the next several years, the treatment-naive population is a relatively small percentage of the revenue and commercial opportunity here. But we think in the long run important. And we also think desperately important for newly diagnosed patients, people who have yet to be diagnosed with Pompe that they have full treatment options. So I hope that addresses all of your points.

Yes, thank you.

Great. Thank you, Robert.

Thank you. Our next question comes from Ilana Zishu with Berenberg. Your line is open.

Great, thanks very much. Thanks for taking my question. I just want to ask two quick ones. First is, in your review with the FDA on ATGAA, was there any indication that an advisory committee meeting will be convened? And secondly, given your workforce rationalization, any thoughts around the Batten Disease French gene therapy franchise? How should we think about the potential there? Thanks very much.

Sure. I'll address both of those questions. So, again, we had an excellent mid-cycle review. We remain very confident now in the path forward to approvability in the United States. The FDA had previously told us in writing that they do not expect to convene an advisory committee, and that hasn't changed. With respect to BATNs, again, we said, unfortunately, given the data that we've seen and where we are that we would be discontinuing the CLN6 program. We're looking at other ways to help the small number of children with CLN6 to take those learnings and to find a way to help that population outside of a formal development program. And then with CLN3, there we have to remind everybody we have treated four patients, four young children, three at a low dose, one at a higher dose, There we had said also back in January that we need more work on the science. So we're not going to be moving that forward into the clinic until we get all the scientific data, and then we'll decide the best path forward for that program. So there's more key science work ahead for us. There's more regulatory discussions. And then for CLN3 in particular, we also want to look toward the end of this year at the longer-term data in those four children. So this program stands exactly as it did in January. No immediate move to further clinical studies.

Thanks very much. Great. Thank you.

Thank you. At this time, I would now like to turn the conference back over to Mr. John Crowley, Chairman and CEO, for closing remarks.

Great, operator. That's all we have. That was a great set of questions. Everybody, you have a great day. Thank you for listening.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.