Amicus Therapeutics, Inc.

Good morning, ladies and gentlemen, and welcome to the Amicus Therapeutics first quarter 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 and then zero on your touchtone telephone. As a reminder, this conference call is being recorded. I would now like to turn the conference over to your host, Mr. Andrew Fonin, Head of Investor Relations. You may begin.

Thank you, Mary. Good morning. Thank you for joining our conference call to discuss Amicus Therapeutics first quarter 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 Queamy, Chief Financial Officer, and Dr. Jeff Castelli, Chief Development Officer. Joining for Q&A, we'll have Dr. Mitchell Goleman, Senior Vice President of Clinical Research, joining. 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 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. You are cautioned 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 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 31, 2020, and the quarterly report on Form 10-Q for the quarter-ended March 31, 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. Good morning and welcome, everyone, to our first quarter 2021 results conference call. I'm pleased to report that the first quarter of 2021 reflects execution across the key strategic priorities that we outlined at the beginning of the year. As we did in this morning's press release, I'd like to highlight several key accomplishments. First, Gallifold continues its strong launch performance and remains the cornerstone of our success. With $66.4 million in first quarter revenue, we're very pleased with the continued momentum of the Gallifold uptake globally. The number of patients on Gallifold at the end of the quarter continued to exceed our internal expectations, despite continued headwinds from COVID-19, as well as uneven ordering patterns. Second, our key regulatory timelines for ATGAA remain on track. and our R&D pipeline of gene therapies continues to advance. Following a successful pre-BLA meeting and written communication with the US FDA, we continue with our plans to complete the rolling BLA submission of ATGAA in the second quarter of this year and anticipate additional regulatory submissions in the European Union and in other geographies throughout 2021. We continue to have great confidence in ATGAA to benefit people living with Pompe disease, and we intend to move it rapidly through regulatory submissions onward towards approval. Within our gene therapy pipeline, we continue to further our lead batten disease programs for CLN6 and CLN3, as well as our most advanced preclinical gene therapy programs. Through our broad research collaboration with Dr. Jim Wilson and the University of Pennsylvania, we are highly encouraged by the preclinical data and progress from our Febre and Pompe disease gene therapy clinical candidates. We are pleased to share that new preclinical data from both programs will be presented at ASGCT this week. Third, the amicus cash position is sufficient to achieve self-sustainability without the need for any future dilutive financings. Our continued revenue growth, prudent expense management, and growth potential has allowed us to reach this important milestone as we continue to realize our vision of delivering groundbreaking and potentially curative new medicines for people living with rare diseases around the world. And finally, as we announced just a few days ago, I'm very pleased to welcome our new Senior Vice President of Strategy and Business Development, Sebastian Martell, to the Amicus team. Sebastian served most recently as global head of rare diseases at Sanofi Genzyme and brings deep expertise in corporate strategy, business development, and commercialization. We look forward to Sebastian's contributions to advancing Amicus's mission for patients as a leading global biotechnology company. Turning to slide four, we are well on track to achieve our five key strategic priorities for 2021. These include Gallifold, our precision medicine for February. We will continue to drive Gallifold to more people living with February disease with amenable variants in existing and in new markets. We look to achieve this year global product revenue of $300 million to $315 million, which reflects the strong momentum and demand behind this precision medicine globally, despite some COVID-related disruptions that we saw in the latter part of 2020 and which continued into early this year. Second, we remain steadfast and passionate in our commitment to advancing ATGAA through global regulatory submissions for the benefit of as many people living with Pompe disease and as quickly as possible. Three, we are advancing our industry-leading rare disease gene therapy portfolio, again stemming from our global research and gene therapy center of excellence in Philadelphia. We will be advancing the clinical development, manufacturing, and regulatory discussions across multiple programs in our gene therapy pipeline. Four, in addition, we are progressing our manufacturing capabilities and capacity to build world-class technical operations to support all gene therapy programs. And five, finally, again, we continue to maintain a strong financial position as we carefully manage our expenses and investments. and we remain fully funded through all major milestones. So with that introduction this morning, let me now hand the call over to Bradley Campbell, our President and Chief Operating Officer, to further highlight the Gallifold performance. Bradley. Bradley Campbell Great.

Thanks, John, and good morning, everyone. As John mentioned, I'll now walk you through in more detail our Gallifold performance for the quarter. On slide six, we have a global snapshot of the Gallifold commercial progress. For the quarter, total product revenue was $66.4 million, driven by strong patient demand and business continuity, despite quarter-over-quarter revenue being impacted by the typical uneven ordering patterns from Q4 to Q1 that were slightly exacerbated by COVID. And I'll provide a little bit more detail on that in a moment. The geographic breakdown of revenue during the quarter was $45.5 million, or 69% of revenue generated outside of the United States, and the remaining 20.9 million, or 31%, coming from within the United States. As we've mentioned before, we expect that split to continue to be roughly 70-30 as we continue to grow both parts of the business. Turning now to slide seven, Q1 was another quarter of global growth, and the number of patients on Gallifold at the end of the quarter was ahead of our internal estimates. The business continues to be incredibly resilient, with patients added in all of our major markets. As I alluded to, first quarter revenue reflected increased patient demand. It was slightly offset by timing of orders in some ex-U.S. geographies, reauthorizations in the United States, and some irregular ordering patterns due to COVID. Specifically, we did see some larger orders in Q4 as relates to Brexit and COVID, respectively. Both of these have now largely worked through the system in Q1, but that did accentuate the typical year-end ordering phenomenon. We also had a couple of large orders in the last days of Q1 that fell into Q2. These examples are consistent with our expectation of nonlinear quarter-to-quarter growth. As we highlighted in our full-year call, with the resurgence of COVID in the fourth quarter and into Q1, we did see some slowdown in new patient starts due to delays at the point of care between patient identification and initiation of treatment. Importantly, though, our supply chain remains fully intact. Our customers have confidence that they can access Gallifolds and our field team has been able to achieve a substantial majority of their pre-COVID touchpoints through a combination of in-person, digital, telephonic, and other means of interacting with physicians. We, of course, continue to monitor the pandemic's impact, but the good news is today we've observed improvements in the latter part of the first quarter and into the beginning of the second quarter. Specifically, and I think this is really important because it reflects what we've been saying about strong underlying demands, In the United States, the month of April saw the largest number of prescription requests since before the pandemic. And in our ex-US business, we've seen a steady increase in our rolling average monthly new patient starts from the last 12 months to the last six months, and now to the last three months. Based on this momentum and continuing to anticipate a second half recovery from COVID, we're confident in meeting our full year 2021 guidance. Although again, we do expect that quarter to quarter growth will be nonlinear throughout the year. On slide nine, we've called out several of the drivers and metrics which lay the foundation for our continued growth in 2021. It really starts with the momentum from 2020, where we finished with over 1,400 patients on Gallifold and opened up several new launch countries. Now, with over 1,400 patients on Gallifold, we're at about a 49% global market share of treated amenable patients. So while we're achieving higher market shares in countries where we've been approved the longest, there's still plenty of opportunity to continue to switch patients over to Gallifold. We also know that there are significant numbers of diagnosed untreated patients who have amenable mutations, and we now have a global mix of about 60% switch and 40% of Gallifold patients who were previously naive to treatment. As we've said before, over the next few years, we'd expect to see that rate of switch in naive patients to move to about 50-50, And in the long term, we expect to see that percentage reverse in favor of naive patients as we continue to fuel market growth. All of that is underpinned by compliance and adherence rates that continue to exceed 90%, reiterating that our belief that those patients who go on Gallifold stay on Gallifold. We think the value of Gallifold has been well recognized by payers with nearly 100% of insurance reauthorizations being granted now in 2021 with U.S. payers. and a similarly strong track record of successfully negotiating and renegotiating reimbursement agreements outside the United States. Our relentless focus on ensuring access to Gallifold continues to be a major strength. Another important driver of growth for Gallifold is continued geographic expansion. In 2021, we expect to add at least five additional countries as we look to expand access to Fabry patients with amenable variants around the globe. And we expect to see continued traction in our newer launch markets in Latin America, Asia Pacific, and of course, U.S., Japan, and the rest of the world. As a reminder, Gallifold has received regulatory approval in over 40 countries and commercial sales in over 30 of those today. So really, despite the recent COVID-related headwinds in certain geographies, demand for Gallifold worldwide has never been stronger. Now, with some cues of potential new Gallifold patients building in some geographies, and we're confident in our guidance of 300 to 315 million in full-year global sales. As part of that guidance, we project net new patient starts this year will be even greater than 2020, and we expect this growth in patients and corresponding revenue to be weighted to the second half of the year as COVID impact continues to ease. Finally, turning to slide nine, now with several years of strong performance and successful track record behind us, we can confidently say we are on a path in approximately the next two years to that important milestone of $500 million in global revenue in one year for Gallifold. And we lay out those drivers here, and really the exact timing of this milestone will be dependent on how quickly things return to normal post-COVID, but we continue to expect to generate $1 billion in cumulative revenue over the next three years, which will contribute a significant amount towards funding our R&D and OpEx over that period. And we have even further confidence now in that $1 billion peak opportunity as we continue to see significant growth in the Fabry market globally, which is driven by continued diagnosis from high-risk screening, newborn screening, and other diagnostic initiatives, which we're investing in as well. And finally, as we have orphan exclusivity in the U.S. and Europe, in addition to our 24 Orange Book-listed patents that give us IP coverage into the late 2030s, 11 of which provide protection through 2038. So lots of opportunity to continue to provide access to Gallifold globally for many years to come. With that, let me now hand the call over to Dr. Jeff Costelli, who's our Chief Development Officer. Jeff will highlight our ATGA program and our gene therapy pipeline.

Jeff? Thank you, Brad, and good morning, everyone. Moving on to our R&D updates on slide 11, we wanted to start with ATGAA, our novel next-generation therapy for Pompe disease. Pompe is a severe and fatal neuromuscular disease and one of the most prevalent lysosomal disorders with significant unmet need that remains today. In addition to all of the individual human tragedies, we've seen multiple publications and natural history studies of Pompe patients that highlight the initial benefit of treatment for a few years That is then followed by long-term decline on key measures of disease for a majority of patients. As a reminder, the high unmet need ERT experience population has only ever been studied in a controlled setting in our phase three PROPEL clinical trial with ATGA. All other controlled late onset Pompe disease studies have been in participants naive to treatment. Slide 12 presents a summary of the top line efficacy and biomarker data. As a reminder, PROPEL was a double-blind, randomized study assessing the efficacy and safety of ATGA in adult, treatment-naive, and ERT-experienced participants against the currently approved therapy. We enrolled 123 patients at 62 sites in 24 countries. One hundred and seventeen of those patients completed the study and all have voluntarily enrolled in the extension study to continue on ATGA as their only disease-modifying treatment for their Pompe disease. On the primary endpoint of six-minute walk distance, patients on ATGA outperformed those on ablucosidase-alpha in the overall population with a difference between groups of 14 meters, which did not quite reach statistical significance for superiority. However, on the first key secondary endpoint of percent predicted force vital capacity, or FVC, In the overall population, ATGA showed a nominally statistically significant and clinically meaningful difference for superiority versus aglucosidase alpha with a difference of 3% and a p-value of 0.023. This is a very impactful finding as progressive loss of pulmonary function is the leading cause of mortality in Pompe. And this was the main endpoint upon which aglucosidase alpha was approved. Here on this slide, we've grouped these endpoints into domains of motor function, muscle strength, pulmonary function, patient-reported outcomes, or PROs, and biomarkers. And you can see that the totality of data favor ATGA over agglucosidase alpha in both the overall and ERT experience populations. We remind everyone that the PROPEL study tested for superiority versus an approved therapy, not placebo, and that the bar for approval of a second-generation product typically requires only non-inferiority to be shown, not superiority for approval. As shown on our full-year call in post hoc non-inferiority analyses for the primary endpoint of 6-minute walk and the first key secondary endpoint of FDC, these non-inferiority analyses were highly significant. Moving on now to slide 13, we have our next steps surrounding the development, regulatory, and manufacturing strategy for the ATGA program. First, as John mentioned, our rolling BLA submission, which was initiated with the FDA in the fourth quarter of 2020, remains on track with the submission of the final module to be completed here in the second quarter of 2021. Additionally, our MAA submission with the EU is expected to be completed in the second half of this year, and we expect additional global filings to follow. We look forward to expanding our ongoing open-label adolescent study in the 12- to 18-year-olds living with Pompe disease this year as well. And our clinical study for Pompe patients with infantile onset disease is expected to begin this year. And finally, in response to the many requests for compassionate use or expanded access that we have received for children with infantile onset Pompe disease, our expanded access programs for both Pompe infantile patients and adult onset patients have enrolled multiple patients. Moving on up to slide 15, to briefly highlight our industry-leading portfolio of gene therapies for rare diseases. Several amicus presentations were given at the World Symposium Conference in February of this year, covering our lead gene therapy clinical programs in CLN6 and CLN3 bat disease, respectively. Data from both studies continue to show the potential to stabilize disease progression in these children when compared to natural history. We remain focused on the manufacturing activities regulatory discussions for both programs to enable dosing of additional patients with GMP clinical-grade material as soon as possible. Ahead on slide 16, we continue to make progress across our preclinical gene therapy programs with Penn, and we are excited to share that new data from our Fabry and Pompei gene therapy programs will be presented this week at the American Society of Gene and Cell Therapy Conference. Data from these studies further validate our innovative approach to gene therapy by combining amicus's protein engineering expertise with Penn's gene transfer expertise and technologies. We believe this is just the beginning of untapping the power of this collaboration. As a reminder, amicus has rights to over 50 diseases under this collaboration, including seven currently inactive preclinical programs. With that, I would like now to turn the call over to Daphne Queeney to review our financial results, guidance, and outlook. Daphne?

Thank you, Jeff, and good morning, everyone. Our financial overview begins on slide 18 with our income statement for the first quarter ending March 31st, 2021. For the quarter, we achieved Gallifold revenue of $66.4 million, which is a 10% increase over the same period last year. This includes year-over-year operational revenue growth measured at constant currency exchange rates of 6% and a positive currency impact of 4%. Total operating expenses were $112.9 million in the first quarter, which is a decrease as compared to $132 million in the first quarter of 2020, primarily driven by the timing of contract manufacturing and research costs. On a non-GAAP basis, total operating expenses were $90.5 million in the first quarter as compared to $116.7 million in the first quarter of 2020. The decrease in research and development costs reflects the timing of investments in our pipeline, specifically the timing of manufacturing batches of APGAA and research costs, which we expect to incur in subsequent quarters. 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 first quarter of 2021 was $65.7 million, or $0.25 per share, as compared to a net loss of $88.9 million, or $0.35 per share, for the prior year period. As of March 31st, 2021, we had approximately 266 million shares outstanding. Turning now to slide 19. With our current cash position, we are on a path to self-sustainability without the need for future diluted financing. We have achieved this milestone through our continued revenue growth with Gallifold, as well as driving efficiencies, cost savings, and careful expense management. For the third straight year, we expect total non-GAAP operating expenses in 2021 to remain relatively flat as we leverage global commercial infrastructure that is already in place for the ATGAA launch and other products in our pipeline. We transition the costs associated with development of ATGAA to multiple gene therapy programs in our pipeline, and we maintain financial discipline while meeting our objectives. To reiterate, all high-priority research programs in gene therapy are moving ahead on schedule, and we continue to fully support the work with the Wilson Lab at Penn. A few comments about our cash position and 2021 financial guidance. Cash, cash equivalents, and marketable securities were $417.4 million at March 31, 2021, compared to $483.3 million at December 31, 2020. We are reiterating our full-year Gallifold revenue guidance of $300 million to $315 million, in addition to our non-GAAP operating expense guidance of $410 million to $420 million. And with that, let me turn the call back to John for closing remarks.

Great. Thanks, Daphne and Jeff and Bradley as well. So as you can see, we have been relentlessly focused on performance across the business, across all programs. driven by a global team of passionate entrepreneurs who have led and will continue to lead us on our patient-focused mission. I am confident that as the world emerges from this global pandemic, amicus will emerge even stronger. Operator, we're happy to take questions.

Ladies and gentlemen, if you have questions, please press star and then the number one key on your touchstone 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. Your first question comes from the line of Riku Baral with Cohen. Your line is open.

Good morning, guys. Thanks for taking the question. I wanted to ask about the recent full approval of Fabrazyme by the FDA. It was certainly unexpected by me and I thought I kept track of these things. Can you guys walk us through what you know that drove that conversion and also what that means for Gallifold, either its current promotion or post-approval requirements? Thanks.

Sure, Ritu. You know, other than what Sanofi has indicated, we really don't know much. I'll just remind everybody of the history that the Fabrizyme product was given approval under the Accelerated Approval Framework in 2003. It then conducted a Phase 4 study that did not meet its primary endpoint, but the drug, I think very appropriately, continued to be on the market and available for patients. And as you saw from Sanofi, it was a combination of their registry data, real-world experience, largely that led to the conversion from accelerated to full approval. For Gallifold, you know, we continue down the path of a Phase 4 confirmatory study. But likewise, we're also building a body of evidence through real-world evidence as well as registration studies that I think could also be very supportive down the road of converting data. Gallifold from an accelerated approval to a full approval. So that's always been part of our strategy. It has no impact whatsoever on Gallifold and getting it to patients today. We've seen no disruption in the marketplace, no disruption with payers. And from our perspective for patients with amenable variants who would be suitable for treatment with Gallifold, it's had zero impact.

Your next question is from Taveen Ahmad with Bank of America. Your line is open.

Hi, good morning. Thanks for taking my question. Just wanted to get a little bit of color on how the quarter for Gallifold was impacted on the specifics of COVID. And if any of the impact that you've seen from COVID in the first quarter has impacted um, improved, uh, over what you're seeing so far this current quarter. And, um, maybe this is a question for, um, you know, for Brad about how, uh, you guys get to your guidance and what level of confidence, um, you have in being able to meet that guidance range for the year. Thank you.

Sure. Thanks to the, uh, Bradley, I'll let you feel those.

Yeah. Thanks to the, so as relates to, um, sort of where we are from a COVID perspective, I thought we provided good color on the call. And I think importantly, you know, some of the metrics that we're following that, you know, the number of prescriptions in the United States, which was the highest this month than it's been in any month since before the pandemic. And then as well, that kind of rolling new patient starts that we provided color on, you know, sort of the six months was better than the 12 month. And now the three months is better than six months. So again, So that tells us that demand is not just stable but increasing. And I think as we look out into the field, it's still patchy, as I know we all know, but I think there are certainly places where it's starting to look better, and we would anticipate that to continue throughout the year. And that's why we've provided that color that we think the second half of the year we'll see higher new patient starts than the first half. That being said, we're very confident in the guidance to your question between 300 and 315. And I think where we end up in that range will be, again, dependent on kind of how quickly things reside here. But what we see right now is steady growth, steady underlying demand. And then all of that is supported by the compliance and adherence rates that continue to be over 90%. So it's a very durable market as well. So we feel really good about where we are, our ability to get product to patients and and we're very confident in the guidance that we reiterated here today.

I'll just add. Thank you, Brad. I'll just add to Zine. In addition to the growth opportunities, the continued demand, patient demand, the new patient starts, the compliance that Bradley highlighted, I'll just reemphasize that reimbursement continues to be excellent as well, with near 100% reauthorizations and reimbursement in the United States and price holding throughout all the global markets.

Your next question is from Kristen Kuska with Cancer Fitzgerald. Your line is open.

Good morning, everybody. Thanks for taking the question. I wanted to ask you one on the gene therapy pipeline, which is what criteria is going into place when considering how to prioritize the candidates you have outside of the Batten, Fabre, and Pompe disease franchises? And then how are you and your collaborators considering items like transgene engineering, capsid selection, and route of administration, especially since you are one of the few to recently show clinical data via an intrathecal administration?

Great. Thank you, Chris. And in terms of how we select within our portfolio, I'll go back to the initial decisions on building our portfolio, and that was very much based on a disease approach. Looking at each disease, we, again, a number of years ago, began with a list of nearly 1,000 rare diseases. We went of that down to under 100. And there, of course, we looked at the unmet need, the technical feasibility of gene therapy broadly. We looked specifically at the technical fit of combining the pen gene transfer technologies with amicus protein engineering. We look at size of, you know, patient populations. We look at availability of natural history. I think all of that, competitive dynamics as well. And then when we look at our portfolio today, if you take, for instance, the Febre and the Pompe gene therapy programs, those continue to be key strategic priorities for amicus. We're moving those forward. We're moving them as fast as the science and the manufacturing and analytical technologies are allowing. And there, if you recall, back in November, we announced our February drug candidate selection, again, combining the Amicus and Penn technologies. And that was 12 to 18 months ahead of our original internal projections. So we had to make sure that we had the financial capital, the human capital, the manufacturing capacity available, which we did by reordering some earlier parts of our priority. So, in effect, Fabry gene therapy has leapfrogged Pompeii based on technical feasibility and our ability to advance it within all of those disciplines. With that, Jeff, maybe if you can comment on how we think about the different pieces of the technology, including route of administration.

Sure. Hi, Kristen. So as you pointed out, our approach to the gene therapy collaboration with Penn is we rely on our expertise from the protein engineering side really to help optimize cross-correction where the cells we can transduce, that those cells can then secrete the protein and treat other neighboring cells. We have a whole host of technologies from Penn that we can rely on for the capsular delivery And the route of administration really depends on whether we're trying to address systemic cells and tissues versus trying to get into the CNS. Sometimes it's a little bit of both. So it's really going across that toolbox to find the right transgene, the right cancer, the right route of administration so that we can really get first, or in this case with Penn, really go to get best in class therapies. So far, we've had great success, as we've shown with Fabre and Pompe in finding what we think is the right combination of those key attributes. And we have ongoing studies across the preclinical programs right now looking at different combinations of all of those factors. So we think that having the ability to do so is a great strength for that collaboration.

Your next question is from Anupam Rama with J.P. Morgan. Your line is open.

Good morning, guys. This is Tessa on the call for Anupam. Thanks for taking our question. Just wondering about the batting disease programs. Can you remind us of where you see timelines for dosing additional CLN6 patients with GMP clinical grade material and also similarly for the CLN3 program? Where are you with respect to manufacturing on the CLN3 program? Thanks so much.

Yeah, of course, Tessa. Thank you. So really the two key activities for both CLN6 and CLN3 have been on the manufacturing, both the scale-up as well as the production itself. And then, of course, all the analytical work necessary to support going into patients with not only commercial grade and quality material and scale, but also having all the analytical components in place so we can properly characterize it to support a BLA. That's been part of ongoing negotiations and discussions with the FDA. They provided very helpful feedback. From a manufacturing standpoint, we're in a really good place. and have commenced GMP manufacturing for both CLN6 and CLN3, the gating factor is going to be to ensure that we have all of those technical assays tightened up to the appropriate levels so that we could go into patients then, of course, with not only GMP-grade commercial-scale material, but as well having all the analytical assays in place. And again, it's not just us. I think you've seen this broadly across the gene therapy field, a tightening of standards. We saw this coming in the fall of 2019, so I think in many regards we've been quite ahead of the curve. Before we received any feedback from the agency, we were already planning on, you know, for instance, the potency assay, ensuring that that was in a very good place, as well as the tech transfer to Thermo Fisher Brammer for the GMP manufacturer. Obviously, all the tech transfer has been completed. There have been some improvements to the manufacturing process, but importantly, they've remained at the same scale. And again, we're in a really good place with our partnership with all the capacity we've reserved and the technical success we've had with the thermal fissure team.

Your next question is from Salveen with Goldman Sachs. Your line is open.

Good morning. Thanks for taking my question. If you could just elaborate a little bit more on your past comment here. Could you just talk about the broader build-out of manufacturing as you look to building out the gene therapy portfolio, not just from the, you know, external work with Brammer, but maybe whether you're looking to build internal, you know, an internal-based manufacturing platform here?

Yeah, thank you, Selvine. Bradley, do you want to talk about our strategy for gene therapy manufacturing?

Yeah, Selvine, it's a great question. As you know, the first step as we moved into this space was to secure, we think, world-class partners for external manufacturing. We did that with Thermo Fisher Brammer. We secured our cathode supply for multiple years and have a very flexible arrangement, and we're doing a lot of work. with our partners at Penn and a number of other collaborators to continue to work on next-generation manufacturing platforms. But the good news is, for the first part of our portfolio, which is the CNS-delivered portfolio, there we, as John, I think, mentioned in the previous question, we've made great progress in working with Thermo Fisher to be able to support the next studies in CLN6 and CLN3. From a medium-term perspective, we're actually well underway towards building out our own internal clinical GMP manufacturing facility. And that facility is state-of-the-art, designed to support both the adherent platform that will support our CNS programs, but also have flexibility to support process development for a suspension-based manufacturing platform as we look towards Pompeii and other systemically delivered gene therapy programs. That'll be a really important part of our capability and capacity to support our pipeline going forward. And in the long term, we think building our own commercial manufacturing could be a strategic asset. And so we would look to do that to continue to support the ongoing growth of our gene therapy portfolio.

Your next question is from Mohit Bansal with Citigroup. Your line is open.

Great, thanks for taking my question, and congrats on your talk with the FDA regarding APGAA. Maybe a question, a big picture question on gene therapy. So last year, within the last 12 months or so, we have seen a lot of challenges for gene therapy programs, be it regulatory or even from efficacy and safety point of view. So with that in mind, given that you are at the cusp of entering into clinics with the Pompe and Fabry. What is your updated understanding in terms of regulatory requirements? It does seem like that FDA is a little bit more cautious about diseases where there is an existing drug out there. And also, from the safety and efficacy point of view, what's the bar and how you are deciding on which drugs for diseases to go after? Thank you.

Yeah, thanks for the big picture question, Moet. I think it's a very important one. You know, when we came into the world of gene therapy for amicus, it really was an evolution, building on our experience in genetic medicine with Gallifold, with biologic development and complex biologic manufacturing with ATGAA, and then also our experience in the broad global regulatory field. paradigm. What we wanted to make sure is that we not only selected the appropriate diseases, but we brought the right technologies to bear. We, like Jim Wilson, were very strongly of the view that high-dose systemic AAV delivery was not appropriate, in fact, could actually be quite dangerous for patients. So part of the thesis of the collaboration between UPenn and Amicus was, again, that we need to be mindful of the protein that's being expressed by the gene therapy vectors and technologies. So if we at Amicus can engineer the appropriate transgenes, again, customized to each disease area, to each molecule. So, for instance, in Febre, a focus on stability in plasma as well as targeting. In Pompe, a focus on targeting so that you're not just transfecting liver cells and hoping to get lots of expression that eventually gets taken up. We think that could be not the most efficacious and potentially an unsafe way to deliver gene therapy. What we wanted to do is to combine the technologies from the two organizations to enhance efficacy and potentially to enhance safety, all the while being mindful of manufacturability. And I think Febre is an excellent example where we think we have a very unique molecule with very distinct preclinical data that could potentially be very efficacious, very safe, and actually could be manufactured at a reasonably small scale, which, of course, gives us lots of advantage in terms of investment needed to bring it to market, ultimately where the price points, where flexibility we may have there. I'll just comment briefly on the regulatory paradigm. I will tell you that continues to evolve. It is a very different world. And we started to see this change in mid-2019 through the second half of 2019. I think the agency was preparing to provide substantial guidance to gene therapy developers throughout 2020. They did to the extent that they had capacity to, but of course, CBER was significantly overwhelmed by the COVID crisis. So I think that's taken longer to develop. We really were with our core technologies and strategic approach, and I think forward-looking to the regulatory paradigm that was changing, I think we'll see that we'll be in a very, very unique place with respect to both Febre and Pompeii and other systemic delivery programs that we have in development. And I'll just maybe conclude that with the CNS delivery programs, a lot of the challenges that we've seen on safety, on targeting of cells, on delivery, on manufacturing, with the CNS programs we have, they inherently I think, are better advantaged in terms of the technical feasibility of addressing each of those. And I think that's reflected in the success, including the safety, that we've seen for both our CLN3 and CLN6 programs. So you asked a big question, so you got a big answer.

Your next question is from Daigon Ha with FIFO. Your line is open.

Good morning, guys. Thanks for taking the question and congrats on the quarter. I guess two quick clarification questions from us on the ATGAA side, John. So with regards to the, I guess, for the ATGAA filing, can you remind us where the manufacturing sites are for that drug material? And secondly, it's a very basic question, and forgive me if it's too basic, but Now that you're dealing with a modified ERT that's somewhat recognized as an approved drug and you're also using Miglustat, does the combination approach that you're employing in ATGAA warrant an adcom? Thank you.

Great. Thanks, Dagon. With respect to ATGAA, again, we think we're in a very good place from a CMC perspective. That'll be one of the final parts of the BLA. The manufacturing currently is in Wuxi Biologics facility in Wuxi that's already been inspected by FDA, previously undergone the PAI inspections. They are also in the final stages of constructing a large commercial facility outside of Dublin in Ireland, and that will come online next year, and that will increasingly be an important part of the commercial supply. So early on, we see a dual supply, both China and Ireland, providing that product. With respect to our having both an ERT and a chaperone component, of course, that does, and we've stated this along the way, this will require both a BLA and an NDA, and we have no indication whatsoever that that would lead necessarily to an adcom.

Your next question is from Joseph Schwartz with SCB Link. Your line is open.

Great, thanks very much. Hello, amicus team. I was wondering if you could expand a little bit on the topics that were discussed at the pre-BLA meeting. Were there any in particular that seemed to be more de-risked than others? Any review issues that you think the FDA might be still have to grapple with? And then will you need a pre-NDA meeting, just to clarify based on the last comments that you just made about both components of ATGA?

Sure. Thanks, Joe. Just on that, the answer is no, we don't need a pre-NDA meeting. One meeting suffice to cover both the large and the small molecule. I'll just comment that the meeting itself was excellent in tone. It was collaborative. It provided us all the feedback we needed to ensure that we have the strongest submission. With respect to will there be review issues, I'm sure there will be. I've never known a BLA that didn't have review issues. So I think yes, but we feel very confident that the data package we have, together with the breakthrough therapy designation, certainly the unmet need in the community. And again, I think this was a really important step forward, having this formal pre-BLA meeting, receiving the written minutes, being aligned with the FDA. on the BLA submission. And again, that submission will go into the FDA by the end of June. And we're fully prepared to bring that product to as many patients as quickly as possible.

Your next question is from Dejit Chattopadhyay with Guggenheim.

Hi, good morning, team. This is Robert for Dejit. Thanks for taking our call. My question today is around how confident the team is on first pass approval for ATGAA. And if you've had any feedback from the EMA on a potential M&A submission with the existing data set. Thank you.

Yeah, thanks, Robert. I'll just say that we continue to be highly confident in ATGAA's approvability. And with respect to the MAA, we're already engaged with the MAA, the authorities, and we're on track and on our timeline for submission in the second half of 2021.

We have a follow-up question from . Your line is open. Hi.

Thanks, guys. I'll make this pretty quick. John, you mentioned that the adolescent study is ongoing. and that you plan on starting the infantile study soon. Can you, I guess, one, give us an update on when that adolescent data might generate first efficacy data? I guess, for perspective, I'm wondering if it might generate efficacy data during the review cycle of the original BLA and if it might constitute a supplemental submission, and then just the design of the infantile study as you're thinking about it to start this year. Thanks.

Sure, Ritu. Of course, the adolescent study we had begun enrolling last year was the one clinical program at Amicus where we did see an effective COVID in delaying or deferring some enrollment. So we'll see a pickup in enrollment. It's a reasonably small study. Unlikely that we'll get all the data from that during the review period, so I think that will come just after what we would expect to be the approval of ATGAA and the late-onset Pompe disease population. So likely the expansion of the label would be part of the, I think, a relatively straightforward supplemental BLA submission. In the infantile study, again, we're not yet prepared to disclose that, full nature of that study, but it'll be reasonably small. It will not be a controlled study, so nobody will have to go to, we don't believe, certainly not to a placebo or to a competitive product, and that we'll continue to evaluate the start of that study here over the next couple of months, but we expect it to start in the next quarter or two, and I'll just remind everybody that it's a very important part of the Pompe population. It's also a very, very small part relatively of the Pompe population, but very important that we study it. And I'll remind people also, too, that we already have treated a number of infants under our expanded access or compassionate use protocol, and we will expect actually to have that data on a rolling basis just to provide some more color of the effect under the expanded access protocol of the medicine on infants.

There are no further questions at this time. I would now like to turn the conference back to Mr. John Crowley, Chairman and CEO, for closing remarks.

Great. Thank you, everybody, for listening. Thanks to all the analysts for the excellent questions. Again, very important quarter for us in Q1 and Q2. We see an equally important quarter for us as we move forward on our mission this year. So thanks, everybody. Have a great day.

Ladies and gentlemen, this concludes today's conference call. Thank you and have a great day.