Amicus Therapeutics, Inc.

Good morning, ladies and gentlemen, and welcome to the AMACUS Therapeutic Full Quarter 2020 Fiscal Year Results Conference Call and Webcast. At this time, all participants are in 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 phone. As a reminder, this conference is being recorded. I would now like to turn the conference over to your host, Mr. Andrew Fawning, head of investor relations. You may begin.

Good morning. Thank you for joining our conference call to discuss Amicus Therapeutics' full year 2020 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 Castelli, Chief Development Officer. Joining for Q&A will have Dr. Hung Do, Chief Science Officer, and Dr. Mitchell Goleman, Senior Vice President of Clinical Research. 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. 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 a full discussion of such forward-looking statements and risks and uncertainties that may impact them, we refer you to the forward-looking statements and risk factors section on our annual report on Form 10-K for the year-ended December 31st, 2020, 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 2020 results conference call. Yesterday, February 28th, marked the 14th annual World Rare Disease Day. The goal of this day each year is to raise awareness with policymakers and the public of rare diseases and their impact on the lives of the millions of people and their families living with any one of the more than 7,000 rare diseases. If you're on this call, you care about amicus and our mission, and you have an interest in rare diseases. I'd encourage you to go to the website, rarediseaseday.org, and learn more. including a moving and creating video of six heroes from six continents, all living with a rare disease. The impact of these diseases is always so personal. The need for new or newer and better medicines is so great. Yesterday morning, I sat down at my computer to edit these remarks today. I opened first an email from our team in Europe that let me know of the deaths earlier yesterday of a brave young woman living with Pompe disease. Her name was Rosella Passero. She was 21 years old and living in Naples, Italy. I first came to know of Rosella when she was two years old in the fall of 2002. Her parents had chained themselves to the front gate of a hospital in Naples, Italy, begging for compassionate use of the then experimental enzyme replacement therapy that we were developing at Genzyme. I was running the Pompe program at the time, And Henry Tremere, with his compassion and wisdom, allowed us to send the experimental enzyme to Rosella. She was the first Pompe patient in the world to receive this ERT on compassionate use. And then in December 2018, while live on Italian television in front of an audience of millions a few days before Christmas, I had the honor and the privilege to meet Rosella in person for the first time. It was a moving experience, as you might imagine. We offer our prayers and our thoughts for Rosella and her family. This is the very human side of this business that we have chosen. Rosella's life, her spirit, sadly her passing, remind us of the great urgency with which we need new treatment options for everyone living with Pompe disease and all rare diseases, and we need them as soon as possible. So with that very important reminder of our mission, we'll turn now to Amicus Business. For Amicus, 2020 was a year of excellent growth and execution across all aspects of our business, including science, clinical, regulatory, and as you see, our commercial effort. As we continue to build one of the next great global biotechnology companies poised to impact people around the world living with rare diseases. 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 $261 million in 2020 revenue, the Gallifold launch continues to exceed expectations and coming in above our guidance range that was set out last year. The full year revenue represents performance across the global business. including new patient starts from both switch and treatment-naive patients throughout the year. Second, our key regulatory and R&D timelines remain on track. Following results from the Phase III PROPEL study of ATGAA in late-onset Pompe disease, we plan to complete the rolling BLA submission 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 continue to move it rapidly toward its regulatory submissions for approval. Within our gene therapy pipeline, we also continue to move forward our lead batten disease programs for CLN6 and CLN3, as well as our most advanced preclinical gene therapy programs. Announced for the first time this morning, our CLN6 program has been granted fast-track designation by the US FDA. This follows the EMA granting the prime designation to this CLN program in late 2020. Through our broad and important research collaboration with Dr. Jim Wilson and the University of Pennsylvania, we are highly encouraged by the preclinical data and progress from our Fabry Disease Gene Therapy clinical candidates. Given the data we have seen to date, this is the second program to highlight the capabilities and potential this collaboration can bring to people living with rare diseases. And third, the amicus cash position is sufficient to achieve self-sustainability without the need for any future dilutive financing. 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. Next on slide five, we'll set, again, our key strategic priorities for this year. We are well on track to achieve our five key strategic priorities for 2021, including 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 new markets. We look to achieve global product revenue of $300 million to $315 million this year, 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 continue into early this year. Second, we remain steadfast and passionate in our commitment to advancing ATGAA to global regulatory submissions as quickly as possible for the benefit of all people living with Pompe disease. Third, we are advancing our industry-leading rare disease gene therapy portfolio. 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. Fourth, in addition, we are progressing our manufacturing capabilities and capacity to build world-class technical operations to support all gene therapy programs. And five, 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, let me now hand the call over to Bradley Campbell, our President and Chief Operating Officer, to further highlight the Gallifold performance, Brad.

Great. Thanks, John. Good morning, everyone. As John mentioned, I'll now walk us through in more detail our Gallifold performance for the year. On slide seven, we give our global snapshot of the Gallifold commercial progress. And for the full year, again, total product revenue was $260.9 million, driven by strong patient demand, favorable reimbursement dynamics, and business continuity. Geographic breakdown of revenue during the full year was 180.8 million, or 69% of revenue generated outside of the United States, and the remaining 80.1 million, or 31%, coming from within the United States. And we would expect that split to continue to be roughly 70-30 as we continue to grow both parts of the business. Turning now to slide eight, Q4 was another strong quarter. the business continues to be incredibly resilient with patients added in all of our major markets. As we previously highlighted, with the resurgence of COVID in the fourth quarter, we did see some slowdown in new patient starts, which led to a lag time in Gallifold treatment initiation, and some of that continues into the new year. Importantly, though, our supply chain remains fully intact. Our customers have confidence they can access Gallifold, 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 their physicians. And most importantly, we continue to add patients in our key geographies coming into the new year. Of course, we'll continue to monitor the pandemic's impact and duration, but the good news is today, we are confident we will deliver on our guidance and see continued growth this year and going forward, and we expect the COVID impact to recede throughout the year. From a numbers perspective, you can see that 2020 sales increased 43% from 2019, which includes a 1% benefit from foreign exchange, From a true operational performance perspective, sales increased by 42% compared to last year. On the left-hand side, we show our quarterly performance over the past several quarters. And as we've mentioned in past calls, while we continue to expect strong growth versus the same quarter as last year, due to a variety of factors, the rate of growth from quarter to quarter is typically nonlinear. On slide nine, we've called out several of the drivers and metrics which will lay the foundation for continued growth in 2021. It starts with the momentum from 2020 where we finished with over 1,400 patients on Gallifold and opened up several new launch countries. These over 1,400 patients on Gallifold now represent 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 you see now that we've a global mix of about 60% switch and 40% of patients who are naive to treatment. As we've said previously, over the next few years, we'd expect to see that rate of switch in naive patients to be about 50-50. And in the long term, we expect to see that percentage reverse in favor of naive patient growth. All of that is underpinned by compliance and adherence rates that continue to exceed 90%, reiterating our belief that those patients who go on Gallifold stay on Gallifold. The value of Gallifold has also been well recognized by payers, with nearly 100% of insurance reauthorizations granted in 2021 with U.S. payers and a perfect track record of successful negotiation and renegotiation of reimbursement outside the United States. So our relentless focus on ensuring access to Gallifold continues. Turning now to slide 10, another important driver of growth for Gallifold is the continued geographic expansion As a reminder, Gallifold has received regulatory approval in over 40 countries around the globe and commercial sales in more than 30 of those today. In 2020, we added multiple new markets, including Poland, Iceland, Luxembourg, Argentina, and Greece to the list of countries with reimbursement for Gallifold. In 2021, we expect to add at least five additional countries to that list as we look to continue to expand access to those Fabry patients with amenable variants around the globe. Moving ahead to slide 11, I'll highlight our guidance for the year. Despite the recent COVID-related headwinds in certain geographies that we've already mentioned, demand for Gallifold worldwide has never been stronger now with queues of potential new Gallifold patients building in multiple geographies. We're confident in our guidance of 300 to 315 million in full-year global sales, which continues our strong track record of double-digit growth year on year. As part of that guidance, we project net new patient starts this year will be even greater than in 2020. And we expect this growth in patients and corresponding revenue to be weighted to the second half of the year as the COVID impact continues to ease. Given this dynamic, as well as the nonlinear quarter-to-quarter growth and ordering patterns that we've seen in previous years, we expect sequential growth from Q4 to Q1 to be relatively flat. Now in slide 12, with several years of performance behind us, we can confidently say we are on that path to 500 million sales opportunity in 2023. We expect to generate $1 billion in cumulative revenue over the next three years, which goes a long way towards funding our R&D and OpEx over that period. We also have even further confidence in the $1 billion revenue opportunity at peak as we continue to see significant growth in the Fabry market globally, driven by continued diagnosis from high-risk screening, newborn screening, and other diagnostic initiatives, which we're investing in as well. In fact, if you didn't get a chance, I'd recommend that you See the posters and presentations at the World LBN meeting in February that highlight two great new initiatives that we've sponsored, screening for Fabry and idiopathic pain populations in Germany, as well as some exciting new work using AI, artificial intelligence, to improve diagnosis of Fabry here in the United States. Finally, we have orphan exclusivity in the U.S. and in 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 continued opportunity to provide access to Gallifold globally for a long period to come. And with that, let me turn the call now over to Dr. Jeff Costelli, our Chief Development Officer, who 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 14, we'll start with ATGA, our novel next-generation therapy for Ponte disease. Before we provide a recap of the recent Phase III PROPEL data and building on John's earlier comments, it's important to recognize the significant unmet need that remains today in Pompe. In addition to the individual human tragedies, we've seen multiple publications in natural history studies of Pompe patients that all highlight the initial benefit of treatment that is followed by continued long-term decline on key measures of disease. Highlighted here on slide 14 is a very recent study of 68 adult patients from Spain, Taiwan, Italy, and Germany with Pompe disease who were on the approved enzyme replacement therapy for at least three years. This real-world study shows an initial benefit from the ERT in the first few years with a secondary sustained decline in multiple outcome measures. Specifically highlighted here are six-minute walk and FEC. And you can see that the weakest efficacy is actually for the lung capacity. and consecutively driving the need for additional ventilatory support over time. The authors go on to note that respiratory insufficiency is the most frequent cause of death in Pompe, as well as recognizing the need for new treatment options for these patients. Before we go into the data, a key point to remember is that the ERT experience population described here on slide 14 has only ever been studied in a controlled setting in our phase three Propel clinical trial. All other controlled late onset Pompe disease studies have been in participants that are naive to ERT treatment. With that as background, we will move to slide 15 to review some of the key data from the COOPEL study. As a reminder, this was a double-blind randomized study assessing the efficacy and safety of ATJA in adult treatment naive and ERT switched participants against the currently approved therapy. We enrolled 123 patients at 62 sites in 24 countries. 117 patients completed the study, and all 117 have voluntarily enrolled in the extension study and continue to receive ATGA as their only disease-modifying treatment. On the primary endpoint of six-minute walk distance, patients on ATGA outperformed those on aglucosidase-alpha in the overall population of ERT-experienced and ERT-naive patients with a difference between groups of 14 meters. This difference did not reach statistical significance for superiority. However, on the first key secondary endpoint, a percent predicted force vital capacity, or FDC, in the overall population, ATGA showed a nominally statistically significant and clinically meaningful difference for superiority versus the proof state of care of leucocytes alpha. with a difference of 3% and a p-value of .023. This is a really impactful finding, as this was the main endpoint upon which agglucosidase alpha was approved, and as mentioned earlier, progressive loss of pulmonary function is the leading cause of mortality in Pompe. Moving ahead on slide 16, the data here captures the 95 ERT-experienced patients, those who have been on therapy for an average of seven years and most similar to the patients described in the publication I mentioned earlier. We saw that EDRT-experienced patients switching from aglucosidase-alpha to ATGA walked approximately 17 meters farther than those remaining on aglucosidase-alpha, with a P equal to 0.046. In these patients switching from aglucosidase-alpha to ATGA, we also saw an improvement in percent predicted FDC compared to a decline in patients remaining on aglucosidase-alpha with a difference of 4.1% and a p-value of 0.006. Slide 17 presents a summary of the top-line efficacy and biomarker data, grouping the data into domains of motor function, muscle strength, pulmonary function, patient-reported outcomes, and biomarkers. And here you can see that the totality of data across the primary and key secondary endpoints favor ATGAA over aglucosidase-alpha in both the overall and ERT experience populations. Moving on to slide 18, we first want to remind everyone that the PROPEL study tested for superiority versus an approved therapy, not placebo, and that the bar for approval of the second product generally requires demonstration only of non-inferiority to approved therapy. As shown earlier, ATGA demonstrated nominal superiority on the first key secondary endpoint of FVC over approved therapy. On slide 18, we show here post hoc non-inferiority analyses for the primary endpoints of six-minute walk and the first key secondary endpoint of FEC, just as referenced. As you can see, these non-inferiority analyses are highly significant. The non-inferiority test for FEC was pre-specified in the SAP, but was only to be conducted if superiority was missed on both six-minute walk and FEC. Thus, this analysis did not need to be performed as we hit on nominal superiority, which by default also indicates non-inferiority. A non-inferiority analysis for six-minute walk was not pre-specified in the SAP because obloquacities alpha historically did not demonstrate a significant improvement on the endpoint of six-minute walk, which impacted interpretability of a non-inferiority analysis. However, as shown here, post hoc demonstration of non-impreordained six-minute walk is clearly apparent across a range of clinically reasonable margins. Based on the totality of the data, moving to slide 19, we see ATGA having a leading position in the treatment landscape for Pompe disease. Here we have our next step surrounding the development, regulatory, and manufacturing strategy for the ATGA program. First, 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 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 will look to expand our ongoing open-label adolescent study in children aged 12 to 17, And additionally, 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, otherwise known as expanded access, that we received for children with infantile onset Pompe disease, our expanded access programs for Pompe infantile patients and adult onset patients are open and have enrolled multiple patients. Further expanded access for all Pompe patients is being considered. Moving on now to slide 21, I will briefly highlight our industry-leading portfolio of gene therapies for rare diseases. Several amicus presentations were given at the World Symposium Conference in February, covering our CLN6, CLN3, and Fabray gene therapy programs. Our Fabray program continues to advance ahead of schedule with an amicus transgene engineered for stability combined with a University of Penn gene transfer technology and the data presented at World further validates this innovative and synergistic approach. We continue to make progress across our preclinical gene therapy programs at Penn and expect further updates and data this year. As a reminder, as part of this collaboration, amicus has rates to 50 plus diseases, including seven currently inactive preclinical programs. On slide 22, and previously presented at World, just in February, we captured the initial results from the first in-human study of our CLN3 Batten disease gene therapy. CLN3 Batten disease is one of the most common neurodegenerative disorders affecting children, which leads to blindness, motor impairment, learning difficulties, epilepsy, and ultimately premature death. The primary outcome measures are determined using the physical impairment subscale of the unified Batten disease rating scale also called UBDRS, which is a clinical rating instrument developed specifically to assess disease progression in children with CLN3. And it includes evaluations of gross and fine motor skills, vision, and speech. Higher scores indicate greater physical impairment. As seen on the right hand of the slide, for the three subjects treated in the low dose cohort, the mean yearly rate of change in UBDRS physical impairment score was stable with only an increase of .07 over those 12 months. A favorable measure versus the almost three point increase expected in untreated patients based on published natural history of over 82 children that were followed. On safety, the treatment was generally well tolerated with the majority of adverse events being mild or moderate and unrelated to treatment. There were no patterns of AEs related to AAD or CLN3 immunogenicity that were observed. For this program, we look to advance the manufacturing and regulatory discussion and plan to submit the protocol for the next clinical study to the IND by the end of the year. With that, I would like to now turn the call over to Daphne Queney to review our financial results, guidance, and outlook. Daphne?

Thank you, Jeff, and good morning, everyone. Our financial overview begins on slide 23 with our income statement for the full year ending December 31, 2020. For the full year, we achieved Gallifold revenue of $260.9 million, which is a 43% increase over 2019. This includes a year-over-year operational revenue growth measured at constant currency exchange rates of 42%, further benefited by a positive currency impact of 1%. Cost of goods sold as a percentage of net sales was 11.9% in the year as compared to 12.1% for the prior year period. Cost of goods sold as a percent of revenues decrease was due to the proportion of sales in countries subject to a higher royalty burden. Total operating expenses were $476.8 million in 2020, increased as compared to $464.3 million in 2019. On a non-GAAP basis, total operating expenses were $415.7 million in 2020 as compared to $411.8 million in 2019. The increase in research and development costs reflected our continued investment to support the gene therapy program pipeline and the Propel study, as well as realignment with our strategic priorities. Our investment in research and development includes the impact of implementation of cost reduction measures, as does the decrease in selling general and administrative expenses. 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 2020 was $276.8 million, or $1.07 per share, as compared to the net loss of $356.4 million, or $1.48 per share, for the prior year period. As of December 31, 2020, we had approximately 262 million shares outstanding. Turning now to slide 24, following our $400 million senior secure term loan facility in the third quarter, we are on a path to self-sustainability without the need for any future dilutive financing. We have achieved this milestone by our continued revenue growth with Gallifold, as well as driving efficiencies, cost savings, and careful expense management. Securing this financing with market-setting terms gives us a strong financial platform to advance both patient and amicus shareholder interests. For the third straight year, we expect total non-GAAP operating expenses in 2021 to remain relatively flat from 2020, as we leverage the global commercial infrastructure that is already in place for the ATGAA launch and other products in our pipeline. and as we transition the costs associated with the 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 the gene therapy portfolio 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 equivalents and marketable securities were $483.3 million at December 31st, 2020, compared to $452.7 million at December 31st, 2019. We are issuing our full-year GalaFold 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. Thank you, Daphne and Jeff and Bradley as well. So as you can see, we have been relentlessly focused on performance across the business, despite the unprecedented change and challenges brought about by the global pandemic. We have a great global team of passionate entrepreneurs at Amicus who have led and will continue to lead us through this. And I am confident that as the world emerges from the COVID crisis, amicus will emerge even stronger. With that, we're happy to take questions.

Ladies and gentlemen, if you have a question, please press star and then the number one on your touch-tone phone. At this time, we ask that you only ask one question. If you have additional questions, please enter back into the queue. If your question has been answered, you may remove yourself from the queue by pressing the pound key. Thank you. Your first question comes from the line of Kazin Ahmad with Bank of America.

Hi, guys. Good morning. Thanks for taking the time. Hi, Kazin.

Morning.

Hi, John. Just maybe can you frame for us some expectations in terms of upcoming catalysts as it relates to Pompeii and the competitive landscape? So the fantasy has a May 18th PDUFA coming up for NEO. And can you just walk us through how we should think about the competitive landscape depending on the type of label that they get? Is it your expectation that they will get a full label, meaning inclusive of switch patients? And what would that mean if they're first to market? And then the second scenario is if they just end up with a label for treatment naive patients, how do you think that portends for your application that's going to be completed around the same time. Thank you.

Sure. I really can't comment much on the NEO product or its regulatory pathways. I will say, of course, it was studied in a controlled fashion only in treatment-naive patients, and I think that's a very significant distinction between what we studied in a majority ERT switch population. So for us, you know, we remain focused. on completing our U.S. regulatory submission, the BLA submission, by the end of the second quarter. And then again, as we've said to Zane, we'll continue the filings throughout 2021 in Europe and beyond. In addition to that, we continue all of our preparations for additional clinical studies in infants and children that are ongoing. We continue our compassionate use program. So there's a lot of activities, a lot of milestones ahead in the next six to 12 months for amicus. And that's where we remain focused. I think our data speaks for itself in terms of the impact on patients who are ERT experienced, particularly those who have been on for many, many years. The vast majority of the Pompe patients treated in this current billion-dollar-plus market have been on the approved medicine for a number of years. And some of the most powerful data that we've shown is in that ERT switch population, particularly those patients who have been on now more than two years again, which is the vast majority of the population. So I've got great confidence in the community, the Pompeii community. These are incredibly talented and experienced physician scientists who will be driven by the data, and the data will carry the day.

Your next question comes from the line of Ritu Barra with Cowan.

Hi, guys. This is Amrita on for Ritu this morning. So ADGA... What additional secondary analyses might be forthcoming at medical meetings this year that could probably help further the drug's profile and differences from your GAA? And then if I can just slip in one more question, what gives you more confidence like what you're going to negotiate for CLN6 pathway with the FDA would also translate to CLN3 or vice versa? Thanks for taking your questions.

Sure. So two different questions there. We'll take the first one on Pompe. What additional secondary data do we expect? You know, we continue to run multiple secondary analyses looking at a range of the secondary endpoints that were pre-specified in the study. And as we do that, we have continued and increased confidence in ATGAA and its impact on these patients. Jeff, do you want to comment on what people could expect ahead at medical conferences? Jeff, I think your phone, I think if you talk to the phone. Sorry, thank you, John.

That's okay. Thank you. That's all right. As John mentioned, it really will be focused on looking at the additional secondary endpoints. So the top-line data really focused on the primary endpoint plus the predefined key secondary endpoints. So we'll have additional measures of motor strength, motor function, muscle strength, pulmonary function, PROs, And really looking to see that those additional measures continue to show the same pattern that we've seen in the primary and key secondaries, which is the vast majority of all these endpoints favoring APGA, showing general improvements from baseline. And we think that as we see more and more of those endpoints all showing that same directionality supporting the main endpoints, that that will strengthen what we've seen. We'll continue to also dig into, you know, subpopulations, patients that have been on ART longer or shorter periods of time, but really the key data we believe we did disclose, you know, in the top line, so we don't see anything that's going to dramatically change that one way or the other. It'll just be supportive in nature.

And then, Jim, maybe if you just want to tackle, I'm sorry, operator, if you just want to tackle the CLN6 part of the question, kind of where we are there and some key activities ahead.

Yeah, so CLN6, you know, we continue to follow the 13 kids that have been treated now over two years post-gene transfer. We continue to be really excited by the stabilization we've seen versus the expected decline in natural history. We've been really working hard on all the GMP manufacturing, engaging with regulators to define the next clinical trial and look to here in the second part of the year to start that next study up. dosing kids by the end of the year with that GMP material made at Thermo Fisher. So really a lot of manufacturing and regulatory interactions this year leading up to that clinical protocol starting to dose additional children.

Your next question comes from the line of Anup Rahom.

Hi, guys. Good morning. This is Tess on the call for Onupom today. Just one from us on the commercial side. What are the core countries of geographic expansion for Gallifold in 2021, and what are the considerations for deeper penetration versus geographic expansion? Thanks so much.

Great. Thank you. Bradley, I'll let you go ahead and field that, please.

Sure. Yeah, we're not giving specific countries just from a competitive perspective, but I can tell you the areas of most geographic growth continue to be Latin America, Asia Pacific, and then Middle East, North Africa countries. And as I said, we're expecting over five to come online from a reimbursement perspective this year, so lots of growth there. Remember, too, from a geographic expansion perspective, there are a number of countries that we've only launched in in the last year or two. Japan and the U.S., frankly, continue to be high-growth countries, but also those newer launch countries, which individually are relatively small but collectively become substantial growth drivers. And I would say it's kind of a third, a third, a third. Part of it is continuing to switch patients in markets where we've been launched and Part of it, as I mentioned, is continuing to find new patients and supporting a growing number of initiatives to do that. And then part of it is, just as we talked about, the geographic expansion. The last point I'll add is that as the numbers, I think, are just being reported, the Fabry market today passed $1.6 billion in global sales, including our product, which is, I think, well on the way to a $2 billion-plus market. And so not only are we confident in our path to that $500 billion milestone, but we're also looking forward to continue to grow past that towards that billion-dollar opportunity.

Your next question comes from the line of Salveen Richter with Goldman Sachs.

Thank you for taking our question, and good morning. This is Elizabeth on for . Just wondering when we may expect, you know, Pompe and Fabry gene therapies to enter the clinic. We're looking for, you know, some updates here. And then we're seeing the competitive landscape grow and the dynamics emerge specifically for Fabry gene therapy. Maybe could you remind us of some areas of differentiation from competitors here? Thank you.

Yeah, that's actually maybe a great place to start with our February gene therapy. Again, this was jointly developed by the Amicus science teams and Jim Wilson and his team, again, combining the protein engineering experience at Amicus with the vector technology and experience at the Wilson Lab at UPenn. And maybe, Hung, if I can ask you just to describe, remind everybody again, what we released back in November, again, what was highlighted at the world meeting just a few weeks ago, Because it is a very unique approach, and we think a very differentiated data set in Febre disease. So, Hung, if you'd comment on the Febre gene therapy that we've developed, and then Jeff, I'll turn it to you for development activities and timelines.

Sure, John. Hi, Salim. So, I think the main distinguishing feature for our Febre gene therapy approach is that The protein that's actually produced from the gene therapy is made as a dimer. That's to say it's comprised of two identical subunits, and they need to be bound together for it to be functional. The reality is that protein is actually not very stable, and therefore it actually starts to fall apart and becomes inactive. What we have done is to engineer the transgene so what actually is produced maintains that dimer structure, so it maintains its activity. end result is actually the protein that's made is much more stable and much more potent. And so, therefore, we're able to achieve significantly greater in vivo efficacy while producing the same amount of protein relative to the wild type constructs. So, Jeff, let me turn it over to you in terms of talk about the development of timelines.

Sure.

Thanks, Tom.

Based on that great science that Hung just described in Fabry, and then also remember for Pompe, our transgene there was engineered for optimized uptake into cells. Those IND candidates with amicus engineered transgenes using Penn's proprietary capsid technologies are declared as IND candidates in ongoing two paths of development. One is focused on the IND enabling toxicology work, and the other is on the CMC process development work to get GMP material for that first clinical trial. Those parallel paths are ongoing. What is likely to be rate limiting is the manufacturing there. We intend to go into those next clinical trials with material from something that is as close to possible as our commercial process. And as we have more clarity on the timeline to that manufacturing GMT material, we'll provide updates on the specifics on the IND, but we're making really good progress on both paths across both programs.

Great. Thank you, Jeff. Elizabeth, I'll just add, too, for the February gene therapy market, I think it's very exciting for February patients that we're finally starting to see, after so many years, some of these February gene therapies come into the clinic. Obviously, a very different range of technologies with different burdens, frankly, on patients. We do see in the decade or more ahead for gene therapy in febrile disease. There will be a role. We do think it would be most applicable, certainly in the early years post-approval, to non-amenable patients, those patients for whom only enzyme replacement therapy is their choice. We do think for patients with amenable variants, those patients on Gallifold that they would be the last to adopt a Febre gene therapy, given the nature of Gallifold as an oral precision medicine, the convenience, and its profile. So we're committed to Febre gene therapy. We think we have a very differentiated approach, and we look forward to taking it into the clinic ahead. And we do know, though, in Febre, especially given the approved therapies, you know, these will certainly be robust development programs for anybody in this field.

Great, thank you.

Your next question comes from the line of Mohit Benzel with Citigroup.

Great, thanks for taking my question. Just one question on the guidance. So if I look at the year-over-year growth in 2021, and even at looking at the upper end of $315 million, you're guiding for a 21% annual increase. However, from this point to 2023 guidance of $500 million plus, it calculates to about 26% CAGR. So just wondering if you could help us understand what goes behind this acceleration of growth assumption there. Thank you.

Yeah, Mohit, thank you. Good to talk with you. I'll ask Brad to field that. I'll just say up front again to remind everybody, continued growth, great demand continues. We do see the building queue of patients. And we see much of that growth then being alleviated post-COVID. We expect, you know, beginning in the mid-year with particularly strong growth in the second half of this year into 2022. So, Bradley, I'll ask you to provide more context and color there, please.

Yeah, John, I think that's right. I think, you know, we are assuming a second half recovery this year from some of the challenges of COVID that we saw at the end of last year. and we do see some acceleration coming out of that and expect that to continue as we get towards that $500 million milestone. You know, you continue to see diagnosis rates increase. The overall market is growing. We're continuing to launch in new countries, so lots of opportunity to sort of take advantage of that acceleration going into the next few years and really continuing to grow beyond that. Again, as I mentioned earlier, we see this as a potential to grow upwards of $1 billion based on all the dynamics we're seeing, so... What we know is that demand continues to be strong, that patients continue to stay on Gallifold at that over 90% compliance and adherence rates, and we continue to focus on those three growth drivers I mentioned earlier.

I hope that's helpful, Moet. Thank you.

Your next question comes from the line of Joseph Schwartz with SBB Learing.

Hi, I'm Jury dialing in for Jo. Thanks for taking our question. I just wanted to ask you a question on your gene therapy program for Pompe. I was just wondering if your strategies for your Pompe gene therapy program has changed based on the heterogeneity of the patient population and your Propel results. You know, could you talk about how you plan to achieve what you envision for this program?

Sure. Thanks, Marie. I'll just say that it hasn't changed in view of Propel. Obviously, Propel and all the clinical work and published studies continue to inform the development program for Pompe gene therapy. Again, to remind everybody, Pompe gene therapy has been in development in the field broadly for well more than 20 years. When we came to this in Pompe, we wanted to bring a different approach, again, reminding everybody that our technology is to engineer the transgenes. to allow for maximal targeting to muscle of the protein expressed by the gene therapy, which will lead not only, we believe, to better efficacy, but potentially improve safety and obviously much more manufacturable of a product. So in that regard, the core technology and the core focus remains the same. I'm sure there'll be continued learnings as we move ahead. We're considering the patient populations all the way from infants through adolescents to adults as well. And that development program is something we're working on in earnest now.

Your next question comes from the line of Kristen Cluster with Cancer Fixed Jail.

Hi, good morning. Thanks for taking my question. Hi, Kristen.

Good morning.

And, John, thanks for sharing your experience with Rosella and for all the work your team is conducting for these patients with rare diseases. So the question I have here is, As you continue to advance your gene therapy pipeline forward, could you remind us which indications you think there are already established natural history data in place? So, for example, you were able to demonstrate the improvements for CLN6 and CLN3 batten disease in light of your understanding of the natural course of these diseases. So, to that end, are you also thinking of conducting any other natural history studies for some of the earlier programs?

Yeah, I'll turn it to Jeff. Thank you, Chris. That's a great question. It's going to be very important in all of these neuro programs to have robust natural histories. Jeff, do you want to comment on kind of where we are with both CLN6 and CLN3, and then more broadly how we think about natural histories as comparator arms for development here?

Sure. And hi, Kristen. So in the bat diseases, there's a pretty, depending on the subtype, the amount of existing natural history data varies. There actually is the most natural history data already currently available. A lot of it collected prospectively with that UBDRS endpoint. We are going to supplement all of that natural history. We have already started up our own natural history study across the batten subtypes to collect both retrospective and prospective data. So we think, you know, for batten diseases, that would be a key part of our development path for CLN6, 3, as well as they get into CLN1 and other subtypes. As you look at some of the earlier programs, you know, CD Cal 5 deficiency disorder, for example, you know, that's a relatively new disease. The natural history data is a little bit less, but we are already looking to start work there, working collaboratively with others in the community to start to work on some of that natural history. And then NPS 3A and 3B, similarly, there's some data that's out there and will continue to, early on in development, start to supplement those efforts and try to pull together natural history, we think it's a key part of development for these ultra-rare diseases. As you look at our February Pompe programs, obviously there we think that there's lots of data, but we think controlled trials will be needed for new gene therapies. So a little less focus, obviously, on that front. But for the early programs, it's something that we think is critical to address early in the development programs, building on what the community is already doing.

Your next question comes from the line of Debjit Chattopadhyay with Guggenheim Securities.

Hi, guys. Good morning. This is Aaron on for Debjit. So just a couple of quick questions. Any interactions from the agency on Propel study and considering the stats plan accounted for evaluation of FVC at a second endpoint, was the significance level specified any different than the usual 0.05?

Yeah, just on the first part, again, our plan remains to complete the BLA submission by the end of the second quarter, and we don't comment on ongoing regulatory discussions. And I just want to be clear on your second. Maybe, Jeff, just remind people of FDC, its importance, and what we saw there, both in the overall population and the switch population.

Yeah, so Propel was designed as superiority versus approved therapy. Primary endpoint was six-minute walk. The first key secondary hierarchically was FEC. What we demonstrated was nominal superiority with that key value below 0.05 that we showed. We had other endpoints as well in the study. As I mentioned in the slide we covered on the post hoc non-inferiority, We'd also pre-specified some non-inferiority analyses on FDC, which we actually did not need to formally conduct as we hit on nominal superiority on that first key secondary of FDC.

At this time, I would like to turn the conference back to Mr. John Crawley, Chairman and CEO, for closing remarks.

Great. Operator, thank you. So, again, 2020 was a great year. We've got a lot of work ahead of us here still in 2021, but I want to reassure everybody that you've got, again, a passionate team of entrepreneurs at Amicus who remain relentlessly focused on our mission. So, thank you, everybody. Have a great week.

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