Amicus Therapeutics Inc (FOLD) 2022 Q4 法說會逐字稿

Good morning, ladies and gentlemen, and welcome to the Amicus Therapeutics Full Year 2022 Financial Results Conference Call and Webcast. (Operator Instructions) As a reminder, this conference is being recorded.

I would now like to turn the conference over to your host, Mr. Andrew Faughnan, Vice President of Investor Relations. You may begin.

Great. Thank you, operator. Good morning, everyone. Thank you for joining our conference call to discuss Amicus Therapeutics' full year 2022 financial results and corporate highlights.

Leading today's call, we have Bradley Campbell, President and Chief Executive Officer; Daphne Quimi, Chief Financial Officer; Sebastien Martel, Chief Business Officer; and Dr. Jeff Castelli, Chief Development Officer. Joining for Q&A is Dr. Mitchell Goldman, Chief Medical Officer; and Ellen Rosenberg, Chief Legal Officer.

As referenced on Slide 2, 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 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, 2022, to be filed the Securities and Exchange Commission today.

At this time, it is my pleasure to turn the call over to Bradley Campbell, President and Chief Executive Officer. Bradley?

Great. Thanks, Andrew. And welcome, everyone, to our full year 2022 results conference call. I'm pleased today to highlight the progress we've made across our business throughout 2022 and now into the start of 2023. As we did in this morning's press release, let me highlight several key points.

First, Galafold continues its strong performance and remains the cornerstone of our success. We continue to be very pleased with the strong demand for and growth of Galafold globally, with now over 2,000 people living with Fabry disease, taking Galafold as their only treatment for Fabry. What an amazing milestone for this precision medicine.

And despite the significant foreign currency headwinds experienced throughout last year, in 2022, we reported Galafold revenue growth of 8% or 16% on an operational or constant currency basis. Throughout last year and into this year, we continue to see strong trends across a number of our key performance indicators, including increasing demand through new patient starts from both the switch and naive populations, continued growth in in-person visits between our field teams and Fabry treaters throughout the world and sustained patient compliance and adherence rates of over 90%.

In 2023, we expect to see continued double-digit Galafold growth fueled by significant demand from patients and physicians. We're also pleased by the growing Galafold intellectual property estate through the issuance of 19 new patents over the last year. There are now a total of 46 orange book-listed issued patents related to Galafold in the United States, 30 of which provide protection to 2038 and beyond.

And importantly, this includes 5 composition of matter patents. We see this patent portfolio, along with our orphan drug exclusivity, providing broad and long-term intellectual property rights well into the late 2030s for this novel precision medicine.

Second, we continue to make progress on our global regulatory filings and commercial launch planning for AT-GAA, our novel 2-component therapy for Pompe disease. We are thrilled today to announce the U.S. FDA has scheduled the required pre-approval inspection of the WuXi Biologics manufacturing site in China during the second quarter of this year.

Pending completion of a successful inspection we anticipate the regulatory approval and launch of AT-GAA in the United States will be during the third quarter of 2023.

Additionally, in Europe, we're on track with the regulatory reviews by both EMA and MHRA on the marketing authorization applications for AT-GAA. As a reminder, in December, the CHMP adopted a positive opinion of cipaglucosidase alfa to be marketed as Pombiliti with the European Commission approval expected this quarter.

We anticipate a CHMP opinion for miglustat, the enzyme stabilizer component of AT-GAA in the second quarter of this year. And as a reminder, the EMA has indicated that it does not require an inspection of the WuXi manufacturing site as a condition of their approval.

In the U.K., the regulatory submission process for AT-GAA was initiated in December and is on track for an expected approval in the third quarter this year.

As we've observed throughout 2022, we continue to see significant interest in participation in our expanded access mechanisms for AT-GAA globally. Programs are now in place in the U.S., United Kingdom, France, Germany and Japan, with a growing number of patients participating in each.

Across all of our ongoing clinical studies and expanded access programs, we're now over 195 patients on AT-GAA today, which we believe represents more than 5% of the total treated Pompe patients around the world. We expect this number to continue to grow as we approach approvals in the United States and Europe and beyond.

In anticipation of these approvals in the near-term, our global launch plans continue to move ahead, including our prelaunch activities, targeted investments and additional personnel and capabilities to support the launch and ongoing investments in building launch inventory.

We're closer to reaching this much anticipated milestone of getting AT-GAA across the regulatory finish line and providing another treatment option for people living with Pompe disease in the United States, Europe and the United Kingdom with further regulatory applications planned in the months ahead.

And third, Amicus has maintained a strong financial position, as we continue to execute on the global expansion of Galafold and prepare for the global launch of AT-GAA. Importantly, based on the projected strong growth of Galafold, our latest assumptions on approvals and launch for AT-GAA, our current operating plan and continued careful management of expenses, we remain on track to achieve non-GAAP profitability, which we continue to expect in the second half of 2023.

And finally, just to round out the key highlights and progress we've made across our Fabry and Pompe disease programs, I do want to mention that we once again had a significant presence at the 19th Annual World Symposium held this February in Orlando, Florida. Amicus had 2 oral presentations and 11 posters highlighting data from our development programs in Fabry and Pompe disease.

Most notably, as Jeff will go into more detail later in the call, we represented for the -- excuse me, we presented, for the first time, encouraging long-term efficacy and safety data from the Phase III open-label extension study of AT-GAA in late offset Pompe disease, demonstrating consistency and durability of effect in patients now out to 2 years.

Also noteworthy, we provided the first results from our own FollowME Fabry Pathfinder's registry, showing stability in eGFR out to 3 years in that population, and this will be a key part of our efforts to continue to build body of evidence supporting Galafold.

Finally, on Slide 4, as we laid out last month, we are focused on achieving our key strategic priorities for 2023, including, number one, sustaining double-digit Galafold revenue growth of 12% to 17% at constant exchange rates, while delivering Galafold to more people living with Fabry disease with amenable variance in existing and in new markets.

Number two, we remain laser focused on securing ATGA regulatory approvals by the FDA, EMA and MHRA later this year as well as continuing to advance preparations for the respective anticipated launches. Given our experience and success with Galafold and our seasoned global commercial, medical and market access teams, we are fully prepared for and anticipate a successful launch of AT-GAA.

Number three, we will continue to judiciously invest in the advancement of our best-in-class, next-generation Fabry and Pompe genetic medicines and capabilities as well as our next-generation chaperone for Fabry disease.

And number four, as always, we will maintain a strong financial position as we carefully manage our expenses and investments on our path to non-GAAP profitability.

With that, let me now hand the call over to Sebastian Martel, our Chief Business Officer, to further highlight the Galafold performance.

Thank you, Bradley, and good morning to everyone on the call. I'll start by walking you through in more detail our Galafold performance for the year.

On Slide 6, as you can see, for the full year 2022, Galafold reported revenue reached $329 million, driven by strong new patient accruals, offset by significant foreign currency headwinds. The geographic breakdown of revenue during the full year consisted of $213 million or 65% of revenue generated outside of the U.S. and the remaining $116 million or 35% coming from within the U.S.

This is in line with the 2/3, 1/3 split that we expect as we continue to grow both parts of the business. We're pleased to see continued patient growth in countries like the U.S., Japan, Germany, Italy and the U.K., just to name a few of our key markets.

Turning to Slide 7. Our results for the full year highlight the strength of our global commercial efforts. The demand for Galafold globally continues to be incredibly strong with patients added in all major markets delivering operational growth rate of 16% over the same period in 2021 at constant exchange rates. The negative impact from foreign currencies was 8% in 2022. As a result, Galafold reported revenue growth was 8% for the full year.

In 2022, Galafold continued to be the fastest-growing treatment for Fabry disease globally and the greatest contributor to the global Fabry market growth. That's remarkable. I'm pleased to report that our monthly net new patient trends continues to increase, and the 3-month trend was the highest in the last 2 years.

And if you look at the growth in net patients on Galafold globally, which is perhaps the truest measure of the underlying business, we saw greater than 19% growth in patients on Galafold at the end of 2022 versus the same period in 2021, all indications of the continued and growing demand for Galafold.

As Brad mentioned earlier, we ended the year with more than 2,000 patients on Galafold, which is over half of the global market share of treated amenable patients. And while the global mix remains about 55% switch and 45% naive. In many geographies, we're seeing stronger uptake in naive populations.

So while we're achieving high market shares in countries where we've been approved the longest, there's still plenty of opportunity to continue to switch patients over to Galafold and to continue to grow the market as we penetrate into the diagnosed and treated and newly diagnosed segments.

All of that is underpinned by impressive compliance and adherence rates that continue to exceed 90%. This is really reiterating our belief that those patients who go in Galafold stay on Galafold.

Importantly, the value of Galafold continues to be recognized by payers, and we have continued on our strong track record of successfully negotiating and renegotiating reimbursement outside of the U.S. Our relentless commitment remains on ensuring access to Galafold for anyone who needs it.

What we've seen in the full year in 2022 is that Galafold uptake continues to track very well. And through the first 2 months of 2023, we're seeing those trends continue with growth across all our key markets.

Turning on to Slide 8. Galafold growth remained strong with $88 million in the fourth quarter. As mentioned on past calls, due to a variety of factors, including uneven ordering patterns and FX fluctuations, the rate of growth within the U.S. is typically nonlinear. We expect that to continue through 2023.

In the table on the right-hand side of the slide, we've provided you with a 5-year historical snapshot of the percent of Galafold sales that occur each quarter during a given year. We would expect a similar trend to occur this year. And so while we don't provide quarterly guidance, the historical breakdown is a very good benchmark for revenue distribution by quarter. As an example, we've also observed in the last 2 years that Q1 sales in the current year tends to be generally aligned with Q3 sales in the prior year.

Moving on to Slide 9. We know that there's a significant patient demand for Galafold, and that it has potential to surpass $500 million in annual revenue over the next few years. We anticipate sustained growth through 2023 to be driven by several key growth drivers: first, continuing to penetrate into existing markets; second, further uptake into the diagnosed and treated population; and third is expanding into new geographies and label extension.

As we just mentioned, all of these efforts are supported by solid compliance and adherence rates and positive reimbursement and access mechanism throughout the world.

I'm pleased to share that we're making continued progress on expanding into new markets. To name a few examples. We received last year market authorization in Turkey and are in the pricing and reimbursement process as we speak. We have submitted the marketing authorization applications in Hong Kong and New Zealand and hope to see those countries -- as new countries for Galafold in the near future.

We have successfully renegotiated pricing and reimbursement agreements for Galafold in countries like Italy, Spain, Poland, Switzerland and Iceland.

In the longer term, we continue to see significant growth in the Fabry market globally, driven by diagnosing patients through a variety of measures, including high-risk screening, newborn screening and other diagnostic initiatives, which we continue to support and invest in as well.

Also important to note, we have orphan exclusivity in the U.S. and in Europe, in addition to our now 46 orange book-listed patents that give us IP coverage into the late 2030s, which provides us the opportunity to give access to Galafold globally to patients who needed for a long time to come.

On Slide 10, we outlined launch preparations for AT-GAA as we are poised for another successful product launch. Amicus today has a presence in over 40 countries around the world, including all the major Fabry and Pompe markets. That team will be launching that the same that launched AT-GAA with only a handful of new FTEs needed.

We have experience across all areas that are needed for a successful drug launch, regulatory, commercial, supply chain, experience with payers, reimbursement and access and in addition and perhaps most importantly, key relationships with physicians. We're very confident in our world-class organization that we can leverage their experience and relationships and deliver AT-GAA to people living with Pompe disease around the world.

From the team, the medical education, the published Phase III data, our experience with reimbursement and access around the world and, again, all the strategic planning we've been doing together with building inventory with our partners at WuXi Biologics, we believe we are in a very strong position for a second successful launch for Amicus.

With that, let me now hand the call over to Dr. Jeff Castelli, our Chief Development Officer. Jeff?

Thank you, Sebastian. And good morning, everyone.

On Slide 12, we'll start with our AT-GAA program. We recognize that Pompe disease continues to pose a range of health challenges for people affected by the disease and having therapeutic choices is crucial. Pompe is a severe and fatal neuromuscular disease and one of the most prevalent lysosomal disorders. And multiple publications and natural history studies continue to highlight the initial benefits of treatment, generally being followed by continued long-term decline on key measures of disease for many individuals.

Moving on to Slide 13. As Bradley mentioned, we are very excited to now be anticipating potential regulatory approvals and launches into 3 of the largest Pompe markets in the third quarter of this year. Here on the slide, we've highlighted the status for our anticipated regulatory milestones this year by market.

First, in the EU, the European Commission approval of Pombiliti is expected in this first quarter, later this month. And for miglustat, we're making great progress on the confirmatory testing and are on track to submit those validated final data to EMA for an expected CHMP opinion in the second quarter, which would then be followed by EC approval in the third quarter.

And in the U.S., we've acquired pre-approval inspection of the WuXi Biologics manufacturing site in China, where cipaglucosidase alfa is manufactured, has been scheduled with the FDA for the second quarter and the anticipated approval of both components of AT-GAA in the third quarter, pending a successful inspection.

Finally, the regulatory submission process for AT-GAA in the U.K. was initiated in December via the recognition procedure based on the CHMP opinion, and we're on track for an expected MHRA approval also in the third quarter.

Moving on to Slide 14 to highlight our ongoing clinical studies and providing expanded access through multiple mechanisms that support the demand of AT-GAA. First, for the younger Pompe community, we continue to enroll the ongoing open-label study in children up to 18 years of age, living with LOPD, and are expanding into patients with infantile-onset Pompe disease ongoing throughout this year.

Importantly, in response to the many requests for treatment that we continue to receive for children living with both LOPD and IOPD, our expanded access programs continue to increase. We now have multiple expanded access programs in place in a number of countries around the world, including the U.S., U.K., Germany, France, Japan and others.

This includes the EAMS framework of which we previously announced that AT-GAA was granted a positive scientific opinion through the early access to medicine scheme by the U.K.'s MHRA. And we continue to see significant enthusiasm for AT-GAA under the EAMS mechanism with multiple physicians having requested access across the leading on Pompe's centers in the U.K. and dozens of patients now receiving this novel 2 component treatment. Since the positive scientific opinion, in December, interest and momentum for AT-GAA has grown, and we are pleased to be able to provide access to those who are eligible.

With this growth in our access programs, as Bradley noted, we are pleased to report that approximately 195 patients worldwide are now being treated with AT-GAA across our clinical extension studies and these expanded access programs. And worldwide experience with AT-GAA is growing with approximately 75 centers now currently participating in trials and access programs.

Moving on to Slide 15. As Bradley mentioned, as part of the growing body of evidence supporting AT-GAA, we just presented at the World Meeting last week, positive long-term efficacy and safety data from a global Phase III open-label extension of the PROPEL study of AT-GAA and late-onset Pompe disease.

As seen here on the slide, these latest data demonstrated consistency and durability of effect in patients after 2 years on the key clinical endpoints of 6-minute walk distance in FVC. And importantly, these results are consistent with the even longer-term 4-year data we've seen presented from our Phase I/II studies. And together, these really support the long-term benefit of treatment for people living with LOPD.

On the slide here, we're showing the results for the large subset of ERT experience patients, and we observed similar results for the ERT-naïve patients' group as well. We were also very pleased by the continued reduction in the key biomarkers of glycogen storage and muscle damage, suggesting a positive effect on muscle tissue, particularly in participants who switched from alglucosidase alfa to AT-GAA and the open-label extension.

This growing body of evidence from all of our long-term clinical studies gives us further confidence that AT-GAA has the potential to become the new global standard of care for people living with Pompe disease.

With that, I would like to now turn the call over to Daphne Quimi, our Chief Financial Officer, to review our financial results, guidance and outlook. Daphne?

Thank you, Jeff. And good morning, everyone. Our financial overview begins on Slide 17 with our income statement for the full year ending December 31, 2022.

For the full year, we achieved total revenue of $329.2 million, which is an 8% increase over 2021. This includes year-over-year operational revenue growth measured at constant currency exchange rates of 16% impacted by negative currency of 8%.

Cost of goods sold as a percentage of net sales was 11.7% in the year as compared to 11.3% in the prior year period. Total GAAP operating expenses increased to $502.8 million for the full year 2022 as compared to $477.5 million in 2021.

On a non-GAAP basis, total operating expenses were $413.2 million for the full year of 2022, as compared to $406.9 million in 2021, reflecting nonrecurring expenses related to the reprioritization of the gene therapy portfolio, offset by decreased program spend.

We define non-GAAP operating expense as research and development and SG&A expenses, excluding share-based compensation expense, loss on impairment of assets, changes in fair value of contingent consideration and depreciation.

Net loss for the full year 2022 was $236.6 million or $0.82 per share as compared to a net loss of $250.5 million or $0.92 per share for the prior year period. Driven by the revenue growth of Galafold and careful expense management, we continue to make progress towards our path to profitability in the second half of this year. As of December 31, 2022, we had approximately 281 million shares outstanding.

Turning now to Slide 18. We continue to operate from a position of financial strength, and our goal remains to achieve non-GAAP profitability in the second half of 2023, as defined in our press release. Profitability is dependent on a number of factors including, of course, the timing of approvals and the launch of AT-GAA.

Our full year 2023 non-GAAP operating expense guidance is $340 million to $360 million. The expected decrease in operating expense for 2023 as compared to 2022 will be achieved by continuing to drive efficiencies and prudent expense management, offset by continued investment in the global growth of Galafold and prelaunch and launch activities for AT-GAA. We will also incur certain nonrecurring costs for manufacturing to support the global launch of AT-GAA.

We expect to see a larger portion of our operating expense be allocated to G&A this year as we reallocate our resources to support launch of AT-GAA and the continued growth of Galafold.

In 2023, we may look to execute sales under our previously announced at-the-market or ATM equity program in a strategic and judicious fashion as we look to maintain a strong cash balance to appropriately fund our operations.

A few comments about our cash position and 2023 financial guidance. Cash, cash equivalents and marketable securities were $293.6 million at December 31, 2022, compared to $482.5 million at December 31, 2021. Our full year Galafold revenue guidance is revenue growth of 12% to 17% at constant exchange rates in addition to our non-GAAP operating expense guidance of $340 million to $360 million.

With that, let me turn the call back over to Bradley for our closing remarks.

Great. Thanks, Daphne, Jeff, Sebastian. As you can all see, we have been relentlessly focused on execution across the business. We continue to operate from a position of financial strength and remain on the path to profitability in the second half of this year. And we continue to advance the growth of our 2 franchises in Fabry disease and Pompe disease, which we believe can enable us to create sustainable long-term value and deliver life-changing therapies to people in need.

Operator, with that, we can now open the call to questions.

(Operator Instructions) And our first question comes from Anupam Rama of JPMorgan.

With the regulatory decisions coming here in 3Q, as you look at the Nexviazyme and Sanofi launch here, what are some key learning similarities, differences that you would highlight as we think about the AT-GAA launch curve?

Yes. Thanks, Anupam, for the question.

Look, for us, it really just comes back down to the data and the population we studied. We were really excited be able to present the long-term data both from the Phase I/II study as well as from our Phase III PROPEL study and the ongoing extension there.

We continue to believe that showing that impact in patients switching from enzyme replacement therapy is going to be the key differentiator for AT-GAA. And as we look at all of the demand for expanded access and those mechanisms that we discussed on the call, in particular, in the U.K., we think that patients and physicians are just really excited to have a new treatment option.

And we're thrilled now to have a clear line of sight to timing and to be able to move forward as quickly as if we can to approvals and then to the launch.

And our next question comes from Ritu Baral of Cowen.

The question itself is, how fast should we start booking revenues after we know of the inspection? I guess, of course, my question has 3 parts. One, how fast should we be thinking about approval after the inspection? Is it a week kind of thing? And how do we model changeover to commercial from the 195 patients that are in your expanded access programs across the world? And do you expect all of them to fall under the approved label time?

Yes. Thanks, Ritu. I'll try to hit all 3 of those.

So the first one is related to timing from inspection to approval in the U.S. What our teams estimate is that takes about 2 months to go through that process, and so that's why we've said the inspection is in Q2, and we expect approvals in Q3.

In terms of converting patients from clinical trials or expanded access to commercial product, our goal has been to do that within 90 days. And we saw that we were able to execute on those time lines with Galafold, and we have the same goals here.

In terms of numbers of patients within that kind of 195, again, that number, we think, will continue to grow. I would say there is a small portion of them who might be infantile-onset patients, but that would be a very small portion. I think the vast majority between the Phase I/II study, the Phase III study and then expanded access programs are going to be late-onset patients who fall within the anticipated labels. So I think the majority of those patients would be eligible.

And of course, not all of them are in the first 3 launch countries: U.S., U.K. and Germany. But certainly, the majority have. And just to give you a flavor of the distribution between regions, about 60 of those patients are in Europe, about 50 in the United States, about 40 in the United Kingdom, and the balance is rest of world. So hopefully, that gives you kind of a flavor of the numbers of patients.

And then in terms of revenue, look, I think what we've cautioned people is that will be a modest contribution to revenue this year. But I think you hit on the really important point, which is our job this year is to put as many patients as possible who are appropriate on to AT-GAA, of course, with the expanded access and ongoing extension studies, but then, of course, with the new commercial patients as well. So our focus is to maximize the number of patients on therapy, and that gives you a really strong run rate going into next year.

And our next question comes from Tazeen Ahmad of Bank of America.

Brad, just a simple one for me. So when you say that the inspection has been scheduled, does that mean that FDA kind of just decides who they want to send over? And that team just goes? Or does there have to be some process that includes, for example, the State Department needing to preclear it? Just wondering what the technicalities are on that.

Yes. Thanks, Tazeen, for the question.

At this point, what we understand from the FDA is it's kind of business as usual as it relates to the inspection. So of course, they'll need these and those kinds of things, but that process is underway. From what we understand, we feel very confident that they now have an inspection scheduled, and we'll be able to executing upon that inspection.

To give you an example, we have our own team members who are now going to China to visit the site, who haven't been able to get there for all the reasons we've discussed for a number of years now. So our understanding is that it's business as usual, and we should be very confident in those dates, of course, caveated by you never know what's going to happen. But I think where we are at this point, what we're seeing from our own team is that it's business as usual, and there's no special requirements in order for them to be able to execute the inspection.

And our next question will come from Ellie Merle of UBS.

Just in terms of maybe your pre-commercial work, how should we think about the uptake in the switches from Lumizyme or Myozyme relative to, say, switches from Nexviazyme, I guess, in the U.S.

And then, I guess, just what's the feedback from physicians on how often they see their Pompe patients and like whether patients might say called in, whether it has been to get Nexviazyme or whether it be to get AT-GAA given the potential approval?

Sure. Thanks, Ellie, for the question. Maybe I'll take a stab at the first one and then Jeff can talk to the kind of frequency of interactions with physicians and patients.

So in terms of who we would be targeting for our launch in the United States, where I think we anticipate a label for experienced patients. We would, I think, target any segment where physicians or patients feel like there's a need or an opportunity to try new therapy. And so for us, that could mean both the Lumizyme patients as well as the Nexviazyme patients.

And again, I would just -- the thing that we are most focused on is the unique data that we have with -- from the only study that's studied in a controlled-portion patients who are on enzyme replacement therapy switching to another therapy during that controlled phase, and we think those data will be highly differentiated and highly compelling for physicians and patients across the population.

Jeff, do you want to talk a little bit about the kind of frequency of interactions between physicians and patients?

Yes. Thanks, Brad. And thanks, Ellie. So physicians typically will at least see their patients every 6 months for a pretty comprehensive assessment. Obviously, it depends if they're getting infusions at the clinic. They may or may not see them more regularly if they're the ones doing the infusions. But that larger work-up every 6 months is really when they get a sense of how the patients are doing from the last kind of comprehensive exam they had.

So as Brad mentioned, physicians and patients are thinking about treatment changes. If they started a new treatment, they probably would go about 12 months before they make a final kind of call or a first call on whether they're doing well enough, they might consider a new treatment.

But as we've seen now, at least in the U.S., many of the patients from the Nexviazyme studies that have switched have been on treatment now for much over a year. So I think there is certainly an opportunity, we expect, from a labeling perspective, from a potential need perspective to have switches from both of the products that are available currently.

And Sebastian, maybe just give us a color for some of the distribution of reported sales for the product.

Yes. Ellie, just to add that as we look to the last quarterly sales reported by Sanofi, looking at the split between Myozyme and Nexviazyme, the vast majority of sales continue to be on Myozyme, 77% for the fourth quarter on a global basis. Outside of the U.S., this is actually a lot higher than that. 93% of sales were coming from Myozyme. Rest of World was 85%. And in the U.S., still 60% also still coming from Myozyme.

So the majority of patients by the time we launch will likely still be on Myozyme, I think the switch data that we have bodes well for the switch strategy we expect.

Thanks, Sebastien. Thank you, Ellie. Anything else?

Perfect.

And our next question comes from Joseph Schwartz of SVB Securities.

Thanks for the update. I was wondering, if you could comment on your Pombiliti launch readiness in terms of manufacturing supply. How much are you accruing? And is there any reason that any of the supply you're building ahead of the launch could not be used? And what's your strategy for continuing to build supply?

Yes. Thanks for the question. So we have, I think, prudently continued to manufacture AT-GAA. And I think we noted last year in our financials that Daphne highlighted quite a bit of an investment there, so we're on track to have significant supply for all of our anticipated launches. We feel really good about that.

We typically move products into country in advance. And so with the positive progress in Europe, I think we've talked about now being able to start the process of release testing around Pombiliti, which is the ERT there. And then likewise, in the United States, we've actually begun to move product here as well. So we feel really good about launch inventory.

Our overall supply strategy, I think we've described before, which is we have plenty of capacity and supply coming out of China to support the first year or 2 of launch. However, we, with our partners in WuXi, have already started the process of standing up the new facility in Ireland. And I think as we've mentioned before, we expect that capacity to come online in sort of the '24, '25 time line, and that would be really when you're starting to see the meat of the balance of Europe coming on board and starting to see some rest of world countries as well. And so that will become, I think, the primary source of capacity for the long-term manufacturer of the product.

So really -- feel really good about where we are today with a clear plan of how to continue to grow and support the globalization of the product launch.

And could you comment also (inaudible) multi-level extension studies. It's been to walk-through data as percent-predicted 6-minute walk rather than change from baseline as it was done previously. How does that change the interpretation if at all? And what impact did you hear in general from physicians who is all the data that you reported at World?

Yes, Joe, you faded a little bit. I think the question -- the first part of the question was in the way we display the data we presented as predicted value, excuse me, versus change from baseline. And then the second question was what was the response from the audience at World. I'll take the second one first, and then I'll ask Jeff to comment on the first one.

So I think overall, it was great to be in-person at World. As you can imagine, tons of activities with patients -- with physicians, excuse me, both in Pompe and Fabry. I think the overall receptivity was fantastic, and you continue to see new data coming out from our program.

And again, just being having a chance to interact in-person at the World conference was really exciting and energizing, and I think it really teases up well for the continued prelaunch activities headed into the third quarter.

Jeff, do you want to talk specifically about Joe's question around the change from baseline versus present-predicted and why that makes sense?

Yes. Sure, Brad. Thanks, Joe, for the question.

So you percent-predicted 6-minute walk is -- takes into account things like patient's height, but importantly, age. And as you go on longer duration of follow-up, it's pretty standard to use present-predicted and 6-minute walk to kind of account for the fact that over 2 years, over 4 years, patients are certainly aging, and that should be accounted for in the calculation of how far they should walk in 6 minutes.

So over a 1-year study like PROPEL, using meters makes sense. But as we go longer-term follow-up, I think you'll see across programs, people usually use percent-predicted 6-minute walk. We did report in the supplement at World, the meters data, and it looks very comparable to the present-predicted. It's just that, that's kind of the more standard way for long-term follow-up.

And as Brad said, I think we had a really positive reception to that data. We also had our 4-year data represented, which was very consistent, showing kind of the durability of effect in the Phase I, II out to 4 years and here in PROPEL over the 2 years.

And our next question comes from Dae Gon Ha of Stifel.

Congrats on the progress. Two-part question on the AT-GAA, if I may. Just thinking about your market research and your physician interactions, kind of curious, if you can maybe walk us through what the pre-Nexviazyme take was based on your data that's been generated in PROPEL as well as Phase III and post Nexviazyme. I just wanted to see if they have a different view there or what the evolution of that process is?

Second part is, now that you have the OLE data presented at World, maybe digging a little deeper on Joe's question, what's been for the physician feedback on the naive segment? What's been sort of the receptivity or willingness to try AT-GAA for the naive patients?

And then a separate question for Daphne. Understanding the pushes and pulls of the variabilities throughout this year, but if we think about modest contribution revenue-wise from AT-GAA. I guess how much -- or should we really be thinking about given that the second half non-GAAP profitability kind of also hinges on that progress? I hope that makes sense.

Okay. So thanks for the questions, first of all. So we've got sort of impressions of data pre and post, I guess, launch with Nexviazyme and then Jeff talking a little bit more about the different segments we showed at World, both the switch patients and naive patients. And then the I guess one last question to date around how AT-GAA revenue impacts our goals for non-GAAP profitability for the second half of the year.

So as it relates to the first one, honestly, I -- and I said it on the call, and I'll highlight it again here. I think the most differentiating data we have is in those switch patients, and I think that will continue to be a hallmark and a highlight of the labels that we have that we anticipate as well as the information we're presenting to physicians. And frankly, that's kind of regardless of what happens on the Nexviazyme side.

Again, we're the only company to have sponsored in the control arm of our pivotal study experienced patients switching from one enzyme replacement therapy to AT-GAA. And I think that's just a critical difference. The other thing, of course, we were really pleased to see was the consistency and the durability of those data as we now see the long -- 2-year data from PROPEL, and then as Jeff highlighted, the reprise of the 4-year data from the Phase I/II study. So I think that consistency and durability is also really important.

Jeff, do you want to talk quickly about the impact we also saw in the naive patient segments from the long-term extension? And then Daphne can get to the financial question.

Yes. Thanks, Brad. And thanks, Dae Gon, for the question. So as we think about the naive patients, as a reminder, in PROPEL, it was 80% about experienced patients and only 20% were naive. And in the naive group, we saw both the Lumizyme arm, and the AT-GAA arm performed better than any other arms we've seen in naive patients and other studies. They were very similar, kind of in the quite significant benefit we saw.

What we weren't heard by in the additional year of follow-up as we saw patients continue to show a leasability even increases on needs from that large increase they had. So the 2-year results in those naive patients combining sort of the Lumizyme and AT-GAA together or 2 years of AT-GAA are really quite remarkable in terms of the increases.

In FVC, because these patients had much higher baseline, we did see sort of both groups had that small decline. It was good to see that, that stabilized, whether that was a true decline or not in the original kind of conservations. But -- certainly, we're seeing really robust improvements in 6-minute walk and stability in FVC in those naive patients.

And from our Phase I/II, out the 4 years, we saw improvements in both 6-minute walk and FVC in naive patients that were maintained over the 4 years. So net-net, I think as physicians look at the data, certainly the bulk of our data is in the ERT experience, as Brad said, the more difficult-to-treat patients. And I think they assume that the benefits observed there would carry over to the naive, and then our naive data is also supportive.

So I think we offer a good value proposition for naive. We've heard positive feedback from physicians. Obviously, we'll see where the labels are in different geographies, and that could play a part in terms of prescribing for naive, but we believe we have a great value proposition for both experienced and naives.

Yes. Thanks, Jeff. Of course, I would remind folks that how this product is positioned will, of course, depend on which region and what the final labels look like. But I think all Jeff's points are very important. Daphne, do you want to speak quickly to the contribution of revenue from AT-GAA to the profitability goal?

Sure. So just to remind everyone that the profitability metric, biggest contributor to that will actually be Galafold revenue. I do want to remind everyone of that AT-GAA revenues will have a modest impact to definitely help profitability. But also just a reminder that once approved, the cost -- production costs will move from the P&L, so from OpEx, and move on to the balance sheet. So I think it's a combination of all of that. So yes, the approval is key, but it's -- it will impact the P&L in a couple of different ways, not just from the reference.

Our next question -- excuse me, will come from Kristen Kluska of Cantor Fitzgerald.

This is Rick on for Kristen. We've just got one for you this morning. You previously mentioned mock inspections at the WuXi facility and the lead up to inspections. Have you been doing or planning any mock inspections at a part of the preparation? And is there any clarity based on what you heard from the agency on what to expect from the real inspection now that it is on the calendar?

Yes. Great question. So we were able to conduct a very successful mock inspection last year. Actually, we had a consultant who was on the ground who was from China, and then supported by our team here in the United States. So we feel really good about the status of WuXi, the manufacturing.

And I would just add a few other points that give us confidence in the outcome of that inspection. The first is that we've mentioned this before, WuXi -- the facility in WuXi, China is a well inspected facility from multiple agencies, both in-person and hybrid for multiple approved products. So they have a very successful positive history of inspections previously.

As you mentioned, we've done mock inspections and a whole host of pre-approval inspection activities. I said on the call, we're actually sending -- or actually to answer a question from the follow-up, we are sending our team over in the coming weeks. We will continue to help prepare and make sure everything is buttoned up.

We also -- as a reminder, a big chunk, and we talked about this during the review, a big chunk of the agency's review was on the manufacturing. So there are a whole host of questions that we've already answered satisfactorily for the agency. And then finally, we've pointed to the rich manufacturing history with our product itself. We've done dozens of successful manufacturing runs at commercial scale, under the quality key process parameters, critical quality attributes that are part of the overall quality control of the product.

So for all those reasons, we feel really excited and prepared for the inspection, and we're thrilled now that we have one scheduled and kind of have line of sight to what we hope will be the eventual approval.

And our next question comes from Jeff Hung of Morgan Stanley.

This is Katherine on for Jeff. We just had one. Can you remind us of what confirmatory analytical testing was requested by the EU regulatory authorities for miglustat? And just as a quick follow-up. What kind of risk, if any, is there that it could take longer for a CHMP opinion?

Yes. Jeff, do you want to just give a little bit more color there what we've spoken to before?

Yes. Thanks, Katherine. We haven't disclosed exactly what the requested testing was. What we have said is it was something that during the submission we had provided in silico data, all sorts of sort of modeling to show that there was we've addressed all the requirements for regulations. What we got feedback was we need to have a test to actually measure for this confirmatory testing of these molecules.

So we -- as we said during the call, initially, we are well on track. We don't believe there currently is any risk to that time line gaps for the 4-month clock delay. We're on track to provide that validated data with a validated assay and to be on track for that CHMP opinion here in the second quarter.

And our next question will come from Salveen Richter of Goldman Sachs.

It's (inaudible) on for Salveen. I have 2 quick ones. Will you be updating the Street post the inspection of the WuXi site by the FDA? And can you provide any color on the pricing of AT-GAA now that we have a PDUFA date time line?

Yes. Thanks for the questions. So as it relates to the update from the manufacturing, as long as there's no material impact to our anticipated time lines, we won't provide any updates on the outcome of the manufacturing inspection. But of course, if there's a material change or impact, then we would provide that in due course.

As it relates to pricing, I think we've described previously is that we would continue to follow our pricing and access strategy and promise, which is parity or modest discount standard of care. Our focus is to maximize access to therapy, and we've found with Galafold that that's the best way to execute against that strategy and to maximize the number of patients who are eligible to receive therapy.

And our next question will come from Yun Zhong of BTIG.

On Galafold, the 65 versus 35 ex U.S. versus U.S. sales, is that mainly depending on -- or driven by the number of patients, given that it's been a few years after U.S. approval? And I was wondering, what could be the implication for AT-GAA? Do you think there could be any big differences in terms of disease prevalence depending on geographic regions? Can that can potentially impact your launch strategy for AT-GAA versus what you did for Galafold?

Thanks for the question. Yes, Sebastien, maybe talk a little bit about the distribution of revenue in Fabry and what we might expect based on current distribution of sales in patients for Pompe disease.

Yes. So the performance in the U.S. was very strong. Last year, we had a strong growth in the fourth quarter of 21.4%. We talked about the trends we've seen over the last 6 to 8 months in terms of new patient adds. We've also talked about, in general terms, about our market share within the amenable population. And the U.S. is one of these markets where we gradually see a greater proportion of naive patients contributing to growth. But there's still a fair amount of switches, probably more than some of the markets where we've been the longest like the U.K. or France, for example.

As we look at the split of revenues on a global basis, if you consider Pompe, there's a bit of a difference from a pricing standpoint between price in the U.S. and price in Europe. So overall, the U.S. market is the largest market. We see the Pompe market being made of about 40% of sales coming from the U.S., 36%, 37% coming from Europe and 23% coming from rest of world.

From a patient number standpoint, the actual number of patients treated, we estimate in Europe is greater than the U.S. We estimate north of 1,300 patients treated for Pompe within Continental Europe, another 200 from the U.K. And in the U.S., that compares with around slightly north of 800 patients. So I think that gives you the overall geographical split. So that highlights that the European approval, and the U.K. approval are also some very significant opportunities for us.

Our next question will come from Gil Blum of Needham Capital -- Needham Company.

A bit of a follow-up on earlier question about Lumizyme and Nexviazyme dynamics. Do you guys have any detail on how many of those new Nexviazyme patients are naive versus switch if at all?

A little hard to tease that out, and I don't want to speak on behalf of Sanofi, obviously. But we know that they're -- I'm sure in the United States putting on naive patients as well as switch patients based on their public commentary. And look, we believe that it's great for patients to have choice and for a new therapy to be out there, and so I think it's fantastic for the community that there are multiple treatment options. And now we're just eager to provide a third treatment option for patients. So a little tough to tell exactly what the distribution is, but I'm sure there's some component of that going on.

And Gil, something we've seen very much in the Fabry market as you see more players entering rare disease space, we also see stronger growth for the overall market. We need to keep in mind that those diseases are unfortunately significantly underdiagnosed and under treated.

So as you see Amicus coming to the Pompe market, you will see more efforts to raise disease awareness to support diagnostics initiatives and hopefully get overall more patients having choices of therapies.

And our next question comes from Zhiqiang Shu of Berenberg.

Sorry, I was on mute. Congrats on the progress. I was wondering if you can comment on the significance of achieving profitability in the second half and your confidence on maintaining that status going forward? And maybe related to that, wondering your thoughts on continued investment in the early stage of discovery programs?

Yes. Thank you for the questions. Look, I think from a profitability perspective, I think that's a really important milestone for any company who started as a preclinical research-based company and has now made it to launching our second product. So I think for Amicus, for our employees, for our investors, I think that's just a really important milestone.

We haven't given guidance yet on what that means in the long-term, but we certainly see ourselves continuing to be prudent in our financial use of resources, but also seeing our top line revenue continue to grow and hopefully now with the addition of a second product. So we'll talk more about kind of what that looks like in the future as we get closer to 2024. But the first step is, of course, getting there, which we're really excited for at the second half of this year.

And then -- yes, sorry, I was just asking my colleagues on the second question around investment in early-stage programs. Yes. So there, what we have said is right now, that is an outcome of the difference between the revenues we bring in, the expenses we have to support those revenues and then that goal of profitability. So this year, it's a very judicial amount of investment. However, we are answering key questions, I think, across each of those 3 programs.

Our goal would be to continue to make progress there over the course of this year, and I think you'll hear us towards the end of the year and start of next year begin to give better line of sight in terms of what our vision is for those programs. And we still very much believe we have differentiated transgenes in Pompe and Fabry and are very excited about the opportunity to deliver those effectively in those therapies.

And again, we also see the next-generation chaperone is a really important part of our commitment to continuing to develop medicines for Fabry disease. So more to come there. But right now, again, it's a very judicious, but I think appropriate portion of our investment.

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

Thank you, everybody. I appreciate the questions. Good luck for today.