Amicus Therapeutics - Earnings Call - Q1 2025

Executive Summary

• Q1 2025 revenue was $125.2M, up 13% reported and 15% at constant exchange rates; Galafold grew 5% (6% CER) to $104.2M and Pombiliti + Opfolda grew 90% (92% CER) to $21.0M.
• Primary EPS (non-GAAP normalized) was $0.03 versus consensus of -$0.052, a clear beat; revenue missed consensus of $136.3M by ~$11.1M as ex-U.S. order timing and a higher UK VPAG rebate weighed on the quarter.
• Guidance was adjusted: Total revenue growth to 15–22% (from 17–24%), Pombiliti + Opfolda growth to 50–65% (from 65–85%); Galafold 10–15% maintained; non-GAAP OpEx raised to $380–400M to include $30M DMX-200 upfront. GAAP profitability still expected in H2 2025.
• Portfolio catalyst: Exclusive U.S. license for DMX-200 (Phase 3 in FSGS) with modest upfront ($30M) and success-based milestones; FDA alignment on proteinuria as primary endpoint supports de-risked path.

What Went Well and What Went Wrong

What Went Well

• Strong underlying demand: Galafold patient demand grew 14% YoY and reached ~69% share of treated amenable patients; U.S. Galafold up 18% with record patient counts in Australia.
• Pombiliti + Opfolda momentum: +92% growth at CER; net new patients and prescriber depth increased; first patients started in newly reimbursed markets (Sweden, Switzerland), with Italy, Czech Republic, Portugal, Netherlands ramping in Q2.
• Strategic expansion: In-licensed DMX-200 U.S. rights; FDA aligned on proteinuria primary endpoint; transaction structured with tiered royalties and success-based milestones.

Management quotes:

• “While some unexpected factors impacted revenue in the quarter, the key performance indicators for both products are very strong and we remain on-track to achieve GAAP profitability during the second half of 2025.” — Bradley Campbell, CEO.

What Went Wrong

• Revenue miss vs Street: Reported net sales $125.2M vs consensus $136.3M, driven by ex-U.S. order timing and higher-than-anticipated UK VPAG rebate (industry guidance 12–15% vs actual 22%).
• Pombiliti + Opfolda guidance reduced: Patient starts in new launch countries shifted right; VPAG headwind in UK; growth guidance lowered to 50–65% at CER for 2025.
• Currency and FX sensitivity: ~60% ex-U.S. revenue; 1% USD move ≈ ~$4M revenue impact, adding volatility to reported results.

Transcript

Operator (participant)

Good morning, ladies and gentlemen, and welcome to the Amicus Therapeutics First Quarter 2025 Financial Results Conference Call and Webcast. At this time, participants are in a listen-only mode. Later, we will conduct a question-and-answer session, and instructions will follow at that time. As a reminder, this conference call is being recorded. I would now like to turn the conference call over to your host, Mr. Andrew Faughnan, Vice President of Investor Relations. You may now begin.

Andrew Faughnan (VP of Investor Relations)

Thank you, Travis. Good morning. Thank you for joining our conference call to discuss Amicus Therapeutics First Quarter 2025 Financial Results and Corporate Highlights. Leading today's call, we have Bradley Campbell, President and Chief Executive Officer; Sébastien Martel, Chief Business Officer; Dr. Jeff Castelli, Chief Development Officer; and Simon Harford, Chief Financial Officer. Joining for Q&A is Ellen Rosenberg, Chief Legal Officer. As referenced on Slide 2 of the presentation, I would like to remind you that we will be making forward-looking statements on today's call.

I encourage you to read the disclaimers in our slide presentation, the press release we issued this morning, and the disclosures in our SEC filings, which are all available on the IR portion of our corporate website.Forward-looking statements are subject to substantial risks and uncertainties, speak only as of the call's original date, and we undertake no obligation to update or revise any of the statements. Additionally, you are cautioned not to place undue reliance on any forward-looking statements. At this time, it is my pleasure to turn the call over to Bradley Campbell, President and Chief Executive Officer. Bradley?

Bradley Campbell (President & CEO)

Great. Thank you, Andrew, and welcome everyone to our First Quarter Conference Call. Before we get into the details with the backdrop of what has certainly been a tumultuous quarter in biotech, I thought it'd be valuable for me to frame the incredibly positive outlook we see for Amicus going forward. First of all, I'm very pleased to share that we have delivered yet another quarter of strong double-digit revenue growth on our core business in Pompe and Fabry. This is now our 11th consecutive quarter with double-digit sales growth, and we see that trend continuing for years to come.

Second, we were thrilled to have entered into a strategic collaboration with Dimerix that, for a modest upfront, brings into our pipeline the US commercialization rights to a first-in-class compound in late phase III development for a rare fatal kidney disease with blockbuster market potential. Third, we continue to strengthen and diversify our supply chain. Through prudent operations and planning, we were able to effectively neutralize exposure to any potential tariffs this year. We also announced today that we are onshoring a portion of our drug product manufacturing from Pombiliti to enhance our diversification strategy even further.

Fourth, while quarterly revenues for the Galafold and Pombiliti and Opfolda were impacted by some unexpected factors, we are highly confident in the acceleration in sales we'll see through the remainder of the year, resulting in combined revenue projections within 2% of our original guidance and yet another year of double-digit growth. Fifth, we reiterated our confidence that these two products, each with potential blockbuster sales at peak, will reach combined sales of $1 billion by the end of 2028. Finally, as we maintain our financial discipline, we reiterated that we are on track to achieve GAAP profitability in the second half this year.

Taken together, we are confident that what we have achieved this quarter leaves Amicus uniquely well-positioned to create substantial value for shareholders and deliver on our mission for patients. With that, let me hand the call over to Sébastien to dive into the business in more detail. Sébastien?

Sébastien Martel (Chief Business Officer)

Thank you, Bradley, and good morning to everyone. For Galafold, on Slide 5, you see that revenue reached $104.2 million, up 6% at constant exchange rates. The underlying growth of this product remains very positive, with the number of new patient starts globally up 14% in the quarter. This puts us on track to deliver the highest level of patient starts this year. We ended the quarter with more than 69% of the global market share of treated Fabry patients with amenable mutations. Galafold is clearly positioned as the treatment amongst prescribers, and there are still many more potential patients eligible for our therapy.

Turning to Slide 6, our leading markets continue to be the biggest driver of strong patient demand. The US contributed significantly to growth, and we reached a record number of patients on Galafold in Australia following the first-line listing. When we look at the global mix, which is about 65% naive and 35% switch, we're seeing stronger uptake in naive populations. We continue to achieve high market shares in countries where we've been approved the longest, but there's still plenty of opportunity to switch patients over to Galafold and to keep growing the market as we penetrate the diagnosed untreated and newly diagnosed segments.

Turning to the revenue impacts in the quarter, while the US grew at 18% this quarter, we observed non-linear order patterns ex US, and Q1 sales in the UK were impacted by the higher VPAS rebates than prior industry guidance had assumed. With underlying growth in patient demand at 14%, our projection of a record level of new patient stock this year, we remain highly confident in our full year 2025 growth guidance for Galafold. The key drivers behind the growing demand for Galafold, which we expect to continue well beyond 2025, are the following:

First, finding new patients and reaching the diagnosed untreated population, including shortening the pathway to diagnosis; second, expanding Galafold into new markets and extending the label; third, driving Galafold's share of treated amenable patients. We're actually seeing in our most mature markets that we can reach up to 85 to 90% share, so we know that there's the potential to reach those levels globally; and fourth, sustaining compliance and adherence above 90% rates so that patients who go on Galafold predominantly stay on Galafold.

With our strong IP protection, we think Galafold has a long runway well into the next decade and a clear path to surpassing $1 billion in revenue in the next 12 years. Turning now to Pompe disease on Slide 8, we outline our global launch progress with Pombiliti and Opfolda. In the first quarter, revenue reached $21 million, up 92% at constant exchange rates. The majority of growth was driven by three of our initial launch countries: the US, Germany, and Spain. The US represented approximately 45% of revenue and contributed to 65% of Pombiliti and Opfolda growth in the quarter.

Outside of the US, revenue growth was largely driven by Germany and Spain, with UK sales impacted by the VPAS rollback. We continue to see patients switching proportionally based on market share, as well as broadening and deepening of prescriptions, with more sites coming online and multiple new prescriptions from physicians. We expect the benefit of patient stocks in new launch markets to be weighted towards the second half of the year. Additionally, in the US, we anticipate sales to accelerate over the remainder of 2025 as the pool of patients eligible continues to expand.

We're already seeing some of this acceleration in the month of April, with the largest number of net new commercial patients globally driven by the US, as well as the largest number of countries with new prescriptions since launch. Despite this momentum, we do not expect that we'll be able to fully catch up with our prior 2025 guidance, and so that's why we're adjusting our full year 2025 revenue growth guidance for Pombiliti and Opfolda from 65% to 85% to 50% to 65% at constant exchange rates. Our revised revenue guidance implies a healthy exit rate heading into next year. We remain highly confident in the long-term outlook of this therapy.

We expect Pombiliti and Opfolda to be a major contributor to multi-year growth for Amicus based on key growth drivers, namely continuing to increase the number of net new patients, increasing the depth and breadth of prescribers, launching in new countries including up to 10 in 2025, differentiating our therapy through evidence generation and real-world evidence, and maintaining 90% plus compliance and adherence rates. Moving to Slide 9, looking at the geographic expansion of Pombiliti and Opfolda, we recorded revenue in Q1 in seven countries: the US, Germany, Austria, Spain, the UK, as well as Switzerland and Sweden.

Of the five recently reimbursed countries, two markets, namely Sweden and Switzerland, had a first patient start during the quarter. In Q2, we anticipate first patients in four more countries, namely Italy, the Czech Republic, Portugal, and the Netherlands. We're very pleased to share that Pombiliti and Opfolda was recently selected as preferred treatment for adults with LOPD in the Netherlands. This is a five-year agreement enabling broad and sustained access for adults with LOPD currently on enzyme replacement therapy. We also recently received regulatory approvals in Australia and Canada, and in Japan, our dossier is under review, and we anticipate approval later this year.

We're also securing broad patient access throughout the EU. Moving to Slide 10, I'd like to take a few moments to provide additional color on the actions we've taken to further strengthen our global supply chain and access to our medicines. Firstly, regarding tariffs, which we recognize are still evolving, we do not expect a material impact to our business operations this year due to our proactive supply chain planning and careful management of expenses. We already have our 2025 sales inventory inside the US. We've also been proactive in diversifying our global supply chain.

In addition to our second source of Pombiliti drug substance manufacturing in Ireland, we're announcing today a manufacturing and supply services agreement with Sharp Manufacturing. This agreement will bring a portion of Pombiliti drug product manufacturing to the US. With that, I will now hand over the call to Jeff to highlight the work we do to further differentiate Pombiliti and Opfolda.

Jeffrey Castelli (Chief Development Officer)

Thank you, Sebastian, and good morning, everyone. On Slide 11, we highlight a few examples from the rapidly expanding and diverse body of evidence supporting the differentiation of Pombiliti and Opfolda in Pompe. First, on clinical trials and long-term data, we continue to see differentiated durability of effect in our ongoing clinical studies, including long-term data from our phase II and phase III open label extensions, which reinforce the sustained efficacy and safety profile of Pombiliti and Opfolda. Second, on mechanistic and translational insights, emerging data continues to support the unique dual mechanism of action of our therapy.

This includes not only the benefits of the Opfolda stabilizer, but also the differentiated design of the Pombiliti enzyme alone, which offers increased Bis-M6P for greater cell uptake, together with retained proteolytic and N-glycan processing for maximal enzyme activity. These mechanistic features are increasingly recognized as key drivers of clinical outcomes. Third, on comparative and real-world evidence, real-world data from early access programs and treatment registries are showing consistent effects that mirror what we've seen in clinical trials, supporting both the efficacy and safety of Pombiliti and Opfolda in broader real-world settings.

Comparative analyses continue to also add important context for how our therapy performs relative to other ERTs. Finally, we're seeing a growing number of powerful and illustrative real-world patient stories. This includes individuals switching to Pombiliti and Opfolda from high-dose high-frequency Lumizyme, as well as those switching from Nexviazyme. These real-world transitions further reinforce the clinical value and differentiation of Pombiliti and Opfolda as perceived by both physicians and patients. Importantly, beyond what's shown here, we continue to actively enroll into our pediatric clinical trials, and enrollment continues to accelerate in the Amicus Pompe registry, which will generate invaluable additional real-world data on the long-term use of Pombiliti and Opfolda across broader populations and geographies.

Altogether, the strength and consistency of our data continue to give us great confidence that Pombiliti and Opfolda will continue to deliver meaningful and lasting impact for people living with Pompe. I'll now hand the call back to Sébastien.

Sébastien Martel (Chief Business Officer)

Thank you, Jeff. Moving to Slide 13, as we announced last evening, we took a major step forward in our strategy to strengthen our portfolio through a successful US licensing agreement with Dimerix to commercialize DMX-200, a first-in-class treatment in late-stage development for FSGS, a rare and potentially fatal kidney disease. This collaboration expands our late-stage pipeline with a potential best-in-class treatment and brings significant opportunities to leverage our regulatory, commercial, medical, and patient advocacy capabilities.

As a promising late-stage rare disease investigational medicine with blockbuster market potential, we believe this asset adds significant value to Amicus today and will create value for patients and shareholders. Slide 14 summarizes the transaction details. Dimerix will receive an upfront of $30 million paid from Amicus cash on hand. The deal is heavily weighted to success-based milestones, for which the next potential milestone payment would be for a positive readout from the phase III study. Dimerix would receive tiered royalties of US sales of DMX-200 that starts in the low teens up to the low twenties.

Dimerix will fund and execute the phase III study, and Amicus will be responsible for submission and maintenance of the regulatory dossier in the United States, as well as all costs of commercialization activities. Let me hand over the call to Jeff to give you more insights on FSGS and the ongoing phase III study.

Jeffrey Castelli (Chief Development Officer)

Thanks, Sebastian. First, I would like to again just reiterate how extremely excited we are to work with Dimerix on the further development of DMX-200 to bring this potentially transformative treatment to patients suffering from FSGS. Starting here on Slide 15, focal segmental glomerulosclerosis, or FSGS, is a rare and serious kidney disorder characterized by segmental scarring of the glomeruli, which are the filtering units of the kidney, proteinuria, which is the leakage of protein out of the kidney into the urine, and a progressive decline in kidney function, often culminating in end-stage renal disease.

The underlying causes of FSGS are various, including immune factors, genetic viruses, adaptive factors, but the key is that all of these converge on some podocyte injury that triggers then a pathogenic feedback loop of hemodynamic stress and inflammation that drives further fibrosis and progressive kidney damage. The average time from diagnosis to onset of complete kidney failure is typically in the five to ten-year range. In the US, FSGS affects more than 40,000 people, with about 5,000 new cases diagnosed each year.

There are currently no FDA-approved therapies, and standard of care includes nonspecific therapies like corticosteroids, calcineurin inhibitors, and angiotensin receptor blockers, none of which adequately address the monocyte-driven inflammatory component of FSGS. DMX-200 is an oral small molecule taken in combination with ARBs that target the monocyte-driven inflammatory component of the disease by specifically inhibiting the inflammatory signaling from angiotensin type 1 receptor and chemokine receptor type II heteromers that are on inflamed kidney cells.

Moving on to Slide 16, we're impressed by the strong momentum Dimerix has built and the growing body of evidence supporting DMX-200 in FSGS. Mechanistic data show that DMX-200 is a precision therapy targeting the monocyte-driven inflammatory feedback loop without broadly suppressing immune function. This is reinforced by compelling preclinical proof of concept data. Phase II studies across 80 patients have demonstrated encouraging efficacy and safety signals, with meaningful reductions in both proteinuria and inflammation shown in FSGS patients.

The pivotal phase 3 ACTION3 trial is progressing very well, with 185 of the target 286 patients enrolled. The study is very robustly designed and strongly powered. Importantly, there is also now FDA alignment on proteinuria as the primary endpoint for approval. Notably, the first interim analysis conducted by Dimerix last year after 36 weeks of treatment showed DMX-200 outperforming placebo in reducing proteinuria. Taken together, we believe these results strongly position DMX-200 to be a truly meaningful advance in the treatment of FSGS.

Turning to Slide 17, as I mentioned, ACTION3 is well underway. This is a global randomized double-blind placebo-controlled study of DMX-200 versus placebo in patients receiving ARBs, and they are followed for 104 weeks. Based on a successful meeting, as I mentioned, with the FDA just here in March, the primary endpoint of the study will be a change in proteinuria measured as urine protein to creatinine ratio, with eGFR slopes serving as a secondary endpoint. Subject to recruitment rates, which is going very well, full enrollment of ACTION3 is expected around the end of the calendar year.

An additional blinded interim analysis is also planned to occur once additional interactions have happened with PARASOL and with the FDA to align on the final primary and secondary endpoint parameters. With that, let me now hand the call back over to Simon, or sorry, to Simon to review our financial results and outlook. Simon?

Simon Harford (CFO)

Thank you, Jeff. Our financial summary begins on Slide 19 with our income statement for the first quarter ending March 31, 2025. For Q1, we achieved total revenue of $125.2 million, which is a 13% increase over the same period last year. At constant exchange rates, revenue grew 15%. The global geographic breakdown of total revenue in the quarter consisted of $75.2 million, or 60% of revenue generated outside the US, and the remaining $50 million, or 40%, coming from within the US. Cost of goods sold as a percentage of net sales was 9.3% for the first quarter, as compared to 12.3% for the prior year period.

Total GAAP operating expenses decreased to $121.5 million for the first quarter, as compared to $124.6 million in the first quarter of 2024, a decrease of 2%. On a non-GAAP basis, total operating expenses increased to $94.5 million for the first quarter, as compared to $85.6 million in the same period last year, an increase of 10%. We define non-GAAP operating expenses as research and development and SG&A expenses, excluding stock-based compensation expense, loss on impairment of assets, changes in fair value of contingent consideration, restructuring charges, and depreciation and amortization.

On a GAAP basis, net loss in the first quarter of 2025 was $21.7 million, or $0.07 per share, compared to a net loss of $48.4 million, or $0.16 per share for the first quarter of 2024. In the first quarter of this year, non-GAAP net income was $9 million, or a profit of $0.03 per share, compared to non-GAAP net loss of $4.6 million, or a loss of $0.02 per share in the same period last year. Cash, cash equivalents, and marketable securities were $251 million at March 31, 2025, compared to $250 million at December 31, 2024. On Slide 20, we outline our full-year financial guidance for 2025.

Total revenue growth guidance is updated to 15% to 22% from the previous 17% to 24%. We are reiterating Galafold revenue growth guidance of 10% to 15%. We are revising Pombiliti and Opfolda revenue growth guidance to 50% to 65% from the previous 65% to 85%. All growth rates are at CER. Gross margin is still expected to be in the mid-80s. We are updating our non-GAAP operating guidance to include the $30 million upfront license payment for the DMX-200 licensing. Non-GAAP operating expense guidance is therefore expected to be $380 million to $400 million.

We anticipate positive GAAP net income during the second half of 2025. As mentioned earlier this year, we anticipate 2025 to be a hybrid year for Pombiliti Opfolda COGS, as we expect to work through the previously expensed inventory during the first half of the year. As a result, we expect our gross margin to be in the mid-80% for the full year as we begin to recognize Pombiliti Opfolda COGS through the P&L later this year. In terms of operating expense, as a reminder, we continue to have R&D commitments, including registry studies in both Fabry and Pompe, the ongoing Pompe phase III study in countries not yet reimbursed, next-generation manufacturing process development for Pombiliti, as well as the DMX-200 upfront licensing fee. With that, let me turn the call back over to Bradley for our closing remarks.

Bradley Campbell (President & CEO)

Great. Thank you, Simon, Jeff, Sebastian. As we come to the end of our presentation, here is a reminder of the strategic priorities for the year, reflecting the updates from today's call. Before I conclude the discussion, I do want to take a moment to acknowledge Mike Kavanagh, he was our President of our US business at Amicus and retired at the end of Q1. Mike is a great friend and colleague who joined Amicus in 2018 to lead the US commercial team. And he has been a critical part of our success with Galafold, Pombilion, and Folda.

I want to thank Mike for his contribution to our mission and wish him so well in his retirement. By the same token, I also want to give a warm welcome to Gwen Whitney, who has succeeded Mike in this role. Gwen is an energetic and accomplished leader in the rare disease space, and I very much look forward to her help in driving the US business in the next phase of our growth. Finally, on the last slide, let me leave you the way I started. We are very pleased with the growing demand for both of our therapies and are extremely excited to bring in a promising phase III asset to our portfolio in an indication of significant unmet need.

I remain highly confident in our growth projections for the remainder of 2025 and for many years ahead, as well as our ability to deliver significant value for shareholders and for people living with rare diseases. With that, operator, we can now open the call to questions.

Operator (participant)

All right. Thank you. Okay. Ladies and gentlemen, if you have a question, please press star 11 on your touchstone telephone. At this time, we request that you only ask one question. If you do have any additional questions, please enter back into the queue. Thank you. Our first question today comes from the line of Anupam Rama of JPMorgan. Your line is now open.

Anupam Rama (Md & Senior Equity Analyst)

Hey, guys. Thanks so much for taking the question. Just one from me. Was there something particular noted in the VPAS assessments for both Galafold and Pombiliti and Opfolda that led to the rebate being a little bit higher than anticipated for both products? Thanks so much.

Bradley Campbell (President & CEO)

Yeah. Thanks, Anupam. You know, it's really frustrating. That's a negotiated rebate by the Industry Association in the UK, and they give guidance to industry of what to expect for the year. Our guidance was between 12% to 15%. We assumed the maximum of that rate, 15%, to be conservative. In the end, they came back with a negotiated rate of 22%, so almost a 50% increase in what we had anticipated. The challenge is, of course, that hits you in the quarter and then throughout the year, which is frustrating, but it is what it is. It's a one-time thing, and it's reflective of just a negotiated settlement with the government for all of industry.

There's a lot of coverage of that in the UK press, as you might imagine. I think we can confidently say with Galafold, we can make up for that based on the patient growth. You saw the revised guidance for Pombiliti and Opfolda.

Anupam Rama (Md & Senior Equity Analyst)

Thanks so much for taking our question.

Operator (participant)

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

Ellie Merle (Analyst)

Hey, guys. Tejas on for Ellie. I guess just in terms of the cadence of ex-US launches and patient starts, what has changed on your expectations there, and how much of that contributed to you guys taking down the Pombiliti guidance?

Bradley Campbell (President & CEO)

Yeah. Thanks for the question. I think there were—there's really two big elements there. The first is exactly as you said. You saw in previous slides as we came into the year, and then we reiterated here, we reached a number of reimbursement settlements at the end of last year and the early part of the quarter, and we had assumed those patients would start on therapy in the first quarter. Unfortunately, many of them started—only a handful started in the first quarter, and many of them are starting to start in the second quarter. That is really a timing thing. It kind of just pushes the curve to the right.

Unfortunately, we do have that impact of VPAS. As a reminder, the UK is one of our top three revenue markets for both Pombiliti and for Galafold. That ends up being a hit for the rest of the year. I would think of it mostly just based on what we're seeing and that acceleration that we've already started to see in April and that we expect to see in the back half of the year, just a shifting to the right. We have some great positives that we're seeing. We've already started patients now in Italy and Sweden and some other markets, Switzerland as well. That Netherlands first position, I think, will be a big growth driver for us in the second half of the year as well.

Ellie Merle (Analyst)

Yeah. I guess just a quick on the Netherlands, how much of that impact is just coming from Netherlands? Because I know you mentioned it in the first quarter, shifting to the right a little bit.

Bradley Campbell (President & CEO)

There are 150-plus patients, LOPD patients in the Netherlands, and they are, as we mentioned, we have now been awarded first position there. That is a significant opportunity. One of the challenges is that it is only one center in the Netherlands that is treating the majority of those patients. There is a bit of a bottleneck there that is taking a little bit longer to get started. Again, we very much look forward to seeing that play out over the back half of the year and beyond. I would orient you also to Sweden, much smaller patient population, however, similar outcome where we were awarded first position and were getting 80% or 90% of the patients there.

I think in the medium term, it is going to be a huge opportunity for us. Because of some of that kind of bottlenecking and getting started, those patients will fall into the second and third and fourth quarter.

Ellie Merle (Analyst)

Really helpful. Thanks.

Operator (participant)

All right. Thank you. Our next question comes from the line of Joseph Schwartz of Leerink. Your line is now open.

Joseph Schwartz (Md & Senior Biotechnology Analyst)

Great. Hey, all. This is Will on for Joe. Thanks for taking our questions today. I'll switch it up and ask about DMX-200. I guess on the licensing agreement here, it'd be a bit helpful to hear some more color on the diligence process and how you ultimately ended up settling on an asset in a rare renal disease and what provided you with the confidence of the asset's differentiation versus late-stage competition. Maybe how do you see this kind of fitting into the overall treatment paradigm if approved? Thank you.

Bradley Campbell (President & CEO)

I think you talked a little bit about the strategy, a little bit about the diligence, and then about the differentiation of the molecule. I'll start with maybe the first two and ask Jeff and Sebastian to add any color, especially on the differentiation, Jeff. First and foremost, you might remember as we came into finished last year and came into this year, what we described as our strategy was bringing into Amicus late-stage de-risked assets that we believed could meet a significant unmet medical need. We also talked about sort of how we would think about disease areas.

Of course, Fabry and Pompe remain center to our focus going forward, but we also talked about disease areas that could bring significant synergies. If you think about FSGS as a rare kidney disease, the endpoints, proteinuria, GFR, the call points, nephrologists, specialty medical centers, etc., very much synergistic with our capabilities and our team today. We really felt like both the structure of the deal, which was a modest upfront and then really success-based milestones going forward, as well as the strategic fit was sort of perfect for what we were looking for as our first deal to expand the portfolio.

In terms of diligence, of course, we looked very carefully through the data that was provided. We did a lot of market research, talked to physicians, worked very closely with Dimerix. It was a very, I think, collaborative process. What gave us particular conviction here from a diligence perspective was, of course, the phase II data, very compelling, the unmet need, very compelling. The interim analysis that Dimerix had previously shown that showed statistical favorability for proteinuria in that blinded analysis. That was a planned interim analysis that had already been conducted.

If you combine that with the very recent FDA meeting and meeting minutes that we saw confirming proteinuria as the primary endpoint, I think that gives us great confidence that this is, again, a highly de-risked asset and likely to succeed. Maybe Jeff just hit quickly the differentiation point on the molecule itself in FSGS.

Jeffrey Castelli (Chief Development Officer)

Yes. Thanks, Brad. I think one of the things we're really excited about here is the mechanism of action of DMX-200 and how differentiated it is. When you look at standard of care, when you look at some of the other development compounds, none of them are targeting this monocyte-driven inflammatory component of the feedback loop. A lot of them are focused more on controlling the hemodynamic side of things through A1TR or through endothelin. What DMX-200 is specifically targeting is the inflammatory signaling in the damaged kidney.

FSGS is a very diverse disease, lots of underlying causes, lots of drivers of the ongoing damage. I think what we're going to see is some patients are going to respond better if it's mainly a hemodynamic-driven challenge to ARBs or to new drugs like Sparsentan that are targeting that side of things. Patients that were really, it's that ongoing monocyte macrophage-driven inflammation that's really driving things, they might respond better to DMX-200. Down the line, obviously, I think there's room for complementary approaches here because all of the drugs are targeting different aspects of the disease.

You might see that actually in some patients, a combination of these approaches might work best ultimately. That sort of also feeds into how we see this fitting in. There's going to be some set of patients that respond better to one treatment than the other. I think you're going to see physicians sort of trying to figure out how to identify which patients are most likely to benefit from which treatment. Really with DMX-200, there are ways you can sort of look at how much the inflammatory component is driving things.

Those would be the patients that I think docs would—those are going to be the patients we are going to see respond best in the trials. Those are going to be the patients that I think doctors will want to focus on.

Joseph Schwartz (Md & Senior Biotechnology Analyst)

Excellent. Thank you.

Sébastien Martel (Chief Business Officer)

Thanks, Jeff.

Jeffrey Castelli (Chief Development Officer)

Maybe Seb, anything on the other strategy? No? Okay.

Operator (participant)

All right. Thank you. Our next question comes from the line of Ritu Baral of TD Cowen. Your line is now open.

Ritu Baral (Md & Senior Biotechnology Analyst)

Hi Bradley. This is Joshua Fleischmann on the line for Ritu. Thanks for taking our questions.

Bradley Campbell (President & CEO)

Hi Josh.

Ritu Baral (Md & Senior Biotechnology Analyst)

On DMX-200, even if UPCR is a fully approvable primary endpoint, what, if any, benefit in eGFR is FDA looking for besides the primary? Two, what timeline should we expect for the next interim analysis, which is gated by Parasol and FDA? Does nine months sound reasonable? Three, what have you seen to justify acceleration of US switches for Pombiliti in 2025? Thank you.

Bradley Campbell (President & CEO)

Great. Maybe I'll start with Pombiliti first, and then Jeff, you can speak to those other points. I think as Sebastian shared with you on the call, we're already seeing a significant acceleration in switches in Pombiliti and Opfolda in the United States and around the world just in the month of April. It was actually our best month for new commercial starts, not clinical trial conversions, but new commercial starts since we've launched. That's really exciting. Why are we seeing that? Part of it for sure is just the dynamic we had already talked about, which is more and more Nexviazyme patients entering into that two-year period.

I'll mention again that we saw in that period a majority of the switchers coming from Nexviazyme. We're winning that game. I think also part of it is what Jeff talked about, which is the growing body of real-world evidence. We presented for the first time, or one of our thought leaders did at a medical congress, case studies supporting the switch from Nexviazyme for the first time. That is, I think, really important real-world evidence that will continue to grow. I do think too, we've talked about this before. We've always seen Q1 as a sort of non-linear quarter in Fabry.

I think you may start to see that in Pompe as well. This could be a reflection of that. If you add in those kind of one-time factors we talked about, XUS, I think that kind of explains the quarter. Jeff, do you want to talk about FSGS and both the proteinuria, GFR feedback from the FDA, which is fantastic from the Type C meeting, and then also some of the early timelines that we have line of sight to?

Jeffrey Castelli (Chief Development Officer)

Yeah. Thanks. Importantly, the alignment with FDA was proteinuria as a primary endpoint for full approval, not accelerated approval within some other TBD endpoint like GFR for confirmatory, which we've seen now in other kidney diseases. I think what's really exciting is we're seeing FDA now move more and more towards recognizing proteinuria is so strongly tied to GFR decline and ultimate kidney progression that they're moving now more and more towards UPCR as the provable full endpoint. That's really driven by data in FSGS from the Parasol initiative.

That's 50 different researchers that have 1,600-plus FSGS patients. They've really been key in helping to show that tight association between changes in proteinuria and changes in GFR. In terms of what we need to see on GFR, it's really not any specific set statistical test at this point. It just looks like we need to have a secondary endpoint on eGFR that's showing supportive data, which we believe the design of the study is well designed to show. In terms of the interim analysis, the main discussion with FDA that Dimerix had was alignment on proteinuria as that single primary endpoint.

There also was some talk about potentially an interim analysis to support accelerated approval. That will require additional analysis of that Parasol data set, collaborating with Parasol, which will take about three to six months to conduct that work, then go back and meet with FDA, make sure there's alignment on all of the potential interim or accelerated endpoints, the full endpoints, and then conduct that interim analysis. I think nine months, as you said, could be in that ballpark. After we get through this three to six months, we can start to get more timing specifically about the next FDA interaction and when that interim might occur.

Ritu Baral (Md & Senior Biotechnology Analyst)

Great. Thanks, Jeff.

Operator (participant)

Thank you. Our next question comes from the line of Dennis Ding of Jefferies. Your line is now open.

Dennis Ding (Analyst)

Hi. Good morning. Thanks for taking our question. I had one on FSGS, specifically on the CCR2 mechanism. I appreciate that Dimerix had already had positive phase two and phase three interim, but ChemoCentryx failed the phase two a few years ago in FSGS with the same mechanism. Can you comment on what happened there, if there was a drug target or trial design issue, and how may the drugs be different this time?

Bradley Campbell (President & CEO)

Yeah. It's a great question. I think it's important that Jeff highlighted this, although maybe Jeff, you can provide just a little bit more color there. This molecule, DMX-200, is a differentiated CCR2 molecule, inhibitor molecule. I think it's very important to highlight those differences. Jeff, maybe share a little bit more of that color, specifically how it acts within the kidney.

Jeffrey Castelli (Chief Development Officer)

Yeah. Thanks. That's a great question. There have been CCR2 inhibitors historically that have been tried by several companies in different diseases, mostly to try to knock down monocyte-driven inflammation. The difference with DMX-200 is it's not a direct inhibitor of the binding of the MCP1, which is sort of the inflammatory signal to the CCR2 receptor. Instead, DMX-200 specifically acts downstream and blocks the signaling coming out of the A1TR CCR2 heteromer that's on in damaged kidney tissue that acts as the amplification for inflammation.

What happened with traditional binding inhibitors is MCP1 couldn't dock, and it actually led to a rebound effect where MCP1 levels dramatically increase, which then would compete with the inhibitor and kind of lead to a muting of effect. The beauty of the downstream blocking is that MCP1 can still dock. That leads to actually MCP1 degradation. The signal is stopped. We're actually seeing MCP1 levels come down with DMX-200 versus increase, which is really sort of the benefit of having that downstream targeting. We think that will really maximize the ability to shut down the monocyte inflammation.

The other great thing about that is it allows monocytes to continue their job elsewhere because we're not directly blocking the MCP1 binding to monocytes. They can still fight infections as they should outside of the kidney.

Dennis Ding (Analyst)

Great. That's very helpful. Thank you.

Bradley Campbell (President & CEO)

Thank you for the question.

Operator (participant)

All right. Thank you. Our next question comes from the line of Tazeen Ahmad of Bank of America Securities. Your line is now open.

Tazeen Ahmad (Analyst)

Hi. Good morning. This is Sharon for Tazeen. Thank you for taking our questions. You mentioned that this VPAS rebate drag is a one-time thing. I wonder, can you clarify on that? Can you make sure that this is not a recurring event? Our second question is, how do you plan to message the positioning of Pombiliti versus the traditional ERT in the new 10 countries you plan to launch? What have you heard so far from the payers and providers? Our third question is, can you elaborate whether this in-license deal represents the beginning of the broader plan into nephrology or inflammation-related rare disease? Thank you.

Bradley Campbell (President & CEO)

Yeah. I think the first question was around VPAS. Just to be clear, we had anticipated, based on the guidance from the Industry Association, up to a 15% rebate. What was provided, in fact, or what was decided and given to us was a 22% rebate. To be clear, that will impact revenue over the course of the year. That is part of why with Pombiliti, we've adjusted our guidance downwards. With Galafold, because again, of the strong patient growth, we believe we will be able to make up for that over the course of the year, which is great. VPAS is something that we've always had in our estimations.

It is part of the arrangement between industry and the UK government. It is always part of our expectations and guidance. It's just very unusual to have this kind of significant increase in the eventual rate versus what they guide us to. Hope that provides some clarity. As it relates to positioning, we've done an amazing job of working through the reimbursement process in Europe. We were the first-ever product to get approval by NICE ahead of MHRA approval. We got first position in Sweden, first position in the Netherlands. We had a very fast launch and reimbursement process in Spain.

We are very clearly demonstrating the value proposition of the product. The positioning from a competitive perspective, of course, is all about the data. Again, the differentiated data we've shown in terms of the only product in a controlled study showing that we can improve patients who switch from enzyme replacement therapy. I think those are the data that are continuing to drive adoption of the product. Hopefully that gives you a flavor there. Maybe Seb, just a quick reminder of the strategy around how we thought of this product and then what we think going forward from a BV perspective or portfolio perspective.

Sébastien Martel (Chief Business Officer)

Yeah, Brad. We did highlight in the past the areas of interest from a standpoint. I think we have shared that we tend to think for our framework in adjacencies to our existing businesses. Looking at neuromuscular and rare kidney and rare cardiology assets, more broadly speaking, at rare metabolic disease, generally speaking. These are clearly the areas of interest. This particular deal here is for US rights in FSGS, as well as in other indications, by the way, given our excitement around the MOA. We think that there's clearly an opportunity to expand in the rare kidney space with that specific asset in the US.

We're also eager to continue to expand our portfolio on a global scale. Interested to also leverage our capabilities ex US.

Tazeen Ahmad (Analyst)

Great. Thank you.

Bradley Campbell (President & CEO)

Thank you for the question.

Operator (participant)

Thank you. Our next question comes from the line of Kristen Kluska of Cantor Fitzgerald. Your line is now open.

Kristen Kluska (Md & Senior Equity Research Analyst)

Hey, guys. This is Rick Miller, on for Kristen. Thanks for taking our question. Just one on FSGS here. You talked about there potentially being kind of subsets of patients, maybe some that respond better from a hemodynamic-driven mechanism versus inflammatory-driven in FSGS. To kind of get at this, is there any stat around what percentage of FSGS patients seem to be poor responders on ARBs, or how should we be thinking about that?

Bradley Campbell (President & CEO)

Yeah. Just as a reminder, Jeff, I'll turn it over to you from a technical perspective. As a reminder, there are over 40,000 patients with FSGS or primary FSGS, at least in the United States. We think a fairly sizable subset of those patients would be prime candidates for this product. Jeff, maybe talk a little bit about sort of how we see as kind of the most obvious, most likely to be responders, and then some of the other opportunities as well.

Jeffrey Castelli (Chief Development Officer)

Yeah. It's a great question. The focus of the patients for DMX-200 in the trial are primary FSGS, which is sort of originally triggered by T cell insults that then cause this feedback loop, and also genetic, which is mainly driven by the APOL1 patients. In that group, what we're targeting there are patients, despite ARBs, despite corticosteroids, still have proteinuria, which is greater than 1.5 gram per gram that are in the trial. Unfortunately, that's actually a majority of FSGS patients that still, despite those treatments, still have significantly elevated proteinuria. In those patients, in particular, the higher the proteinuria levels, it's more and more likely that they have an uncontrolled inflammatory component going on.

There's not great numbers about how many patients in that group have significantly elevated MCP1, for example. Through some of the work that Dimerix has done, what we'll continue to learn through the phase three, we think that is a significant percentage of those patients. Those are the ones in particular where we expect to see potentially a very robust response in terms of reduction of proteinuria. Also, in others that might not be as elevated that are in the trial or out there that might be treated down the line, inflammation does start to kick up in these patients.

You might actually prevent kind of a worsening in addition to actually driving some improvement, in particular in those that sort of have major ongoing inflammatory components. I think we're going to learn more and more with FSGS that there's a lot of different mechanisms going on. I think we're going to start to really start to refine the different MOAs that are better for different types of patients. We're super excited that we think DMX-200 is going to address a significant percentage of those patients where it's really that inflammation that's driving things.

Kristen Kluska (Md & Senior Equity Research Analyst)

Thank you.

Bradley Campbell (President & CEO)

Thanks, guys.

Operator (participant)

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

Gil Blum (Senior Biotech Analyst)

Good morning, everyone. Thanks for taking our question. Just maybe a couple of macro items. You mentioned very limited impact of tariffs in 2025. Looking into the future, is there going to be additional investment required in order to control potential for tariff impact in later years? What is the impact of the weakening dollar? Thank you.

Bradley Campbell (President & CEO)

Yeah. Thanks, Gil. On the manufacturing side of things, I don't foresee significant additional investment to be made to navigate around the tariffs. You might remember that we already are well underway in moving the majority of our manufacturing to Ireland. That will, I think, help diversify and de-risk the manufacturing, both cost and geopolitical location. Sebastian and I mentioned on the call, we're moving some of the drug product manufacturing here to the United States, which again, further diversifies. I think we feel very good about our ability to manage that going forward, despite the uncertainty that's out there.

As it relates to the second one, just as a reminder, a significant portion of our revenue comes from the pound, the euro, and the yen. A weak dollar for us generally gives us some FX benefit. However, we've tried to, I think, show in some of our slides just an example of what changes in the value of the dollar could impact our revenue. That's also why we focus on growth from a constant exchange rate perspective. Hopefully, that gives you some flavor of, in our case, a weakening dollar tends to help on the top line based on the majority of revenues coming outside the United States.

Gil Blum (Senior Biotech Analyst)

Thank you.

Operator (participant)

Thank you. Our next question comes from the line of Salveen Richter of Goldman Sachs. Your line is now open.

Salveen Richter (Md & Lead Analyst for the US Biotechnology sector)

Hi. This is Sharnaaz Rafa Salveen. Thank you for taking our question. Regarding Pombiliti, could you maybe give some more color on the competitive dynamics in the US with a good portion of patients on Nexviazyme coming into that appropriate window for switching? Basically, how are physicians at this point deciding between the two products, and what sort of market feedback have you been getting?

Bradley Campbell (President & CEO)

Yeah. Great questions. One thing we would note, actually, and this is just public information, the global franchise for Sanofi and Pompe actually declined by 5% in the first quarter. I think that shows that for the first time, we are starting to meaningfully take share and impact their growth. You can see our 90% growth, obviously, in stark contrast with that. In terms of positioning, I think it continues to be what we've shared, which is in the United States, in particular, once physicians start a patient on Nexviazyme, and that was the only choice they had because we were not on the market yet, they want to give about two years of time before they are ready to switch again.

Having just big numbers of Nexviazyme patients coming into that switch period is helpful. I think if you look at the acceleration that Sebastian Martell talked about and the proportion of patients coming majority from Nexviazyme, that continues to say that we will and are switching those patients. Most importantly, what they're looking at is decline in both six-minute walk and forced vital capacity, but also some other patient-reported outcomes. That is where the data that Jeff Castelli mentioned, the growing body of evidence looking at long-term impact, not just on those two endpoints, but also PROs, but then also these case studies and showing improvement from showing the support for the switch from Nexviazyme to Pombiliti, I think is really important.

Those are the things that we think are going to continue to drive the switch and support that acceleration over the course of the year.

Salveen Richter (Md & Lead Analyst for the US Biotechnology sector)

Thank you.

Bradley Campbell (President & CEO)

Thank you.

Operator (participant)

All right. Thank you. Our last question comes from the line of Maxwell Skor of Morgan Stanley. Your line is now open.

Maxwell Skor (Stock Analyst)

Great. Thank you for taking my questions. Could you elaborate a bit more on other potential indications amenable to DMX-200's MOA? Also, given the evolving regulatory landscape, could you share any insights or potential changes you might like to see at the agency to improve rare disease drug development or review efficiencies? Thank you.

Bradley Campbell (President & CEO)

Yeah. I'll start the second one. I will say that's maybe the one bright spot in all the craziness out there, as you are hearing from senior officials, including the new FDA director, a nod towards rare disease drug development. We would love to see more use of real-world evidence. We'd love to see an acknowledgment that in rare diseases, you can't always have a placebo control arm in a rare fatal disease. We would love to see some other incentives that would, I think, appropriately recognize some of the modernization of regulatory ability and clinical trial design.

I think there is maybe a silver lining there, which we look forward to continuing to see that play out. Maybe Jeff, quickly take the second one, any of the at least maybe one of the indications we're thinking about.

Jeffrey Castelli (Chief Development Officer)

Yeah. I mean, with the mechanism of action and it being very kidney-specific, just looking across rare kidney diseases where monocyte macrophage inflammation seems to be playing a key part and it's not well addressed, I think there's a number of potential interesting areas. Diabetic nephropathy and IgA nephropathy have been looked at. I think there's a lot of potential players in those spaces. There are ones like proliferative lupus nephritis that also looks like this could be a key mechanism to address. I think we're looking at sort of a number of different areas and saying, "Where is really mechanistically the best fit?"

What also sort of fits in terms of building off of our FSGS kind of learnings clinically, as well as those physicians that we'll call on. I think there's a few really good candidates there that we're going to start to dig into. There already is proof of concept data for some of those with the general pathway of CCR2 being involved.

Bradley Campbell (President & CEO)

Yeah. I think that's where, again, that turning profitable in the back half of this year, and then obviously that leads eventually to positive free cash flows, that gives us our own capabilities and resources to start to expand the portfolio even within the products that we have. Now with DMX-200, that should give us some opportunity there as well.

Maxwell Skor (Stock Analyst)

Great. Thank you.

Bradley Campbell (President & CEO)

Thank you.

Operator (participant)

All right. Thank you. That was the last question for today. This does conclude today's conference call. I do hope everyone has a great day. Thank you.

Bradley Campbell (President & CEO)

Thanks very much. Thanks, everybody, for tuning in.