Amicus Therapeutics, Inc. (FOLD) Earnings Call Transcript & Summary

Hi, everyone. Thanks for joining us at the Cowen Healthcare 2021 Conference, hopefully, our only virtual conference -- healthcare conference ever. So thanks for joining us at the Amicus Therapeutics fireside chat. I'm covering analyst Ritu Baral. With us from Amicus, as I'm sure all of you know, based on who's in the room, we have Chairman and CEO, John Crowley; President and COO, Brad Campbell; and Head of Research, Jeff Castelli. Jeff, I'm forgetting your new official title but...

Chief Development Officer.

Chief Development Officer. Congrats on that. No, that's not too old a title. And yes, thanks, everyone, for joining us.

I want to dive right into the main topic of conversation, which is the recently disclosed top line results from the Phase III PROPEL study of your next-gen ERT for Pompe. So the statistics on the primary analysis of the primary endpoint, this was a superiority analysis of 6-minute walk, missed, but you had not just many statistical trends, including very, very strong non-inferiority p-values, and maybe you can review that for us in just a bit and as were presented on your earnings call on Monday. But you also had consistency between pretty much all of the analysis. Can you spend a few moments since this is so new, just to review that, the trends, the consistency and those statistics that you presented on Monday on your call?

Sure, Ritu. Thank you for hosting. Good afternoon, everybody. So let me just begin by saying, we continue to have great confidence in AT-GAA to make a difference in the lives of everybody living with Pompe disease and all of Amicus is focused on the next steps toward -- through the regulatory process and everything needed to bring this medicine to people in the world. So maybe Ritu, if I can, I'll just level set everybody on a couple of the pieces that give us confidence. And then I'll go through kind of a summary of the data that you requested. So first is just to remind everybody of the unmet medical need here. For 15 years, people living with Pompe disease had only had 1 approved medicine for their Pompe disease. And despite any improvements on that medicine typically in the first couple of years, what you almost universally see is a plateauing for most all patients and then a steady inexorable decline in mobility and muscle strength, importantly, in the ability to breathe and respiratory function, often leading to needing wheel chairs, ventilatory support, and in many cases, tragically to death while on therapy. So a huge unmet need. I think hopefully, we could take that question off the table. There is a desperate need for newer and better treatments and more treatment options. Second is the data from the PROPEL study. I'll come back in just a moment to summarize some of it in your specific questions for the non-inferiority. But when we look at, to your point, Ritu, the magnitude, the consistency, which seems to be the durability of the treatment effect, we see a very differentiated data set from the approved standard of care, and in many regards, different from any medicine ever studied in Pompe disease. Particularly impressive is the difference that we saw in forced vital capacity, breathing ability and what we saw particularly in the switch population. Again, all patients taking Lumizyme in the world represent that opportunity to potentially switch to a new standard of care. So we're excited about all of that. And again, when you line that up with all the secondary endpoints, the biomarkers, we think it's an overwhelmingly compelling data set here. Importantly, too, I'll just remind everybody of the regulatory precedent in this rare disease, in particular, Lumizyme had a very similar study to the PROPEL study. While they described it as 2 co-primary endpoints, the statistical analysis plan originally for Lumizyme and what was presented for review at the agency years back focused all the alpha and all the attention on the primary endpoint, the mean change in 6-minute walk. After 78 weeks compared to placebo, they just missed on statistical significance, a P of 0.06, and that's in the Lumizyme label. The FDA then exercised their regulatory review powers and flexibility, and they looked at the first key secondary of change in forced vital capacity, where they did show a statistically significant improvement, and that was the basis of approval for Lumizyme.

A key secondary?

It was the first key secondary.

[Technical Difficulty] we see was key secondary. The same way in your stats plan, it was the key secondary.

Exactly, as it was described in Lumizyme, that's correct. And of course, for the Genzyme's -- for Sanofi's neo product, their basis approval presumably would be on forced vital capacity. So incredibly important in that there's regulatory precedent here in this exact scenario, we're broadly looking at the importance of meeting next-generation therapies for rare diseases, incredibly important for the public policy, public health, public interest, but it's really just so needed here in Pompe disease. And I'll remind people a major distinction, the PROPEL study is the only Pompe study whoever have studied in a controlled, blinded, randomized fashion, the switch population, people on ERT, switching to our drug. Again, 80% of the PROPEL patients were switch patients. When you put all that together, we think this means there's great potential for AT-GAA to not only play an important role in the treatment paradigm ahead for Pompe, but I think with the continued potential to be the standard of care treatment. Maybe, Ritu, I'll just take a moment then and highlight some of the statistics you asked for as well. To remind everybody, the primary endpoint of the study was to show superiority versus the approved medicine against Lumizyme on 6-minute walk. AT-GAA in the combined overall population outperformed on that endpoint by 14 meters. We missed by about 2 meters on statistical superiority. So we missed on the primary. The p-value was 0.07, even with that the numerical advantage of 14 meters. But again, importantly, with the SAP, the statistical plan then said, if you miss on the primary, the next step down would be to look at the first key secondary endpoint of mean change in forced vital capacity. We did that per the prespecified SAP and in the combined population on the prespecified statistical tool, the MMRM, we showed a statistical difference of 3% absolute p-value of 0.02 on that first key secondary. So very important. And again, when you look at 8 of 8 key secondaries favored AT-GAA over the approved medicine, oftentimes statistically significant, both key biomarkers in Pompe disease, X4, a measure of glycogen reduction, and CK, a measure of muscle integrity showed significant improvements favoring AT-GAA that were highly statistically significant p-values of less than 0.001. So that -- and I'll just finish by your question. We did release this. We've heard this over the last couple of weeks that we didn't show the non-inferiority analysis. But we didn't show it because the SAP said if we missed on the primary, to step down to the first key secondary. We did that, and we achieved nominally significant statistical superiority. So by the SAP, we didn't have to conduct the other analyses. We went back and conducted them anyway. And what we showed is on 6-minute walk, no matter where you're setting non-inferiority margin, whether you set it at 10 meters, which would be reasonable, 5 meters, or even as tight as 3 meters, at 10 meters, the non-inferiority, the p-value was 0.0008. And just at 5-meter delta, the p-value on non-inferiority on 6-minute walk was 0.005. And even as tight as 3 meters, non-inferiority was 0.04 and of course, we didn't run the non-inferiority originally on the SAP for forced vital capacity because we hit on superiority. If we had missed on superiority and tested for non-inferiority with this data set, in the prespecified combined population, setting the non-inferiority margin at 1.1%, which was the exact non-inferiority margin in the neo common study, the non-inferiority here would have been 0.001. So hopefully, that puts those questions to bed.

Great. So as long as we're talking numbers, I want to address one thing that was brought up in our panel yesterday on neuromuscular diseases. How should we be thinking about the nominal superiority on FVC? One of the comments was that the variability of the measure, the inter -- intra patient, rather, variability of the measure can be as high as 5 percentage points depending on the day and the patient. So how should we be thinking about the 3% when actually the 5% is bigger essentially?

Yes. So we were aware. I'm going to ask Jeff to comment. We're aware of that, of course, going into the study, incredibly important that we were able to train the sites, that we're able to do multiple measurements to get that as tight as we possibly could. And you're right, at any one point, there could be some variability, but importantly, over the 52 weeks to look at those trends, and remember, every 12 weeks, patients went in for evaluations. And the differences, again, on forced vital capacity in the overall population were striking, they were even more striking in the switch population. Really important on 6-minute walk, we showed 17-meter improvement in the switch population, and that was a p-value of 0.046. On forced vital capacity, we showed that we kept our patients -- AT-GAA patients completely stable, while you saw a continued significant decline and there was clear separation between those groups. So the difference was more than 4%. And the P there was 0.006, but Jeff, maybe you want to comment a little bit more on how we control to ensure that we had a high-quality data in the pulmonary measurements?

Yes. So in both on the 6-minute walk and the FVC assessments and other assessments in the trial, we had multiple baseline measures that were done to make sure we got good baseline. Same thing done at the end of the trial. As John mentioned, every 3 months, patients came in, got assessments. There were expert CROs that we engaged specifically on conducting 6-minute walk and conducting the FVCs to make sure they were done right, they were blinded data reviews of those assessments for the 6-minute walk. The FVC data was looked at actually by 2 independent different experts to make sure that those assessments were done and met all the standards that are out there for FVC. So and this was all done through the global pandemic and the data completeness was over 97% of all the assessments were done on track. So we are really confident in the quality of all the data collected and the robustness of those assessments on both 6-minute walk and FVC. And as John said, those differences of 3% or 4% predicted are quite impactful in terms of these patients, especially those that have been on ERT for a while and are pretty depressed already within a few years who end up needing ventilatory support if they continue progressing at the rate that we saw, and it was great to see them stabilize.

What was encouraging as well, Ritu, is when we look not only at all the neuromuscular endpoints, but at all the pulmonary and the respiratory endpoints when you include MIP and MEP, when you look at, I think, it's standing and lying prone -- lying flat on forced vital capacity was all consistent and all favored AT-GAA. So we think it's incredibly high-quality data and the integrity of the data is very strong. And obviously, the nature of the end point is relevant in Pompe disease. 80% of people living with late onset Pompe disease, die from respiratory insufficiency. So it's incredibly important to keep in mind.

Great. Can you discuss for a second, how you guys see the path to ultimate approval both in the U.S. and the EMA? I think most of my -- most of my conversations with clients have started with how is the FDA going to look at this? Is this fileable? Is this approvable? And it has ended with literally the same set of questions. You reviewed the Myozyme Lumizyme precedent. Are there other precedents and other communications that you're having or have already had that give you confidence that you'll be able to make it across the finish line?

Yes. I won't and can't comment on ongoing discussions with the agency. What I can do is just share with you a little bit about the background of how we came to where we are. We were actually the first company to take advantage of the new joint scientific advice process that's available for rare disease programs between EMA and FDA that began -- those discussions began in the fall of 2018, we aligned both agencies on the study, but then we also further aligned them on the SAP. And it was important, in fact, recommended by FDA to us that the SAP, that the second look after looking at the 6-minute walk distance for superiority, the second analysis would be to look for superiority on forced vital capacity. And then they also agreed that if we were to miss on that, we could then look at non-inferiority on forced vital capacity. Of course, a competitor product is seeking approval on non-inferiority on forced vital capacity. So we think the history here, the regulatory precedent, the great unmet patient need, this being in the rare disease division, importantly, about a year ago, the FDA broke out rare diseases, inborn errors and metabolism from the GI division to create a separate, which I at Amicus and others for years have advocated for to have a division of rare disease. I think having that expertise is going to be incredibly important. So look, we can control the things that we can control. We began -- we asked the FDA if we can begin enrolling BLA last year. They agreed. We completed the first module of that in November submitted. We expect to complete the remaining modules by the end of the second quarter. And likewise, we're going to pursue approval in Europe. We expect to file the MAA in the third quarter. We're also evaluating the potential for early approval in the United Kingdom under the EAMS framework now that we have the PIMs designation as well. So for us, everything that we can control, we're moving forward full steam ahead to bring it to patients. That includes we continue to entertain a significant number of compassionate use requests, particularly for infants who are struggling on the approved medicine. We're planning for a formal infantile study to begin in the second half of this year. We're already enrolling an adolescent study. So a lot of ongoing activities that hopefully will bring this to patients.

The SAP that you mentioned where FDA asked for FVC superiority as the secondary analysis. EMA signed on to that? Or do they have their separate statistical analysis plan?

No, they reviewed the SAP as well.

Okay, they reviewed.

Same protocol, same SAP, correct.

Got it. Okay. And so as we look to potential approval, how is the commercialization effort and marketing? How is that going to play out, given -- well, 2 things to keep in mind, as you answer that question. One, again, in our neuromuscular panel last night, the general impression from our surveyed docs was that both neoGAA and -- I'm sorry, AT-GAA were probably better than standard of care. Just based on a very simple survey question, we asked them, and we were not able to get detail outside of our panelists. And I guess the second thing is that when we think about you guys and maybe Sanofi Genzyme marketing and detailing this drug because of the unique nature of the respiratory complications in Pompe, will you still be forced to do it sort of in a virtual format even into 2022 and potential approval?

Yes, let me -- I'm going to ask Bradley to comment in a moment. I'll just say, Ritu, the neo data will speak for itself. We think we're going to have a very differentiated data set. And the most important thing to remember, again, all the patients on Lumizyme, by definition, are potential switch patients who may benefit from a new medicine. AT-GAA was the only drug to have studied it in a randomized blinded control fashion with now years of data, and we think that will be a very differentiated data set. These are really sophisticated physician scientists in the Pompe community, and that's really important. They're going to be driven by the data. They're going to be driven by product labels, and they're going to be driven by scientific publications and ongoing studies. We're going to continue to do a lot of post-marketing studies to evaluate this.

Right. And that actually drove my question because as one of our KOLs said yesterday on the genetic lysosomal panel, this stuff gets hashed out at the bar at the [Indiscernible] at world.

Late into the night, no doubt.

No, [indiscernible] but he actually did say that. So I'm not using his name, but I don't think any of us are going to disagree. So as we think about World Muscle being virtual this year and next year and the fact that Pompe patients are particularly prone to respiratory distress, how are you going to make that discourse work in a virtual environment?

Sure. We've made it work very well in Galafold, for instance, in a very competitive environment. We have really transformed our business model, if you will, on the commercial side to a hybrid model. We've completed virtually the same number of touchpoints post COVID now with a lot of work, a lot of retooling, than we had pre COVID. So Bradley, maybe I'll turn it to you to kind of take that link from how successful we've been in a very competitive environment with Galafold and still successful with the launch ongoing and how we're going to translate that success to Pompe?

Yes. I mean, John hit some of the highlights there, but we had to transform our business model last year in order to continue to stay in front of physicians and really drive the scientific dialogue. This is -- as you know, Ritu, this is a very scientific community, both the physicians, but also the patients for that matter, and being able to put the data in front of them, stay front and center, ask tough questions, look at tough, challenging issues in the scientific community is part of how we add value, and we were able to do that successfully. We had a great presence at world. We've had a great presence at local congresses, many of these physicians have much more regular local congresses in their home countries, which we were a part of, we sponsored our own as we have every year. Fabry conference last year, which was -- had more attendees than actually we had ever had in person. So there are pros and cons, certainly. I fully agree with you. At some level, there's that personal interaction, but that's actually happening more and more as countries are starting to unlock the ability to do that. So we feel very confident in our ability, based on our Fabry experience to compete effectively with not just one but 2 large competitors in the Fabry market and do that in the virtual world. But we're eager to get back in front of physicians, and we'll do that. I think if you translate into where we are with Pompe, look, these data are brand new, and it is a discussion, it is a dialogue. And Sanofi has had the chance with their data set to be out there in the community, both at congresses, but also with medical affairs out with physicians, having the discussion around their data set. Our data set are brand new, and we have a robust medical affairs communication strategy over the course of this year and then, of course, after launch with the sales and marketing organization to make sure that physicians see the data. And at the end of the day, this is a data-driven story. That's how it's played out in all of the lysosomal storages, we see it's a data-driven story, and we feel very comfortable, as John said, both with the overall FVC, but then in particular, in the switch population of how our data stacks up against either of the potentially competitive products. We're fully prepared for and anticipating a commercial launch, the time lines that I think we've talked about. We have a highly seasoned team and it's highly leveragable. We'll add less than a dozen FTEs to support the launch of Pompe globally. And remember, too, we have a growing number of patients, 150 -- over 150 today, a growing number of patients on AT-GAA, which, of course, will be an early focus at launch. So...

Thanks Brad. I'll just finish the thought to remind everybody, we're not new to the Pompe world. We are -- I am 9 days shy of 23 years working in Pompe disease. Amicus was founded in part to develop new medicines for Pompe disease. So we know the patients, we know the patient communities, we know the entire ecosystem. The clinicians are going to be guided by data. I think it's great if they have multiple choices. I think that's excellent. And that's all I ever asked for is to develop a great medicine, create the data set and let doctors and patients decide. This is already a $1 billion market. It's growing to a $2 billion market by the end of the decade. If doctors have 2 drugs to choose from, that's fine. We'll describe our data. That's our job. And again, we'll continue to think about obsoleting our own technologies as we move forward with Pompe gene therapy and other technologies that we're looking at in Pompe. I think that's the obligation we have to patients.

So can you remind us about your potential pricing strategy around Pompe and does speaking statistics that [indiscernible] has generated, does that change how you might think about?

Gives us more confidence in the drug, the overall picture, again, that very meaningful data set that we have, but philosophically, it's the same approach. Brad, do you want to describe how we think about pricing? And importantly, for us, pricing and access go hand-in-hand. And I think we threaded that beautifully well with Galafold, and I think we'll apply the same principles in Pompe.

That's exactly right. I mean our focus is on access and getting as much access for as many patients as quickly as possible around the world. And with Galafold, we are able to do that successfully, oftentimes far more quickly than the industry average, and our pricing philosophy is parity to or modest down to existing standard of care. And that takes the pricing conversation off the table. You are showing the value of the product is what's in the data, what's in the efficacy and safety data, rather than negotiating for a 5% premium over a course of months, which delays you get into the market. So that will continue to be our focus here. And again, it's been a winning strategy. And of course, it's right for patients, but we found it to be a very successful commercial strategy as well.

Got it.

So we have 5 minutes left for 2. We do have an approved on almost 1/3 of $1 billion in revenue this year. But...

I did want to get to that. I'm just double checking the last PROPEL questions, but doesn't look we have any. So yes, let's talk about your $300 million and growing current drug. How are you looking forward to continuing growth? Where is that growth going to come from? And especially since the more mature this drug gets, the more naive patients are getting on board. How is that going? Do you want to touch on your gene therapy program?

Yes. Look, it's great to see Galafold now for patients with amenable variance, having become the standard of care medicine in most major markets. And that's after just 2 full years of launch in Japan and the United States, about 4 years now just shy of 4 years in Europe. But -- so that's where we are now. It's been a great launch right? How do we get it to $500 million to $1 billion in revenue in the next few years?

Yes. Just a couple of quick statistics because I know we don't have a ton of time. We ended the year last year with a 60-40 distribution between switch patients and naive patients. So our strategy of focusing on switch first and then starting to bring on diagnosed untreated patients is working well. To give you an example in our more mature markets, we have 70%, 80%, 90% share of treated amenable patients. So as John said, we're winning the game for the switch market. But in those markets this year, we expect for every switch patient that comes on board, we will bring a diagnosed untreated patient on board as well. So we're starting to see that 1:1 in our more mature markets. Whereas, as John said, Japan, U.S., et cetera, are still earlier and still it's a switch conversation. Globally, we have about a 50% share of treated amenable patients, which means there's a lot more room to continue to switch patients as well. And that's, as we said, $300 million to $315 million this year. So lots of opportunity to continue to switch patients. And then the last leg of growth is really geographic growth. So we added a number of new countries last year. We'll add more this year. We're present at about 80% of the global market opportunity for Fabry. We already have reimbursed Galafold. So there's another 20% to go there. And so those really -- those 3 legs of the stool get you past $500 million frankly. It's a $1.6 billion market today and growing. The other piece, though, is longer-term continuing to support diagnosis. And I'll just highlight 2 things we touched on in the call. At World LDN, we showed a great poster on screening idiopathic pain patients in Germany, finding Fabry patients trapped in that system, putting them onto therapy. And then likewise, some really cool artificial intelligence diagnostic work. So we're really starting to now fund in earnest the longer-term diagnostic pathway, and that gets you up to that $1 billion-plus opportunity, which has long-term protection from an IP perspective, but also continues to be supported by our compliance and adherence rates of over 90%, which means when patients go on therapy, they stay on therapy.

Great. And then the last question on your gene therapy -- gene therapy portfolio. One, you're going to be talking to FDA about, I believe your CLN6 and your CLN3 program and the pivotal trials going forward. What is your hope that the pivotal trials end up looking like based on these conversations? And then two, remind us of time lines on your Fabry and our Pompe gene therapy candidates or programs.

Yes. I'll turn it to Jeff. Just to remind everybody for CLN6, we did receive the prime designation in Europe, and we just received a fast track designation in the U.S. So Jeff, do you want to go through Ritu's questions there?

Yes. I mean, real briefly on CLN6 and 3. So we continue to follow the kids that were treated in the Phase I/II. We continue to work on the GMP manufacturing to conduct that next in some pivotal studies in both cases. Ongoing regulatory discussions. We envision for CLN6 that, that next study would look very similar to the first study, how many kids and how much data on those kids to support the submissions is part of the ongoing discussions. For CLN3, we would again hope it would be -- in this case, we've only treated 4 kids to date. So that would be a larger study in this next study, something in the 20 to 30 patient range, we would hope, compared to natural history, there's a great natural history set. So that's, again, part of the discussions on that.

[Technical Difficulty] not a better natural history set. So those 2 could offset each other, correct?

I'm sorry, you cut out the first...

[Technical Difficulty] disease process, but you have a bigger natural history data.

Exactly. Exactly.

[Technical Difficulty] each other a little bit.

Yes. So it certainly helps a lot to have that much more robust natural history set for CLN3. So we're excited to get those studies up and running this year. We expect to dose our first patient in the CLN6 study this year and to get that CLN3 protocol submitted by the end of the year. And again, using the GNP process material from Thermo Fisher for those studies. For Fabry and Pompe, we continue -- we declared candidates. Pompe is with a targeted transgene. Fabry, it's a stabilized transgene. We've shown that in both cases, the engineered construct is much more potent at reducing substrate than the wild-type transgenes, combining with pen capsids, we're on ongoing paths of IND-enabling tox and manufacturing and are looking to get those INDs started as soon as we can with right now sort of manufacturing likely being rate limiting, and we'll have updates later this year on more definitive time lines. But great progress on those programs, and we're excited at the potential there, clearly fit with our focus.

Great. I think we are at time, just doing a quick question check. No, we're all set. For those of our audience that may have some outstanding questions, please feel free to e-mail me. I'll make sure to be in touch with the company and get them answered for you. But thank you, Brad, Jeff and John for [Technical Difficulty] super help. Thanks.

All right. Have a good day. Thank you.

Thank you.

Thank you.

Thanks. And thanks, Andrew. Take care. Bye.