Vertex Pharmaceuticals Incorporated

Making prepared remarks on the call tonight, we have Dr. Reshma Kewalramani, Vertex's CEO and President, Stuart Arbuckle, Chief Commercial Officer, and Charlie Wagner, Chief Financial Officer. Dr. David Altshuler, Chief Scientific Officer, and Dr. Bastian Osana, Chief of Cell and Genetic Therapies, will join the Q&A portion of the call following the prepared remarks. We recommend that you access the webcast slides on our website as you listen to this call. This conference call is being recorded. and a replay will be available on our website. We will make forward-looking statements on this call that are subject to the risks and uncertainties discussed in detail in today's press release and our filings with the Securities and Exchange Commission. These statements, including without limitation, those regarding Vertex's marketed CF medicines, our pipeline, and Vertex's future financial performance, are based on management's current assumptions. Actual outcomes and events could differ materially. I would also note that select financial results and guidance we will review on the call this evening are non-GAAP. I will now turn the call over to Dr. Reshma Kewalramani.

I'll begin this evening's call with comments on our 2020 performance and then turn to the pipeline, including an overview of a number of our R&D programs and upcoming milestones. 2020 was an unprecedented year for governments, businesses, and people around the globe. It was also a remarkable year for Vertex. Despite the challenges we all faced against the backdrop of the pandemic, Vertex delivered extraordinary commercial performance, generating $6.2 billion in product revenues, representing more than 50% growth compared to 2019. We also meaningfully advanced the pipeline and significantly strengthened our financial position. Vertex has discovered and developed medicines that have transformed the treatment of cystic fibrosis. and the latest of these, Trikafta, or Captrio as it's known in the EU, has the potential to treat up to 90% of patients with cystic fibrosis. In 2020, the first full year after Trikafta approval in the U.S., the number of patients with CF treated with our medicines increased substantially, and by the end of the year, the vast majority of eligible patients 12 years and older in the U.S. were on Trikafta. In Q3, We received early approval for CAF TRIO in the EU and also secured reimbursement in England. By the end of the year, with direct access at marketing authorization in Germany, portfolio agreements in Ireland and Denmark, and the reimbursement deal in the UK, thousands of patients across the EU gained access to CAF TRIO. In terms of next steps in CF, We have line of sight to continued significant growth as we expand access to the triple combination to more patients in the EU, secure approvals in new geographies, as well as extend treatment to patients with rare mutations and younger populations, starting with the 6 to 11-year-olds in the U.S. We're also advancing additional small molecule combination regimens and other approaches that will further define our long-term leadership in CF. Our goal remains to bring transformative therapies to all people with this disease. 2020 was also an important year for our pipeline. We delivered proof of concept in two disease areas and advanced several clinical programs spanning multiple modalities. And we are now poised to move the VX880 program into the clinic for type 1 diabetes, our seventh disease area in clinical development, and our first cell-based therapy. Turning to our financial position, which continues to strengthen. As we treat more patients, our revenues and profitability are growing, and we finished the year with $6.7 billion in cash. We are steadfast in our belief that the best way to drive continued growth and create long-term value is to reinvest this capital in innovation, both internal and external. With respect to external innovation, Our strategy remains the same. Invest in assets that complement our internal CF pipeline, seek assets that fit our R&D strategy, and identify tools to add to our toolkit. What has changed is our position in CF and our growing financial firepower. Given where we are with Trikafta and Caftreo, plus line of sight to novel regimens and treatment for the last 10%, and given our balance sheet, we are now in a position to focus on assets that fit our R&D strategy and consider assets in mid and late stage. Moving on to an update on the pipeline. I'll focus on our R&D portfolio outside of CF and provide additional detail, including upcoming milestones on a number of programs. In total, we're active in clinical development in seven disease areas spanning multiple modalities, including small molecule, gene editing, and cell therapy, with each program holding the potential to transform the course of the targeted disease. I'll start with CTX001, our most clinically de-risked program outside of CF, which we're developing with our partner, CRISPR Therapeutics. In December, groundbreaking clinical data in sickle cell disease and transfusion-dependent beta thalassemia were published in the New England Journal of Medicine and presented in a plenary session at the American Society of Hematology annual meeting. These data demonstrated proof of concept and showed that CTX001 has the potential to be a one-time functional cure for people living with these diseases. We're also pleased to share that the first patient treated in the thalassemia study recently completed two years of follow-up and has enrolled in the long-term follow-up study. We are advancing through clinical development with urgency, and our goal is to be able to bring this therapy to patients as soon as possible. Over the course of 2021, there are three key milestones that will mark our progress with CTX001. First, the presentation of additional clinical data for more patients and for a longer duration of follow-up that will further define the efficacy and durability of this therapy. The completion of enrollment of our two ongoing studies of CTX001. And third, the progression of our discussions with regulators about the data needed for a filing package for approval of CTX001. In our Alpha-1 Antitrypsin Deficiency, or AATD program, we're focused on the development of small molecule correctors to address the ZAAT protein folding defect, the underlying cause of this disease, and thereby treat both lung and liver manifestations of the disease. Our most advanced molecule is VX864, which is progressing through a dose-ranging phase two proof-of-concept study. The goal of the study is to assess safety, PK, and levels of functional AAT protein. The study continues to enroll in dose patients, and we expect to have the results in the first half of this year. Consistent with our portfolio approach, that is to say our strategy of advancing multiple molecules simultaneously through early clinical development for each target across our disease areas, we are also on track to advance an additional small molecule AAT corrector into the clinic in 2021. Our lead molecule in the APOL1-mediated FSGS program, VX147, is also currently being studied in a Phase II proof-of-concept study evaluating the safety, PK, and reduction of proteinuria over 13 weeks. We expect to have results from this study in 2021. We also have a second molecule for ApoL1-mediated kidney disease that is now completing phase one. In our pain program, we have a molecule that continues to progress through phase one, and we have at least one additional NAV1.8 inhibitor that we expect to enter the clinic this year. Lastly, we submitted the IND for VX880, our first cell therapy for type 1 diabetes, towards the end of last year, and we are very pleased that the FDA recently cleared the IND. This allogeneic cell transplant program has the potential to transform the treatment of type 1 diabetes. In type 1 diabetes, insulin-producing islet cells are destroyed. Our approach is to replace these cells with fully differentiated stem cell-derived pancreatic islet cells. This approach follows the well-established precedent of cadaveric islet cell transplants, which have proven clinical benefit. Advancement of VX880 is a significant achievement. It is Vertex's first cell-based therapy to enter the clinic, and it is the only fully differentiated pancreatic islet cell program in development. We expect to initiate the Phase I-II clinical trial, which is a single-arm study of people with severe, difficult-to-control type 1 diabetes in the coming months. The goal of this study is to assess safety and measures of glycemic control. We are focused on quickly getting the clinical trial up and running, and we look forward to updating you as we make more progress over the course of this year. With that overview, I'll now hand it off to Stuart.

Thank you, Reshma. I am pleased to review with you our continued strong commercial performance. Our Q4 global revenues were $1.6 billion, with full-year revenues of $6.2 billion. This reflects significant growth over 2019, as we launched Trikafta and Kaftrio in the U.S. and EU, respectively. As expected, in addition to considerable continued U.S. demand for our medicines, we saw a significant increase in revenues from outside the U.S. in the fourth quarter. following the approval and launch of CAF TRIO. Starting in the U.S., it is now well over a year since the launch of Trikafta, and we have made tremendous progress in bringing Trikafta to nearly all eligible patients 12 and older, as reflected in our Q4 revenues. In 2021, our commercial focus now turns to maintaining the very high rates of persistence and compliance that we have seen to date, and we anticipate that these rates will normalize over the coming months. We expect the majority of near-term growth for Trikafta in the U.S. to come from approvals in rare mutations and younger age groups. Trikafta was recently approved for patients 12 and older with rare mutations, and the FDA recently accepted the SNDA for 6 to 11-year-olds and granted it priority review. We expect an approval around mid-year. In Europe, enthusiasm and interest in Cafetrio amongst the CF community is high. Our fourth quarter revenues reflect substantial uptake of CAF TRIO across all countries where patients have access, most notably in the larger markets of Germany and England, where the majority of eligible patients have already been initiated. We are seeing similar uptake in other countries where we have secured reimbursement agreements, including Ireland, Scotland, Wales, and Denmark. We remain focused on continuing the launch in these countries, as well as completing new reimbursement agreements to provide all eligible patients across the EU with access to our medicines. We have high confidence that, as was the case in the US, ultimately the vast majority of CF patients in the EU will be treated with CAF TRIO. However, while the destination is the same, the journey to get there will be different. In addition to the time and work required to secure new reimbursement agreements, the COVID-19 pandemic also presents significant uncertainties around the rate of uptake for our medicines. We are conducting fully virtual launches in the EU amidst evolving country-level COVID lockdowns. The ability of patients to attend in-person consultations with their physicians as the pandemic continues is a dynamic we are monitoring closely. I will now outline what's next for Vertex's CF franchise and how to think about future growth. We recently shared with you an updated and expanded view of the CF market opportunity based on an accumulation of new data from registries and other sources around the world. We now estimate that there are 83,000 patients living with CF in the US, Europe, Canada, and Australia. Today, we are treating around half of these patients. Notably, this leaves more than 30,000 additional patients in these regions who could benefit from our medicines and who are not treated today. Approximately two-thirds are 12 and older, and we expect to reach these patients through the continued launch, uptake, and reimbursement of CAF TRIO in the EU and through approvals and reimbursement agreements in other countries, such as Australia and Canada. The remaining one-third of patients are in lower age groups or have other mutations, and we are making progress toward reaching these patients through label expansions. Finally, I'd like to take a moment to recognize the CF teams at Vertex, both in the U.S. and internationally, for their unwavering dedication, despite the unprecedented global challenges of the past year. And I would also like to thank the CF community, for their partnership as we work together to bring transformative medicines to patients around the world. Charlie will now review our fourth quarter and full-year results and financial guidance.

Thanks, Stuart. In the fourth quarter of 2020, we continued our exceptionally strong financial performance. And of note, Q4 was our first quarter with more than $1 billion of sales for the triple combination, a significant accomplishment for the commercial team. Fourth quarter total product revenues were $1.6 billion, a 29% increase compared to 2019, bringing our full year revenues to $6.2 billion, an increase of more than 50% compared to 2019 revenues of $4 billion. Our fourth quarter revenues included $1.21 billion in the U.S. and $421 million in revenues outside the U.S. Our ex-U.S. revenues for the quarter grew 70% over the prior year, driven by the uptake of Captrio and our other medicines following the completion of several reimbursement agreements over the last year. Our fourth quarter 2020 combined R&D and SG&A expenses were $539 million, compared to $496 million for the fourth quarter of 2019. And our full year expenses were $1.98 billion, compared to $1.69 billion in 2019. Our full-year expenses reflected increased costs to support the rapid global expansion of our CF business, as well as targeted investment in expanding our pipeline into new disease areas and progressing our high-priority clinical programs. Our remarkable growth in revenues combined with disciplined spending resulted in a 2020 operating margin of 56% and operating income of $3.49 billion, an increase of 95% compared to 2019. Net income was $2.72 billion, compared to $1.39 billion for 2019. With continued substantial revenue growth and profitability, we finished the year with $6.7 billion in cash. Consistent with our corporate strategy, our top priority for capital deployment is reinvestment in innovation. both internally in our R&D programs and externally through business development aligned with our R&D strategy. For example, in 2020, we executed important collaboration agreements with Athenia, Skyhawk Therapeutics, and Moderna. Additionally, we also used over $500 million of cash to acquire Vertex shares through our ongoing share repurchase program. The primary purpose of this program is to offset dilution and approved very effective with nearly 2.5 million shares repurchased. Now to guidance. Our 2020 performance reflected considerable Trikafta uptake as we achieved nearly full penetration of eligible patients in the U.S., as well as strong uptake of Captrio in key EU countries where patients have access. For 2021, we project that we will achieve total product revenues of $6.7 to $6.9 billion, reflecting 10% growth at the midpoint. This guidance reflects our expectations for currently approved products in regions where we are reimbursed, plus an expectation of Trikafta approval for the 6 to 11-year-old population in the U.S. in mid-2021. In our 2021 revenue guidance, there are fewer significant variables compared to 2020. However, an important continuing factor is rates of patient persistence and compliance. We saw high rates of persistence and compliance with Trikafta maintained in the U.S. throughout 2020, and we expect these levels to normalize throughout 2021. This dynamic is factored into our guidance, as is uncertainty related to the ongoing pandemic. As Stuart mentioned, moving forward, we expect to see further contribution to international revenues with subsequent waves of reimbursement agreements and launches in the EU, as well as other ex-US geographies. However, the timing of these agreements is not predictable, and they are therefore not included in our 2021 guidance. For non-GAAP OPEX, we are guiding to a range of $2.25 billion to $2.3 billion. We expect to continue allocating greater than 70% of OpEx to R&D with year-over-year growth largely driven by investment in our pipeline programs in order to advance key programs further into the clinic and generate important proof-of-concept data in 2021. Our non-GAAP tax rate for 2020 was 21%, and we are guiding to a range of 21% to 22% this year. In closing, 2020 was a tremendously successful year for Vertex and our business, and we look forward to continuing our growth and significant profitability in 2021. Now, back to Reshma for a few closing remarks.

Thanks, Charlie. 2020 was an unprecedented and grueling year for the entire world, and while these challenges have not yet subsided, I have confidence that science will lead the way out of the pandemic, and we look forward with optimism. Throughout the past year, Vertex has demonstrated our resilience in the face of these challenges, and this was reflected in our business performance and pipeline progress. Vertex has a proven track record of creating breakthrough medicines and transforming lives. We have an ambition to transform many more diseases, and our pipeline of small molecules, cell and genetic therapies are poised to do just that. Thanks, and we'll now open the call to questions.

Thank you. To ask a question, you will need to press star then 1 on your telephone. To withdraw your question, please press the pound key. Again, that is star then 1 if you would like to ask a question. Our first question comes from the line of Corey Kasimov with JP Morgan. Your line is now open.

Hey, good afternoon, guys, and thank you for taking my questions, two of them for you. On the AAT program, has the IDMC been taking regular looks at the 864 safety database? And would you characterize this as a situation where no news is good news on the safety front, or is that still premature where you are in enrollment? And then also in this program, in terms of relative levels of functional serum AAT data, What would give you conviction that you're onto something here and provide added confidence going into the next stage of development? Thank you.

Hey, Corey. This is Reshma. Let me take both of those questions for you. The AATD program is indeed followed very carefully, as we do all of our programs, honestly, from a safety perspective. And that is just part of what we do. So that is ongoing. With regard to levels and maybe broadly speaking, what are we really looking for from this VX864 Phase 2 Proof of Concept Study? Really three things. The first is safety. This is the first time that VX864 is going to patients with AATD. The second is PK and exposure. And the third is increases in functional AAT levels. I'm also going to be looking to see if there's a dose-effect relationship. The key here, remember, is that this is our first time to close the loop on cracking the biology. That's to say, if we see levels of functional AAT increase in this study, we see a dose effect, what that tells us is that the mechanism that we projected to be the mechanism that could target both lung and liver, raise AAT levels, we got it. And as I always say, you know, we divide drug development at Vertex into two parts, cracking the biology, pouring on the chemistry. Pouring on the chemistry is the easier. It is not easy, but it's the easier of the two parts. And so that's what we're really looking for is an assessment of safety, PK, and we're looking for elevations of functional AAT levels.

Okay. Thank you, Reshma.

Sure thing.

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

Good afternoon. Thanks for taking my questions. So one question here on the CF guidance, could you just comment on how you're accounting for uncertainty related to the pandemic and what reimbursement agreements or approvals could be expected this year that are not accounted for? And then secondly, You made a comment about your BD strategy, and I recognize while it's aligned with R&D, you know, but at the same time, is there any clarity you can give us with regard to areas of focus, size of deals, and how much of an interest do you have in technologies as you look to kind of fill your toolbox there?

Sure. Salveen, this is Reshma. Why don't I start us off with the second part of your question, and then I'm going to ask Stuart to just comment a little bit more on the launch dynamics in the EU and a little bit more about the US. I think that'll cover your question on CF. So, Salveen, with regard to BD, what we're really talking about here is an interest that is exactly the same as the strategy we've laid out for many years, probably the last eight years now. We are interested in assets that complement our internal efforts in CF. We're interested in assets that fit our R&D strategy. And you know our R&D strategy is very, very diligent. We are very serious about the causal human biology and biomarkers and transformative potential, specialty markets. It has to fit all of that. And we're looking for tools that fit our toolkit. We've transacted in these areas. A lot of the recent transactions like Afinia and Skyhawk and Ribometrics fit those tools, and you should expect to see us continue doing that. We've also transacted on, I think Sema is a great example. It's a good one to talk about today given the clearance of the IND. Acquisitions like Sema that fit our R&D strategy like a glove and those that have transformative potential. And if you're thinking about, okay, what kind of falls in and what falls out, You can think back to a slide we showed at J.P. Morgan with our funnel, if you will, that goes through our criteria. Certain diseases fall in. Clearly, things like CF and AATD and ApoL1-mediated kidney disease. But other examples of diseases that fall in would be Huntington's disease, would be polycystic kidney disease. And then there are diseases that fall out because they don't fit our criteria. criteria like specialty markets or understanding of causal human biology or having biomarkers that translate well. Stuart, I'm going to turn it over to you to tell us a little bit about the CF market.

Yeah, thanks, Reshma. So, Salveen, I'm going to break down what's incorporated into our guidance into U.S. and ex-U.S. and talk about what the drivers of growth are. So, in the U.S., As you know, the vast majority of eligible patients across all patient groups have been initiated on Trikafta in the U.S. during the course of 2020. And so incorporating our guidance is the kind of the annualized effect of those patients having been initiated, offset to some degree by persistence and compliance, which we expect to normalize during the course of 2021. In terms of growth drivers for the U.S., probably the most notable are is the expected approval of Trikafta for 6- to 11-year-olds, which we expect to happen in the mid-year. Moving to XUS, we have obviously launched the CAF TRIO triple combination in those markets where we do have reimbursement agreements, like the UK and Ireland and Denmark, or markets where you can get early access, like Germany. And the majority of patients actually have already been initiated in those markets. The launch has gone very strongly. We do anticipate, obviously, initiating more patients in those countries. But we have only included in our guidance countries where we already have pricing and reimbursement agreements. So to the last part of your question, which is then where else would we be seeking pricing and reimbursement, the major countries in the EU where we will continue to seek reimbursement are like France, Spain, and Italy. Obviously, as Charlie said in his prepared remarks, it's impossible for us to predict exactly the timing of when we will reach those agreements, and for that reason, we don't include them in our guidance. Outside of the EU, obviously, the major countries are Australia and Canada. In both of those, we have filed for regulatory approval and are also in parallel seeking reimbursement approval as well. Again, those are not included within our guidance. And then if I can just kind of turn to the longer term, because obviously 2021 is sort of one year in a long journey that we've been on. We continue to believe that we will be able to treat up to 90% of patients with CFTR modulators like the triple combination over time. That has for a long time been our goal and continues to be our goal, and we still feel very confident, if not more confident than ever, that we're going to get there over time.

Thank you.

Thank you. Our next question comes from the line of Phil Nadu with Cowan. Your line is now open.

Good afternoon. Thanks for taking my question. I also had a follow-up on AT&V X-864. I was curious whether the team has come to any further understanding of what tripped up VX814 or the issues idiosyncratic to that molecule or class effect. It may be an extension of that. In the past, you had noted a difference in exposures between healthy volunteers and patients with AAT. In any way, could that be a sync effect because there's a lot of protein aggregated in the liver? And if so, how could that be overcome? Thank you.

Sure. This is Reshma. Let me answer those questions for you. You know, I think the best way to think about the AATD program is the following. We are very enthusiastic about the mechanism because it's the only one that holds the potential to treat both liver and lung. 814 was simply not the right molecule. And unsurprisingly, because the study was terminated early, We didn't fully enroll it, and patients who were enrolled didn't all complete the trial. There's not much more we can learn there. We are looking forward to VX864 and those results. The study is enrolling. We are dosing patients. And we need to be a little bit more patient, but it's not that much longer now. We will have the results this half, this first half of 2021.

Great. Thank you.

Thank you. Our next question comes from the line of Michael Yee with Jefferies. Your line is now open.

Hey guys, thanks and congrats on a great quarter and great year to close out. I had two questions. One was on BD, maybe Reshma or the team, you know, mid to late stage can span a whole gamut of size and market cap and certainly financial resource capacity. you know, Vertex is a much bigger company now, much more cash, but mid and late stage and different sizes can mean different things to different people. Can you maybe just comment about where Vertex is balance sheet or where you strategically feel comfortable along the range of, you know, sizes of what that can be, whether that's 5 billion, 10 billion, 15 billion, maybe just think about that, which is the other side of doing a deal. And then the second question, you made a nice comment about CF and how you're advancing, um, I know there was a super corrector that had really high levels of chloride transport, and there's also a once daily potentiator. Can you just remind us where those are and if those are still moving forward and doing well? Thank you.

Hi, Michael. It's Rachel. Let me take the second question first, and then I'll come back around and talk a little bit more about BD. So the once-a-day potentiator is VX561. And you're right, we have been busy at work. David Altshuler and the team in San Diego have been busy at work with the development of more correctors. We have the combination of VX121. Let's call it a next-gen corrector. VX561, that's the once-a-day potentiator, and TEZA, That's made its way through phase two development. And you'll remember the agency asked us to also do a monotherapy study with VX561. All of that's been completed. And what we're really doing now is looking at all of the data, planning forward to our regulatory interactions. And as soon as we get through all of those, we'll certainly give you an update on that program. Just remember, at a high level, drug development and CF going forward is going to be completely different than anything that's come before it because there is no placebo anymore. And so don't be surprised if you don't hear from me on this program until we're through all of the conversations and we're ready to give you concrete next steps. But I'm very pleased with how that's progressed. Okay, let's tackle BD. You know, let me take a couple of minutes and just really walk you through this in a little bit of detail. When I think about where we are in terms of the business today and where we're going, and then try to give you a little bit more color and texture behind capital allocation and BD, here's a way to put it all together. If you look at the company three years ago, so back to January 2018, we were active in the clinic with programs and patients. So I'm not counting healthy volunteers, just patient-based studies, in CF and pain. That's it. That's where we were. Fast forward three years, and we are now, if I count the type 1 diabetes program, which is going to be going into patients very quickly, we're looking at molecules in six disease areas right now in patients, right? If I count the pain molecule in healthy volunteers, that's seven. So it's very different. If I think about revenues, 2018, January, I think we closed out the previous year at something a little bit north of $2 billion. And if I think about cash, again, a little bit north of $2 billion. Where we are today, we closed out 2020 with revenues of more than $6 billion and cash close to $7 billion. we are indeed in a different place. And it's really that different place that allows us to think about mid and late stage assets. And that's a way of indicating the balance sheet and the strength of the balance sheet. I want to be very clear that the strategy is exactly the same, what I outlined previously. And if I just focus in on the assets that fit our R&D strategy, We are now able to look at, for example, phase two assets, assets that might be in phase three, and those are assets that we're going to look at. We're also going to continue to look at tools for our toolkit. I'm not looking at, I have no preconceived notions about the timing of a transaction, and I have no preconceived notions about the dollar amount of a transaction. It has to fit our R&D strategy. It has to be transformative. We have to be able to add value. And when we find that asset and we have the patience and the judgment to be very thoughtful about that, we're going to be ready to evaluate.

Thank you very much. Appreciate that.

Yeah.

Thank you. Our next question comes from the line of Jeff Meacham with Bank of America. Your line is now open.

Afternoon, guys. Thanks for the question. Just two main ones. Charlie or Stuart, you guys recently updated your assumptions on the CF epidemiology. Can you address what data helped lead you down that path and whether this updated view of the CF market by patients is reflected in your 2021 outlook? Second question, Raishman, when you look at the pipeline and strategy, you guys have been obviously busy on the BD front, but essentially have maintained somewhat of a rare disease or specialized focus. I know you've been reluctant to label yourself an orphan drug company, but is it fair to say that future BD could be similar or as a bigger company, could you go after larger indications that share the same spirit of having transformational efficacy? Thank you.

I'm going to ask Stuart to comment on CF epidemiology first, and then I'll come back for your second question.

Hey, Jeff. Thanks for the question. So, as you noted, and just to ground everybody, we recently updated our view on the epidemiology of CF in the U.S., Canada, Europe, and Australia from 75,000 patients living with CF in those countries or regions to 83,000. And the reason that drove that change was really improvements in data quality and capture in the various registries, and indeed some establishment of new registries in these regions. We periodically review all that data, and on our latest review, it was obvious to us that over the last few years, the epidemiology had increased. Just to answer a question you didn't ask, but one that we have been asked consistently is, you know, was that increase concentrated in any one country, any one region? And it really wasn't. It was really an across-the-board phenomenon. And something that's not uncommon as well in rare and orphan diseases is when you have really great transformative medicines, often you see increases in the number of eligible patients. And we believe that was also a factor here. In terms of whether that new epidemiology is included in our long-term, in our 2021 guidance. Absolutely, it is. That's the denominator that we are using now. And indeed, a number of those patients are already being treated with our CFTR modulators in the US, Canada, Australia, and the EU.

Hey Jeff, it's Reshma. I'm really glad you asked the question about rare disease and orphan drugs. So you know the reason I don't like calling us a rare disease company is because we aren't a rare disease company. What we are is a company that is about specialty markets. And the best example I can give you of that is type 1 diabetes and our SEMA acquisition. So when you think about type 1 diabetes, it's well over 2 million people, right? So far away from being a rare disease that suffer from type 1 diabetes. And the key there is that the SEMA acquisition and the cell-based therapy holds the potential to be transformative. So you're very correct. That is a key that we're looking for. And the type 1 diabetics are treated by endocrinologist, a specialty group. So really the key for us is not rare disease, but specialty markets.

And type 1 diabetes is the best example.

Thank you.

Sure.

Thank you.

Our next question comes from the line of Mohit Bansal with Citigroup. Your line is now open.

Great. Thank you very much for taking my question. A couple of questions. One for Stuart, if you could help me understand that you did talk a little bit about new prevalence numbers for CF in these developed markets. But when you look beyond these markets, likes of Latin America or even going as far as China, I understand the prevalence is lower there, incidence is lower on that population basis, but it's not zero. Do you still think about expansion opportunities outside of these, you know, core markets at this point? And the second part is more on the R&D side. As you mentioned, so can you help us understand for VX147 trial, how are you thinking about meaningful reduction in proteinuria there? Because these patients, if I understand correctly, They start at using protein to creatinine ratio of nine or 10 at some times.

Sure, sure. Stuart, do you want to start? And then I'll take one for seven.

Yeah, Mohit. So absolutely, you're right. The HFC-1000 patients living with CF is specific to the US, Canada, EU, and Australia. But in terms of other markets, We continue to believe that there are patients in other countries that we could serve. Indeed, we have established an affiliate in Brazil, and we are in the process of securing reimbursement for our medicines down there. The issue really with epidemiology in some of these other countries is that it's much less robust, much less mature and we have much less confidence in it than we do in some countries like the U.S. and the E.U. where the prevalence of the disease is much higher and there are much more established and longstanding registries. So we continue to see opportunity to serve patients outside of those core markets, but those are the ones where we have a really, really good handle on the epidemiology.

And Mohit, about your question With regard to VX147, to remind everyone, that's the small molecule that we are studying in Phase 2 proof of concept for FSGS, focal segmental glomerulosclerosis. You're right. It's a disease that is unfortunately unrelenting. Heavy proteinuria, usually in the nephrotic range, so more than 3 grams. And what happens to these patients is they either progress on to dialysis or to transplantation. We're looking here, as we are for all of the programs, for a transformative effect. And to me, that would be, you know, double-digit protein reduction. As I said, for the AATD question with regard to what are we looking for from this Phase II study, safety. First time it's going into patients, PK, and in this regard, proteinuria, NC. A double-digit decrease in proteinuria would be great to see and something that I'm going to be looking for. I'll remind everyone that we do expect the results from that study this year.

Thank you very much.

Sure.

Thank you. Our next question comes from the line of Paul Matisse with Siebel. Your line is now open.

Great. Thanks so much for taking my questions. A couple quick follow-ups. On the BD side, you know, I know there's been a lot of discussion around potential indications or disease areas you're interested in, but if you take a step back, you guys have your hands in gene therapy, editing, mRNA, a bunch of different tools. Are there any platform modalities that you don't have your hand in that are especially interesting to you? And then on April 1, one quick follow-up, Reshma, we did a few doc calls, and the feedback was how you interpret the proteinuria data in part depends on the severity of the population and how heavily pretreated they've been by the standard of care. Is there anything you can tell us about the patients you're enrolling in this study? Thanks so much.

Yeah. With regard to the patients that we're enrolling, these are patients with heavy proteinuria. There is some, as you say, there's some background treatment that patients can be placed on, including steroids. But unfortunately, these treatments are not particularly effective. And even when you sometimes can see effect, the durability is often not there. So we're studying heavy proteinurics, and that's what we're looking at. With regard to your question about... tools for our toolkit and what do we have. We are really about transforming diseases. And when you are committed to transforming diseases, the key is to not let the tool be limiting. You know that a small minority of the proteome can be impacted by small molecules, for example. And so if we're going to target a disease and we can't get there by small molecules, we're certainly going to get there with one of the other modalities. And I'm going to ask David Altshuler just to give you a couple of words on mRNA therapies that we are working on, some of the collaborations we've done, and give you a sense of where we are with our gene editing tools. David, do you want to make a couple of comments?

Sure. Thanks, Reshma. As you said, our strategy starts with the disease, and we select a target which is validated as playing a causal role in the underlying biology of the disease. And then we either invent or through partnership we'll find the tools and technologies needed. In the case of CF, aiming for therapies to get at the last 10% of people who don't make a protein and won't benefit from our CFTR modulators, we've collaborated with multiple companies, including Moderna, as you mentioned, for mRNA therapy. In other cases, We've identified a small molecule approach, but we think that adding, for example, protein degradation technology, such as through our collaboration with Chimera, or drugging RNA, I should say, as with our collaborations with Ribometrix or Skyhawk, are the right way to approach those diseases. And you will continue to see us do deals and partnerships where there's a particular technology that opens up a target that we think has transformational potential, and we'll continue to do those as time goes on.

Thanks very much. Thank you.

Our next question comes from the line of Alethea Young with Kantor. Your line is now open.

Hey, guys. Thanks for taking my question, and congrats on all the progress. And I guess I just want to talk a little bit about this VX80-IND. Can you talk a little bit more about kind of your clinical trial plans and designs and how you plan on navigating in light of COVID and that transplant population thing.

Hey, Althea. Thanks so much for the question. I'm really very enthusiastic about the VX880 program. This is the cell-based therapy program for type 1 diabetes. It's actually pretty remarkable that we are at a point where we can now very seriously think about this therapy going to patients and being on the brink of being able to see results. This is a disease and an approach and a clinical trial that I would think about like CTX001 and our CRISPR approach to beta-fouled sickle cell disease. It's a single arm trial. the cell therapy product goes directly into patients. There's no healthy volunteer step. And I would say that in a reasonable number of patients, we're going to be able to tell what the performance of our therapy is. The measures that we are looking at, the outcomes, are very straightforward. Glucose, hemoglobin A1C, C-peptide levels. And so I think this is, you know, the brink of something very special. And I'm very eager to see this program progress.

Any impact from COVID, you think? Or is it going to be pretty straightforward to navigate that?

You know, COVID is something that is top of mind for all of our clinical trials, for sure. But that being said, this is... an approach that is done in specialized centers. And I don't see us having a lot of challenge with it if the COVID pandemic continues in this way, which is to say vaccines are coming, people have learned how to manage, and hospitals are able to continue to do clinical trial work. And so that part looks pretty good to me.

Great, thank you.

Thank you. Our next question comes from the line of Gina Wang with Barclays. Your line is now open.

Thank you for taking my question. I will also follow Alicia's question regarding 880. Just wondering, Rishma, you know, any particular benefit or goal, you know, or benefit you want to achieve with, say, glucose or, you know, anything you can share with us that will lead to the next step for this program. And my second question is regarding the CCX001. For the complete, the trial, current, you know, the trial enrollment completion anticipated in 2021, that's 45 patients each for beta-selicemia sickle cell Could that be registration trial for the next step?

Okay.

There are two questions, one about CTX001 and one about type 1 diabetes. Let me take the CTX001 question first, and then we'll come back around to type 1 diabetes. So with CTEC-SER01, really remarkable, but you are correct. We're looking to complete enrollment in both trials, beta-falcemia and sickle cell disease, and we're looking to do that in 2021. And yes, I do anticipate that the patients that we're studying in these trials that are ongoing will be the patients that... constitute the regulatory package. As you've heard us talk about before, we've initiated those conversations, but we have not yet completed them. So we're looking forward to doing so this year. But yes, I do expect these patients to be the composition of our filing package. On the VX-880 program and what are we looking for? First things first, this is the first time that these fully differentiated stem cell-derived insulin-producing islet cells are going to patients. So what we're really looking for is to get to our clinical trial sites with urgency. We're looking to get the cells dosed. We're evaluating safety. And the outcome measures are really fairly straightforward, C-peptide, glucose, hemoglobin A1C. And what we're looking for here is obviously to see an impact in terms of bringing down blood sugar and being able to see C-peptide levels rise, an indication that there is insulin. It's a little too early to call exactly what the results will be in such but I am very excited that we're on the brink of enrolling patients and getting these trials up and running.

Thank you. Thank you. Our next question comes from the line of Brian Scorney with Bayard. Your line is now open.

Hey, good afternoon, everyone. Thank you for taking my question. Also sticking on the type 1 diabetes program, I was wondering if you could kind of help us understand how your program works differs from sort of the historical islet cell transplantation efforts. I understand it comes from stem cells, but maybe kind of walk us through any engineering or process that goes into the derivation of the cell that ultimately gets transplanted and how you sort of plan to try to mitigate immunosuppressive effects. Thanks.

Yeah, what a great question. And again, thanks so much for asking it. I guess you must be hearing my enthusiasm just brimming over. So the way I would think about the Type 1 Diabetes Program is really two programs, and I would think of them as two separate programs. The first one, the one for which the IND just cleared, let's call that one the Naked Cell Program. I would expect that there are, you know, maybe 60,000 people who could benefit from that Naked Cell Program. that program does require immunosuppression. And the way I get to 60,000 is maybe there are 10,000, 15,000 people who have type 1 diabetes, have end-stage renal disease because of their type 1 diabetes, and for that reason have had a renal transplant and are on immunosuppressants anyway. And then maybe another 40,000 or so people with very brittle diabetes who would be comfortable with immunosuppression for the benefits that the cell therapy would bring them. Now, of course, the high fruit here is the cells plus device program. For that second program, we are in late preclinical development. The really important thing to know there is that the SEMA team, prior to acquisition, and one of the reasons we were so excited about the SEMA team coming into Vertex is that they designed using the right materials, the right geometry, and a clear understanding of how to avoid the pitfalls of fibrosis, allowing oxygen to flow, allowing insulin and glucose to flow, but not allowing the immune cells to attack the cell-based therapy. So that program is... particularly exciting because that does not require immunosuppressive. As we make progress on that program, we'll certainly keep you updated, but that is making its way through preclinical development, late preclinical development right now.

Great. Thank you. Thank you.

Our last question comes from the line of Lisa Baco with Evercore ISI. Your line is now open.

Hi there, I'm just going to jump on the bandwagon and ask a couple more questions on this note. Can you maybe speak to sort of how curable a pancreatic island cell transplantation is today? You know, what you think might be different with. Vx 880 and then a little bit about durability. I think I understand it's quite durable. And then just the final question on inventory. Were there any inventory build in Europe, let's say, given the recent launch there of Trikaft or anything like that to note? Thank you very much.

Hey there. This is Reshma. You know, I'll start with type 1 diabetes and keep on that theme, and then I'll ask Charlie to comment on inventory. Okay. So the question that you ask is an excellent one, and it is, how should we think about... our cell-based therapy vis-a-vis what's been done with pancreas transplant or islet cell transplant. All right. So maybe three or four key things to know. The most important, by far and away the most important thing to know is this. We know exactly what causes type 1 diabetes. It's autoimmune destruction of the pancreatic islet cells. And we know that when you can replace those cells, be it by whole pancreas transplant or islet cell transplants, you get benefits. So we know those two things. What's the problem? Well, the problem is the quantity and quality of islet cells. That is actually the essence of the problem. Not that we don't know that this will work. We know it'll work. And the real... real seminal discovery here that the SEMA team made, and that was so exciting to us, is they developed a way to take stem cells differentiated, fully differentiated into insulin-producing islet cells and make that in industrialized quantities. And so now what we have is the quantity and quality of cells to transfuse, to transplant into patients with type 1 diabetes. So that's really what the real discovery here has been and why this program is so exciting to us. Charlie, from that excitement to an inventory question that I'm going to ask you to address.

Yes, thanks. And I'm going to take this opportunity actually to give a plug to our colleagues in the supply chain and manufacturing organization. I think the most noteworthy comment I can make about inventory is that those teams have worked flawlessly throughout the pandemic to ensure that we have inventory available for our patients, to ensure that we were ready for the CAF TRIO launch in Europe, and to ensure that we will be ready for future launches in 2021. I think your question, of course, is specifically about the impact on revenue. I could tell you that there was nothing noteworthy in the fourth quarter or in our 2021 guidance related to inventory levels.

Thank you. This concludes today's question and answer session. I will now turn the call back to Michael Partridge for closing remarks.

Thanks, Operator. So we're at the one-hour mark. We will conclude the call here. I know there are other folks in the queue who didn't get a question, but the Investor Relations team is in the office tonight and happy to take your questions. And thank you very much for connecting tonight.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.