Good evening. This is Michael Partridge. Welcome to the Vertex Third Quarter 2021 financial results Conference Call. On tonight's call, making prepared remarks, we have Dr. Reshma Kewalramani, Vertex's CEO and President, Stuart Arbuckle, Chief Operating Officer, and Charlie Wagner, Chief Financial Officer. Dr.

Baoxian Asana, Executive Vice President and Chief of Cell and Genetic Therapies at Vertex will join us for Q&A. We recommend that you access the webcast slides as you listen to this call. This call is being recorded. 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 in our filings with the securities initiative commission.

These statements, including without limitation, those regarding for Vertex's markets 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 review on the call this evening is non-GAAP. I will now turn the call over to Dr. Reshma Kewalramani..

1. NaV1.8 is genetically validated. 2. NaV1.8 is also pharmacologically validated with our very own 3 positive Phase -2 proof-of-concept studies in acute, neuropathic and musculoskeletal pain. And third, our lead molecule in the program, VX-548 has the key drug - like properties that we're looking for including high selectivity and potency.

The 2 Phase-2 dose ranging studies in acute pain, bunionectomy and abdominoplasty, with VX-548 are well underway. Based on enrollment progress, we currently expect data from these studies in Q1 of 2022. With that, I'll now turn it over to Stuart to review the commercial progress..

Thanks, Reshma. I'll begin by reviewing the Q3 revenue performance of our CF medicines, which reached nearly $2 billion in Q3. U.S. revenues were $1.38 billion, an increase of 13% compared to the prior year, driven by the performance TRIKAFTA, including the launch in the 6- to 11-year-old population.

The launch in the 6- to 11-year-old is progressing rapidly, which is not surprising given the profile of the medicine and the recognition of the importance of early treatment of this relentlessly progressive disease. Outside the U.S.

revenues were $601 million, an increase of more than 90% over the third quarter last year, driven by the ongoing launch of KAFTRIO in the 12+ population. In particular, KAFTRIO is off to a strong start in France and Italy. 2 major markets where we achieved reimbursement in June of this year.

We also signed a letter of intent for public reimbursement of TRIKAFTA in patients 12 and over in Canada. And since then, we've achieved multiple provincial reimbursement agreements and some 90% of patients covered by government insurance now have reimbursed access to TRIKAFTA.

We have achieved reimbursement agreements KAFTRIO TRIKAFTA, in more than 20 countries outside the U.S. just over 1 year since approval. And importantly, we've continued to achieve reimbursement at levels that reflects the high value of the triple combination regimen.

As Reshma mentioned in her remarks, the profile of our CF medicines continues to be enhanced by long-term data. The sort of the North American CF Conference is tonight.

And amongst several important abstracts, are data from the ongoing, 192 week open-label extension study of TRIKAFTA, which shows there has been no loss of lung function during long-term follow-up. This is a first for any CFTR modulator to-date, an important milestone for the field.

All previous long-term data for our other medicines showed a slowing of lung function declined. In contrast, these data show no loss of lung function for patients on TRIKAFTA after 96 weeks of follow-up.

Real-world data also being presented at the conference on KALYDECO show at an average of 6 years of follow-up, a 78% reduction in the mortality rate, and an 89% reduction in the rate of lung transplantation compared to patients who were not eligible for the treatment. These data are very important for patients and the medical community.

Because they more fully illustrate, how our medicines address the long-term progression and complications of the disease. These data also have important implications for the future competitive landscape. As they raise the bar, in terms of what will be required to compete effectively.

Now, turning to some of the other opportunities in our pipeline beyond CF. Our commercial experience in CF provides foundational capabilities, which we will be able to leverage to commercialize our next wave of transformative medicines. As Reshma mentioned, regulatory submissions for CTX001, are planned for the end of 2022.

And so, our launch preparation activities are well underway to ensure we are able to bring this potential medicine to patients globally immediately upon approval. We see CTX001 as a potential one-time curative approach for the approximately 32,000 patients with severe sickle-cell disease or transfusion-dependent beta thalassemia in the U.S.

and Europe. We've developed a deep understanding of the sickle-cell and beta thalassemia markets, including where patients with these diseases are, and the role that key referral and treatment centers will play to facilitate the treatment journey for patients. Consistent with our own internal market research, published physician surveys in the U.S.

consistently indicate that, they would expect a quarter to a third of their patients with sickle-cell disease to be good candidates for a one-time curative approach using the current conditioning regimen. Which is in line with the estimates of the numbers of patients with severe disease, approximately 25 thousand sickle-cell disease patients.

We are focused on three key areas of launched preparation for CTX001. First, people. We've hired many of the key people who will support the launch. Second, manufacturing. This is an area we have focused on from the earliest days of our work on CTX001.

To ensure we can supply our consistent and high-quality product to the large number of patients we believe will benefit from the medicine on day 1 of the launch. Importantly, we are using the same manufacturing sites and processes for commercialization that we are using for our clinical trials.

And third, patients, making sure we really listen, understand them and their experience. So, we can provide them at launch with the information, resources and support they need as they consider treatment with CTX001. Now turning to pain. With our acute pain studies well underway, I thought I would remind you of the large market opportunity there.

Acute pain accounts for 1.8 billion treatment days a year in the U.S. alone. And despite more than 90% of prescriptions being generic, this is still today, a $4 billion market.

That's typical branded pain medicine pricing of approximately $10 a day, a new medicine that takes even a portion of the current treatment days has multi-billion-dollar potential. In light of the unprecedented data for VX-880, it's also worth highlighting the market opportunity in type 1 diabetes, which is very large. Let me start with the disease.

Type 1 diabetes is a disease affecting more than 2.5 million people in the U.S. and Europe alone. It is a severely debilitating and life-shortening disease in which due to auto-immune destruction of pancreatic islet cells, the body produces little to no insulin. There are 2 patient populations to consider.

First, those with severe enough diabetes for whom the benefit risk profile is positive for the sales alone plus standard immunosuppressive therapy. And secondly, the broader population, who would be candidates for the cells encapsulated in our propriety device or hyper-immune cells where immunosuppression would not be needed.

There are at least 60,000 patients with type 1 diabetes in the U.S. and Europe who are potential candidates for the first approach with VX-880. This group is made up of people who have severe, difficult to control forms of type 1 diabetes, characterized by impaired awareness of hypoglycemia and severe hypoglycemic events that can be life-threatening.

There were approximately 45,000 patients in this category. And then there are people type 1 diabetes who have had previous organ transplants, primarily kidney and so are already on immunosuppression. There are about 15,000 patients in this category.

Cadaveric islet and whole pancreas transplants are already performed, albeit in small numbers of these patients and give some sense of the value of this type of intervention in a patient with severe disease. For illustrative purposes, if you use the benchmark price in the U.S.

for a pancreatic transplant of approximately $400,000 per patient as the price for a cell-based treatment, treating even a minority of the eligible patients would represent a multi-billion-dollar opportunity.

Beyond Vx 880 the cells plus device program, which encapsulates the same cells for which we recently reported the unprecedented clinical data into our proprietary device that protects these cells from the immune system, could address the broader type 1 diabetes population, 2.6 million patients in the U.S. and Europe.

In summary, I'm pleased with our continued progress in bringing our CF medicines to more patients around the world, and excited about the many opportunities in our pipeline. And with that, I'll turn it over to Charlie..

Thanks, Stuart. In the third quarter of 2021, Vertex's long-term track record of strong revenue growth continued. Total product revenues were $1.98 billion, a 29% increase compared to the third quarter of 2020. Notably, TRIKAFTA represented nearly 80% of third quarter revenues as most eligible patients have switched to TRIKAFTA.

Our third quarter revenues included $1.38 billion in the U.S., and 601 million outside the U.S. Ex-U.S. revenues for the quarter grew 92% over the prior year, driven by continued strong uptake for KAFTRIO.

Our third quarter combined R&D and SG&A expenses were $561 million compared to $497 million for the third quarter of 2020, driven largely by investment in our clinical stage programs and our research pipeline.

We expect our R&D investments will continue to be substantial as we advance our mid and late-stage programs and make further clinical and regulatory progress across the pipeline. Our continued growth in revenues combined with disciplined growth in OpEx, translates to a year-to-date operating margin of 59%.

And with our strong revenue and profitability, we ended the second quarter with $7 billion in cash. Now to guidance. We are again revising our 2021 guidance upward for total product revenues in the range of $7.4 billion to $7.5 billion. This increase reflects continued out-performance, as well as the rapid uptake we have seen with new launches.

Year-over-year, this guidance represents 20% growth at the midpoint. As Stuart highlighted, the 6 to 11 launches in the U.S. and the uptake in France and Italy are proceeding very rapidly. Even with the outstanding growth in the number of patients treated this year, we have approximately 30,000 patients left to treat with our CFTR modulators.

Given our proven track record of securing new reimbursement agreements in additional markets, executing successful launches and expanding access to younger age groups, we are confident that we will be able to reach the vast majority of these patients with our medicines.

We are maintaining our non-GAAP OpEx guidance for full-year 2021 at 2.25 to 2.3 billion. And for our non-GAAP tax rate, we continue to guide to a range of 21 % to 22% this year.

In conclusion, 2021 will be another year of rapid growth for Vertex and we're confident in our continued growth trajectory in CF and our ability to lead in this therapeutic area over the long term. TRIKAFTA an exceptional medicine that sets a very high bar for efficacy and safety with IP that extends to the late 2030s.

With the emerging profile of our next regimens beyond TRIKAFTA, as well as the progress we're making in genetic therapies for CF, we are well on our way to fulfilling our vision for achieving carrier levels in all CF patients.

The VX-121 tezacaftor VX-561 regimen is the only regimen with clinical data that shows the potential to meet or exceed the performance of TRIKAFTA and is years ahead of any other regimens in development. Our pipeline beyond CF is both advancing and delivering.

Progress with CTX001, and more recently, Vx 880 continues to demonstrate the value we can create by investing in external innovation. We look forward to sharing additional data with you as ongoing trials come to completion in the coming months.

We anticipate Phase 2 data for VX-147 in APOL1-mediated FSGS and Phase 2 data for VX-548 in acute pain in the near-term. With growing revenues and margins at the top of our peer group, we will deliver strong cash flows as we continue to reinvest in internal and external innovation to drive future growth.

We're confident that the execution of our business strategy will continue to drive exceptional results for patients and the medical community, as well as for our shareholders. We will now open up the call to questions..

. Our first question comes from Salveen Richter with Goldman Sachs. Your line is open..

Good afternoon. Thanks for taking my questions. 2 on the pipeline here.

With regard to your collaboration with Moderna, I recognize that you're moving forward nicely with the -- with delivering mRNA via LNPs; could you just talk about where you stand with mRNA to explore the use of gene editing in lung cells? And then secondly, on the development plan in Type 1 diabetes, maybe you could touch base on the expanded collaboration with Arbor and how that fits into that outlook here..

Yes. Hey Salveen, this is Reshma. Two questions in there. One about the mRNA program with Moderna and another question I think on type 1 diabetes, but specifically with regard to our collaboration with Arbor and how we're thinking about the hypo-immune cell programs. Let me break it up into two parts.

And maybe I'll expand a little bit on type 1 diabetes even beyond the collaboration with Arbor. Let's start with Moderna.

We are very excited about the recent breakthrough we made in -- that I shared in my prepared remarks on the mRNA program for the last 10% of Patients with CFTR -- we simply don't make any CFTR protein, right? And when you step back and think about what do you really need to do to make a breakthrough here. It's really about sweet things.

It's about the HBE cells. It's about mRNA constructed cells, and then for sure it's about delivery. And it's this last one, delivery, that's been a vexing problem for us in the field as a whole and that's really the exciting news for today.

With regard to the HBEs cell, these have been the workhorse for the 4 medicines that we have brought forward already. And I say that because they're the only model that translates from the bench to the bed side.

And it's not only qualitatively so but quantitatively so and it's these HBE cells that have also been the workhorse for the program with Moderna. The second is the mRNA construct itself in a number of years ago. We have struck up a partnership with Moderna, arguably the best Company in this space of mRNA.

And in all honesty, we have for some time been able to express full-length CFTR mRNA, the protein, and demonstrate its functionality. We've been able to do all that in vitro and HBE. But over the last several months, what we have now been able to do, is demonstrate that we can deliver using nebulized LNPs to the appropriate cells.

So that is to say to bronchial epithelial cells and we've done this in small animals and large. And we can see that we've delivered them to deliver the mRNA construct to the bronchial epithelial cells. No one else has claimed to do this, and certainly no one else has been able to do this.

So that's the big advancement that allows us to go and start our GLP enabling studies. Those are already underway and I do expect the IND to go in next year. On type 1 diabetes, Salveen, there are the cells themselves and then there are the mechanisms to cloak the cells.

In the first program with Vx 880, we use simple off-the-shelf Pharmacologic Immunosuppressive. In the second program itself plus device, those IND studies are already underway, IND next year. The third program is using these same cells, and for the cloaking, we use or plan to use gene editing, for example, to make hypo immune cells.

I'm going to ask Bastiano to comment just a little bit more on the hypo immune program.

Bastiano?.

the allogeneic rejection and out immunity..

Great. Thank you..

Our next question comes from Michael Yee with Jefferies. Your line is open..

Hi, good morning -- good afternoon. I had 2 questions; it's been a long day.

1 is actually, the announcement this quarter that you had moved your new CF program into Phase 3, and I would like for you to comment about it in the context of how much clear differentiation you're confident it is from Trikafta, but also in the context of the fact that everybody knows there's a competitor with data coming and how we should interpret that in the context of your data that you put out in the press release and how differentiated it could be.

The second question is more a question around the fact that you had commented about M&A earlier this year. In fact, Rush Med commented even about areas like Huntington's and I just want ed you to refresh that view in the fact that you haven't really commented about that so much like you did earlier this year and recent prior quarters. Thank you..

Sure. Hey, Michael, good afternoon. Let's do the question first and then I'll come to capital allocation and M&A So we have obviously established ourselves as a leader in CF over the last decade plus. And over the recent few years, we've expanded that leadership first with TRIKAFTA that can serve up to 90% of people with CF.

And then with the specific program that you're asking about VX-121 / 561 Tez, which pre -clinically in these HBE cells that are a model that translate from bench-to-bedside have demonstrated the potential to have even better efficacy than TRIKAFTA.

And in the clinical program from the Phase 2 results that we shared earlier in the year, where it looks that 121-561 test has Tsikata the ability to provide even more benefit than TRIKAFTA. Make no mistake about it, TRIKAFTA set an incredibly high bar.

It's an extraordinary medicine with a very high benefit risk profile, but 121, frankly, is the competitor to TRIKAFTA. It's years ahead of anything else in the field. If I just stand back and look at this, Mike, we have the best medicine for CF today in the form of Trikafta. We the best medicine for CF tomorrow in the form of 121561 Tezacaftor.

And as I look, long-term, when you really think about CF, a chronic disease, children are born with this disease. They're going to take medicine for a lifetime. Chronically, you're going to need long-term data. The kind of data that Stuart talked about in his prepared remarks.

Mortality, lung transplantation, rate of decline, and to be clear, the only Company that has the short-term data and the long-term data is Vertex. With regard to capital allocation, Charlie, I'll ask you to comment on that one..

Thanks, Reshma and Mike, thanks for the question. Listen, it's very clear to us that innovation is the greatest driver of value in this industry. And we have shown that in CF that innovation that leads to transformative medicines for serious disease creates tremendous value both for patients and for shareholders.

And we hope to do that in a number of other disease areas that are represented across our broad pipeline. So, when it comes to capital allocation, our primary focus is on reinvestment in innovation, both internally and externally. You can see in the numbers we've never invested more internally than we are today.

And you can also see in the pipeline the benefit of some of the smart external investments that we've made over the last couple of years. I would call out CRISPR and Semma specifically but there are many others. and so, from a capital allocation standpoint, that reinvestment in innovation will continue to be the top priority.

And we've not commented specifically on types of deals because we're not looking for a certain type of deal. We are looking for tools and technologies and assets that fit and are well aligned with our research strategy and as we identify those, you can expect that we'll continue to be disciplined and move quickly when we see an opportunity..

Thanks, guys..

Our next question comes from Phil Nader with Cowen and Company. Your line is open..

Good evening. Thanks for taking our questions. 2 from us, if that's okay. 1 commercial, 1 pipeline. On the commercial, the growth quarter-over-quarter was pretty impressive. Could you give us some sense of where you think you are penetrating the 6- to 11-year-old in the U.S.

and then those XUS markets that you highlighted like France, Italy, and Canada, and whether the type of growth that we've seen this quarter could continue into future quarters.

And then second on the pipeline and FSGS, as the date approaches, we're just curious to hear your most recent thoughts on what would be proof-of-concept for the molecule and what gives you confidence to go from the narrow FSGS population to the broader APOL1-mediated kidney disease population based on this initial data. Thank you..

Yeah. Hey, good afternoon, Phil. I'm going to ask Stuart to comment on the question around CF and how we see growth. And then I'll come back and tell you a little bit more about the FSGS program.

Stuart?.

Hey, Phil. Yes, thanks very much for the question. And, yeah. I'm enormously proud of our execution in this third quarter that led to the results that you commented on and led us to increasing our revenue guidance today. It's hard to comment specifically on kind of quarter-on-quarter what our growth rates going to be.

But I'll give you a sense where we are in our overall growth trajectory. As you said, we got the approval further, 6- to 11-year-old for TRIKAFTA in June. So just prior to this quarter starting. We also secured new reimbursement agreements in important markets like Italy and France, and also most recently in Canada. And the launches there are underway.

What I can tell you is that the level of enthusiasm for the 6- to 11-year-old TRIKAFTA here in the U.S. and overseas. KAFTRIO is exceptionally high in line with that. We've seen in every other market where we've launched Trikafta, Kaftrio. So, there's launches are off to a strong start. Obviously, we're in the first few months of those launches.

So, looking ahead, what do I see despite the fact that we've had really successful launches for Trikafta and Kaftrio. We're still actually only treating today about half of all the patients with CF who could benefit from medicines, overall.

And specifically, to CFTR modulators is about 30,000 patients yet to go in terms of patients who could benefit from our medicines. Now, you might ask yourself who are those patients? Well, those patients are patients in countries where we have reimbursement, where we're early in the launch sequence.

Some of the markets I just described, there in countries where we have regulatory approvals with most of the world now, but where we have yet secure reimbursement agreements and they're in younger age groups, obviously 6- to 11-year-old. Outside the U.S.

we don't yet have an approval and also, we're going to be pursuing approvals for TRIKAFTA KAFTRIO down to even younger age groups as we have done with KALYDECO and ORKAMBI.

So given our track record in securing approvals, getting reimbursement, and successfully launching, I have no doubt that we're going to get to the vast majority of those 30,000 patients over the coming years until I see substantial growth for our CF franchise between now and the middle of the next decade.

And then as we announced today, we also made great progress with our mRNA program, which has the prospect of developing a medicine for the 10% of sober patients who don't respond to CFTR modulators. So, I think we've got substantial growth runway yet to go in CF. And Reshma back to you..

so, in Phase 2, we're studying APOL1-mediated FSGS. That is 1 kind of APOL1-mediated kidney disease. It's a very aggressive form of renal disease, about 10,000 people who have that. But APOL1-mediated proteinuric -- let's say, primary proteinuric kidney disease. I know it's a mouthful. There's about 100,000 people who have that.

And if the Phase 2 study is positive in FSGS, what that really tells you is that we have now for the first time, found a small molecule that interdicts on APOL1 and can potentially be a therapy for that broad FSGS. Not only FSGS, but the broad AMKD market. So, the full 100,000. And then with regard to what would we consider successful. Okay.

So, the Phase 2 studies in FSGS, right? And the entry criteria are such that it's a very severe population. It's APOL1-mediated FSGS with a high burden of proteinuria and we allow stable doses of standard of care therapy. So, these patients are already on ACE s, ARB s, immunosuppressives, and steroids.

So, in that kind of patient population with an aggressive disease with high levels of proteinuria already in standard of care, double-digit improvements in proteinuria, that would be impressive.

Now, of course, higher is better but double-digit improvements in proteinuria, that would not only be important, it would be something that we've not seen before..

That's perfect. Thanks for taking our questions..

Yes. Yes..

Our next question comes from Brian Abrahams with RBC Capital. Your line is open..

Hi guys, congrats on the quarter and thanks for taking my questions. We'd love to learn more about the mRNA program. And I guess, I'm curious how translatable non-human primate lungs are to human CF lungs, especially given the mucus layer.

Do you have any sense of what the half-life for the resonant time in the lung would be in terms of, what type of frequency of administration one might look at a general range? And might you see any opportunity down the line for this to be usable? Perhaps in combination for the other 90% of patients who don't have nonsense mutations, but with CF.

Thanks..

we have been very, very diligent and deliberate about dose and making sure that the mRNA, transcript and protein expression are in the right cells.

I would say that in drug development in this area, that's the most important part that many others have not gotten right and that's specifically why I talked about the HBE assays in vitro, and the small and large animal studies and the targeting of the mRNA construct to the relevant cells, which are the bronchial epithelial cells.

And I feel very good about the dose selection, about the schedule of dosing, and the targeting to the appropriate cells. Now, with regard to the question about down the line, do we think this could be extended to the other 90%? I would actually look at it the other way. CF is a systemic disease, it's not only a lung disease.

And so, the real value of small molecule correction of the CFTR protein is that, you get systemic benefit. So, in the setting of the last 10%, and what I would contemplate is, if our -- we're successful with our mRNA program when we are in the clinic next year, it's combining the mRNA with a small molecule.

We're obviously the only ones who could do that, and I think the opportunity to bring benefit to the last 10% is therefore tremendous..

Thanks so much, Reshma..

Our next question comes from Robyn Karnauskas with Tuist Securities. Your line is open..

Great. Thanks for taking my question. So, 2 quick ones. So, for during lung stability. In the real world, what percentage of the population would benefit from you think the new drugs that you are developing, meaning that their sweat chloride levels are below normal range in these might be able to put them into that bucket.

And second question I had is for your device for diabetes.

How does the devices -- you talked about how getting the cells in, they go to the liver and then blood vessels form, how they interact with the liver to function? How does the device not only protect the cells from the attack by the immune system, but also allow them to have the interaction with blood vessels to work and function? How does it work? I was just wondering if it might not be able to interact with the blood vessels because it's in a device.

Thank you..

Yes. There are 2 different questions in there, Robyn. 1 about Type 1 diabetes and the device. And then a separate question about how we think about VX-121 561 test. And maybe I'll expand that to the next generation of CFTR modulators. Let's do CF first and then we'll -- let's do Type 1 diabetes next.

Robyn, you know this, the TRIKAFTA KAFTRIO medicine can treat up to 90% of people with CF and it has really extraordinary efficacy.

And what we see is that large numbers of patients, as you saw in the clinical trials program, get benefit in the double-digit improvements in ppFEV1, significant improvements in sweat chloride, in weight, in quality of life. Now what we are trying to do in our long-term goal is to get all CF patients to carrier levels of sweat chloride.

And the reason we want to do that is because carriers really manifest almost no disease. And what I can tell you is 121, 561 Tez in our pre -clinical experiments in these HBE cells that have this quantitative and unquantitative relationship to what we see in the clinic.

The 121 Tez 561 has the potential to be even better than TRIKAFTA on that dimension. But we've already identified another generation of molecule that, in our HBE assays looks like they're going to get us to that ultimate goal of getting all patients with CF, but 90% to carrier levels.

With regard to the device program, I'll ask Bastiano to comment, but here is the quantitative important thumbnail sketch of the field and what the real breakthrough that we have made. The problem with device historically has been foreign body reactions or fibrosis. And the second challenge with devices has been vascularization.

Both of those challenges are what we tackled with our program and what we do not see with our device. So, what we do not see is fibrosis or foreign body reaction. And what we do see is really excellent vascularization.

I'll let Bastiano to comment about the materials and the geometry and the configuration of the device that allows us to have the kind of effects that we have. Bastiano..

Thanks, Reshma. And Robyn just wants to maybe start with making clear that this completely novel device that is made with different materials, different geometry, different configuration from everything else that has been described by others in the field.

It will specifically design, rationally design to exactly address the causes of failure in the field of encapsulation like Reshma said which is foreign body response and vascularization.

It's called Cells in Device for that particular reason, is proposed design to really minimize fibrosis and to allows the device to integrate in the body, allow vascular beds to form throughout the device on top and the bottom. So that serves as always opportunity distance to a source of oxygen and nutrient.

Allowing for installing glucose, of course, to be exchange. This competitive from what we think those in the field. And we have evidence in our pre -clinical models that, we do not see it by the response, we see a robust neovascularization, we see rapid insulin responsiveness, immuno protection, even in immuno -competent animals..

Thank you..

Our next question comes from Lisa Becker with Evercore ISI. Your line is open..

Hi. Thanks for taking the question. I wanted to ask about CTX001.

So, when you file at the end of next year, can you talk about for how much data and follow-up data you'll have on how many patients? And then I also want to ask just a commercial question as you're doing a lot of your commercial craft, can you maybe describe like what the -- what -- how many patients per year can be treated in the U.S.? kind of, given that hospital environments and all that kind of stuff.

So how should we think about kind of what -- at time of launch, what that will look like, and then how that may evolve overtime? Thank you..

Lisa, I think you're asking about how we see commercial launch for CTX001..

Yes, I just wanted to what the throughput of patients, like capacity-wise; is there some upper limit on that that we should think about as we think about the population, there's quite a bit population, in fact, but I'm trying to understand what the capacity is in the United States, at least, and how you think that may evolve over time? But -- from the onset, what would that look like?.

Yes, sure thing. Let me ask Stuart to comment on how we see the CTX001 launch and the launch dynamics. Taking into account the question specifically about, whether there are capacity constraints in such. And I'll come back and tell you a little bit more about how we see the filings, Stuart..

Yes. Thanks, Lisah for the question. So, we saw the highest level with the overall opportunity and then I'll get to your question about the launch dynamics or our views on them at this early stage. So, in terms of people who have severe sickle cell disease and beta thalassemia between the U.S.

and the EU, we think there's about 32,000 we estimate patients who have severe disease in both of those in the combined populations of sickle cell in vivo beta thalassemia. In sickle cell, it's about 25,000. And because of the nature of the disease, the vast majority of those are in the United States.

And that number is going to be validated by external physician surveys which would indicate that they think they would treat between 25% in the third of all of their sickle cell disease patients with a 1-time curative approach with the existing conditioning regimen.

So, we think that's about the order of magnitude of patients who might be eligible for this initial phase of a gene-editing curative treatment. In terms of launch dynamics, it's really going to be a function of probably 4 things. The first one is to the physician - and -patient interest in the technology.

And based on the results that we've seen to-date and enthusiasm we've seen in the field, particularly as it translates into interest in our clinical trials, we expect the enthusiasm from the community to be high. The other end, it's going to be a function of our ability to manufacture.

And as you can imagine, we're working diligently on our manufacturing processes to make sure that we have capacity to treat patients. But the bottleneck is likely to be in treatment centers. And as you know, the treatment is going to be administered in transplant centers, there is a limited number of those in the U.S.

and they also have competing priorities with malignant hematology conditions. And so, that is likely to be the right limiting step. We're obviously in the initial throws of evaluating those treatment centers and working with them.

Again, we do think that enthusiasm to treat these patients is going to be high, given the very significant unmet need in sickle cell disease and thalassemia and the outstanding results we've seen to date. So, without commenting specifically, because I wouldn't know the exact answer to that.

But at this early stage, Lisah, those are likely to be some of the pinch points that were -- in terms of the launch dynamics. What I can tell you though, is we are expecting demand to be very, very substantial amongst those 32,000 patients, given the unmet need and the results we've seen..

1. What is the sample size that is -- that they will require? And, 2. What's the duration of follow-up? I expect we're going to finish those discussions in the next couple of months and I do expect that the filing will go in towards the tail end of next year..

Okay. Thanks..

Operator we'll take two more questions..

Okay. Our next question comes from Cory Kasimov of JPMorgan. Your line is open..

Hey, thanks. Good afternoon, guys. I wanted to follow-up as well on CTX001 and just to piggyback on the filing. I recognize we should get more clarity in the coming months, but can you talk about your comfort level on the regulatory front when it comes to addressing any CMC requirements.

We see -- frequently see delays there with regards to cell and gene therapies. And then also, you speak about the 32,000 patients between the U.S. and Europe.

Wanted to ask about your comfort level with Europe as we recently saw Bluebird back out of that market with LentiGlobin for betasal based on the fact that they couldn't come to agreement on pricing. So, your comfort level that you can get around this? Thank you..

Cory, let me start with telling you a little bit more about the regulatory process and come a little bit more on the factoring, which is your specific question. And then I'll ask you to comment on Europe.

Obviously, we are -- we have the opportunity, not only in Europe, but the opportunity certainly including Europe to leave for the front with our CTX001 for both beta thalassemia and sickle-cell disease. Okay.

Quick on the regulatory filings, because of these designations which had been -- had benefits of multiple conversations with the agency and as I said earlier, been able to address most of their questions and we're really now wrapping up conversations around two clinical points, which is how big is the database and what's the duration of follow-up.

On the manufacturing side, we are using the same processes. And actually, the same sites as we did for the clinical trials for the commercial product. And in the grand scheme of things, when you think about what we're doing with CTX001, it's ex vivo gene editing. And really, it's the tax enzyme and the guide RNA.

And in the grand scheme of things that's just simply an easier manufacturing situation than other manufacturing challenges. So, I feel very good about our conversations with the agency. We've been able to de -risk by addressing their questions along the way.

And we are using the same processes in the same sites that we used in the clinical trials for the commercial product.

Stuart, a couple of comments maybe from you about Europe and CTX001?.

Yeah. Cory, thanks for the question. I feel very confident in the team that we have on the ground in Europe and their ability to secure reimbursement and access for patients who have rare diseases.

The transformative medicines, likely, I think may go to demonstrate the capability to capture and describe the unmet need in these types of conditions to gather and generate evidence on the both economic and clinical benefits of our medicines, translate those into value propositions, which makes sense to payers and then work creatively with payers to develop bespoke solutions country-by-country to secure reimbursement and access for our medicines.

I think we've demonstrated that very, very successfully in CF and I'm looking forward to us being able to use those same capabilities to get access for patients with sickle cell disease and beta thalassemia in Europe..

Great. Thank you, guys..

Our next question comes from Geoff Meacham with Bank of American. Your line is open..

Hi guys, this Olivia Brokaw on for Geoff. Thanks for the questions. I have got two follow-ups on the next-gen triplet program.

First is, can you give us a better sense for when we might start to see those Phase 3 data on that, now that both of those trials are up and running, and whether there could be an opportunity for an earlier look at you, guys 1 or maybe both of those trials as we get into next year? And then I know you guys have talked about moving forward even more next-gen triplets at some point.

So, are there specific areas where you're maybe more focused on when you think about the optimization or differentiation of those newer assets? And just as a follow-up to that, could there be some potential ways to accelerate development timelines once those agents move into the clinic?.

Yeah. Hey, good afternoon. With regard to your questions which really center around the next wave, whether it's 121, 561 Tezacaftor, which is already in the clinic in Phase 3 clinical trials, or the molecules that we've identified in San Diego that are going to be coming into the clinic.

How are we thinking about this? How quickly can we go? What's the overall goal? So, to be clear, the goal here is to bring all patients with cystic fibrosis to carrier levels of sweat chloride. That is our long-stated goal, and that is what we are aiming for.

And I feel really good about where we are with 121/561 Tez, based on the pre -clinical results that I shared and the Phase 2 results that we shared earlier this year. And the next wave of molecules looks like they can be even better.

So, we are well on our path to bringing forward therapies that can bring all CF patients to carrier levels of sweat chloride. With regard to speed and how fast can we go, right? I don't think that, anybody can go faster than us in cystic fibrosis for a couple of reasons. 1. We've already demonstrated that, we can do this very quickly.

In TRIKAFTA, we went from the bench, so first synthesis of the molecule to U.S. approval in less than four years. Outside of oncology, it's one of the fastest drug development programs ever.

The second reason I say that we do this really fast is we have a lot of experience in this, right? We've already done it with 4 medicines on the market, the fifth one being 121, and 561. And with regard to where should we expect results in such, remember, the trials for TRIKAFTA, we enrolled in about 6 months.

So that's a benchmark for the last set of clinical trials we did. I expect this to continue to use the -- what we know when our experience to move fast with 121, 561 test and the molecules behind that..

Okay, great, thank you very much..

Thank you all for tuning into the call tonight. If you have additional questions, please reach out to the Investor Relations team. We are in the office tonight and happy to follow up. Have good evening..

This does conclude the program. You may now disconnect..