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# Vertex Pharmaceuticals Incorporated presents at Morgan Stanley 22nd Annual Global Healthcare Conference

Thursday, September 5, 2024 11:30 AM

# Event Participants

Analysts 1 Terence Flynn

Executives 2 Reshma Kewalramani, Charles Wagner

# Terence Flynn Analyst

Thanks for joining us, everybody. I'm Terence Flynn, the U.S. biopharma analyst here at Morgan Stanley. Before we get started, for important disclosures, please see the Morgan Stanley research disclosure website at [www.morganstanley.com/researchdisclosures](http://www.morganstanley.com/researchdisclosures). Very pleased to be hosting Vertex this morning or this afternoon.

Joining us from the company, we have the company's President and CEO, Reshma Kewalramani; and Charlie Wagner, the company's CFO. Thank you both so much for being here. I really appreciate you taking time out of your busy schedules -- disclose it after the end of summer, but really looking forward to the conversation. So thank you. Reshma, maybe I'll turn...

# Vertex Pharmaceuticals Incorporated presents at Morgan Stanley 22nd Annual Global Healthcare Conference

Thursday, September 5, 2024 11:30 AM

# Event Participants

Analysts 1 Terence Flynn

Executives 2 Reshma Kewalramani, Charles Wagner

# Terence Flynn Analyst

Thanks for joining us, everybody. I'm Terence Flynn, the U.S. biopharma analyst here at Morgan Stanley. Before we get started, for important disclosures, please see the Morgan Stanley research disclosure website at [www.morganstanley.com/researchdisclosures](http://www.morganstanley.com/researchdisclosures). Very pleased to be hosting Vertex this morning or this afternoon.

Joining us from the company, we have the company's President and CEO, Reshma Kewalramani; and Charlie Wagner, the company's CFO. Thank you both so much for being here. I really appreciate you taking time out of your busy schedules -- disclose it after the end of summer, but really looking forward to the conversation. So thank you. Reshma, maybe I'll turn it over to you just for some opening remarks to set the stage and then I actually have a lot of questions we can run through, but I'll turn it over to you to start.

# Reshma Kewalramani Executive

Sure. Well, Terence, thank you so much for hosting us. It's nice to see everyone in person. Maybe three things to start with. First, in our cystic !brosis franchise, we continue to reach more patients than ever before as we go out to more geographies, get regulatory and reimbursement agreements for the lower and lower age groups.

And we are very excited about the vanzacaftor NDA, which is also in for review with the European regulators that brings -- I know it's hard to believe, but it brings what looks like even more e"cacy than TRIKAFTA. That PDUFA date is January of next year. Also in CF, we're very excited about the VX-522 program, which is an mRNA program with our partners at Moderna, which aims to treat the last $10 %$ . So there's about 5,000, 7,000 people with cystic !brosis

who simply do not make any protein. So the small molecule approach just won't work for them.

And for those last $1 0 % .$ , the VX-522 program is making its way through its Phase I/II study in patients, the SAD, single ascending dose, is complete, and we're working through the MAD. The other exciting news to share, which we haven't been able to do in the past when we talk about our commercialized assets, is our newest franchise in hematology, the CASGEVY program in sickle cell disease and beta thalassemia. The regulatory approval was historic as was the clinical trial and the results. And now I'm really pleased to see that translate to realworld bene!t for patients. You'll hear from Charlie and me talk about the early launch, which is going very well and the metrics that we're following and the patients that are getting to bene!t from this in the real world.

Moving then to the mid- and late-stage pipeline. In the past, we could cover at least most of the pipeline, if not, all of the pipeline in a quick 1-minute summary, that won't be possible today. So I'll just pick a couple of programs. In Phase III already submitted for regulatory approval is the suzetrigine program previously known as VX-548 and NaV1.8 inhibitor for acute pain. There is several programs behind that, but I'll just call out the program in Diabetic Peripheral Neuropathy, which is in Phase III and the program in LSR, a di#erent kind of peripheral neuropathic pain, which is in Phase II.

That one is accelerated in terms of enrollment in dosing and we now expect results from that Phase II program sometime this year. There's a Phase III program with povetacicept in IgA nephropathy and a whole host of potential indications behind that in Phase II. There's a Phase III program in a particular kind of kidney disease called AMKD, and there are Phase I/II programs in type 1 diabetes, a fabulously interesting, innovative program with regenerative medicine and using allogeneic stem cells to basically restore pancreatic function and another program in patients in something called DM1, myotonic dystrophy type 1. And then lastly, if I think about the earlier-stage pipeline, there's a lot going on there in our way of doing R&D, and I'm happy to talk a little bit about that. The punch line is we are a disease !rst company.

We don't work by platform or modalities, nor do we work by therapeutic areas. So there's a whole host of diseases that !t our very strict criteria for what we believe will yield disproportionate success. And I'll just mention in the early stages. There's a NaV1.7 program in late preclinical development that I'm super excited about because of its potential as monotherapy, but more interesting to me is possible combination therapy with our NaV1.8 molecules. There's a very neat program and improved conditioning, which might make CASGEVY available to even more patients and I'll pause there.

# Terence Flynn Analyst

Great. Well, now, I appreciate the breadth of the pipeline. As you said, it used to be -- you could talk about CF for the whole session. But now you guys are in so many di#erent areas. So the diversi!cation strategy is really playing out here.

I guess, !rst, again, Reshma, you started with vanzacaftor, you have the PDUFA date coming up in January. Maybe just help us think about kind of the early launch dynamics as we go into '25. It's going to be another product cycle. You guys know that market and all the patients

phenomenally well. Maybe just level set us in terms of where you're going to be focused in terms of that early opportunity in terms of the launch next year?

# Reshma Kewalramani Executive

De!nitely. I'll ask Charlie to talk about that. The only thing I'll say is the results that were so impressive to us for Phase III, which is exactly what we wanted is a medicine that matches the ppFEV1 lung function gains of TRIKAFTA but do even better in terms of sweat chloride, which is a measure of the protein function, and that's the protein that's dysfunctional in CF patients. And our big goal here is to get all of our patients to carrier levels of that particular function. Over to you, Charlie.

# Charles Wagner Executive

Yes. Maybe just to add on that. Our -- we're in the fortunate position that our patients and their physicians are incredibly well informed on our medicines, and there's a lot of anticipation around vanza, and the bene!t that it can bring. So I would have you think in terms of two cohorts of folks. One, there are roughly about 6,000 patients who have discontinued one of our prior medicines for a variety of reasons.

Those folks would be very eager to try a new therapy, and vanza certainly represents a great opportunity there. To give you a sense, I mean, that discontinuation rate is quite low. But sometimes folks will discontinue because of minor side e#ects like a rash or maybe they've had a life event, that sort of thing makes it very easy for them to come back and try a new medicine. And so that's obviously an incremental opportunity to what we have today. Additionally, we would expect over time, signi!cant transition from prior medicines to vanza.

We're not, at this point, going to call exactly what that looks like for 2025, speci!cally. But based on our conversations, based on our market research, we think over time, the majority of patients will switch to vanza. That said, those that choose to stay on TRI, for example, are on a fantastic medicine, and that's a great result as well. So I think in addition to the clinical pro!le that Reshma described, vanza has the bene!t of once-a-day dosing, which is meaningful in terms of convenience, in terms of compliance, and then from a company standpoint, it has the bene!t of a meaningfully lower royalty burden. So we're really excited about the launch, and we'll have more to say on that as we get into early 2025.

# Terence Flynn Analyst

Okay. Great. I guess just in the interest of time, I want to cover a lot here. Moving on to suzetrigine. You're going to have the Phase III data presented in October at the ASA meeting.

Maybe just, again, high level, I know when we saw the data earlier this year, you gave a pretty in-depth overview of all the data, kind of primary, secondary endpoints, the safety. But any additional analyses or things we should be focused on heading into this presentation?

# Reshma Kewalramani Executive

Yes. The VX-548 suzetrigine data have been accepted -- the RCTs have been accepted as best in ASA, American Society of Anesthesiology, conference. So they'll be presented there. You're right. Some people would say our press releases were novelas because it was a very

detailed.

I think you know all of the key data from there, but it will be the !rst presentation in a congress to the medical community, and I think that's always exciting. But I think you know the thrust of the information, we're well into the part where we've submitted the NDA. They've completed their initial review. The !ling has been accepted. It's been assigned a priority date.

So I think well into the process, but it's always exciting to have data presented to physicians in a congress.

# Terence Flynn Analyst

Yes. Okay. Great. And I guess on the commercial prep, Charlie, maybe you could just elaborate. I know it sounds like you've been having more recent discussions with folks out there in the channel.

And so just what are you and the team doing here to get ready for this launch. Again, you guys will have two launches next year. So again, I'm sure it's all hands on deck.

# Charles Wagner Executive

Yes. Stuart Arbuckle, our Chief Commercial and Operating O"cer and his team are fully into the launch at this point. We've mentioned previously, we've hired roughly a couple hundred folks in the !eld for pain over the last 18 months, including sales reps, key account reps, MSLs, they're all fully onboard, fully trained and fully in the !eld. And it's signi!cant because we're having conversations with a wide range of stakeholders. And we've commented previously that there are roughly 80 million people a year in the U.S.

seek treatment for moderate to severe acute pain. Half of those people have prescriptions written in an institutional setting, so a hospital or a surgical center. And given that concentration of prescribing, that's going to be the initial focus of our commercial organization. That said, for those prescriptions that are written in institutions, $70 %$ of them are !lled in a pharmacy or in a retail setting. So we will focus on the institutions from a prescribing standpoint.

But we're also -- and there, we're having conversations with physicians, with hospitals, with IDNs, all the way throughout to help them understand the pro!le, the signi!cant bene!ts of suz relative to opioids. Those conversations are going really well. We know that there is -- post approval, there is a kind of a well-understood, well-trodden path to go through P&T committees, get on formulary. So we're laying all of the groundwork for that, anticipating that it's going to take a little bit of time once we get approval. Simultaneously, we're talking with payers, PBMs, pharmacies to make sure that the product will be available for patients who want to get their prescriptions !lled at retail.

And in fact, we think the uptake, the revenue opportunity might be a little bit quicker there just because we think that once we get through contracting with payers and some of these organizations, the ability will be there for patients to get their prescriptions !lled. We're also sort of evaluating patient assistance programs and other things to aid with the momentum in the !rst year of the launch. So we're fully in it at this point, really excited and feeling very

con!dent in our readiness for an early 2025 PDUFA date.

# Terence Flynn Analyst

Okay. Great. What -- in terms of -- I mean there's a lot of unique features of this launch. But any analogs that you would point us to as we think about the kind of rollout or -- again, it is somewhat unique because there's not -- as we all know, many branded pain medications that have launched recently. So are there -- what analogs would you encourage us to think about as we think about the pace of ramp?

# Reshma Kewalramani Executive

Maybe I'll answer it in the inverse, and maybe Charlie can add. It is really the case where there are no analogs, which makes it challenging to sort of get your head around what should I expect, but there hasn't actually been development of a new pain class in more than 20 years. So there genuinely isn't something to look at. What would I not look at? I would not look at medicines that are -- that have launched in the recent past in the hospitalized environment, but are only used in the surgical setting.

So there are certain medicines that you can use intra-op. There are some medicines that are a gel or a patch or something like that. But they are not really analogs because this is an oral small molecule. And sometimes in thinking about the vastness of it all, we can lose some of the sort of important smaller threats. It's an oral small molecule.

You take it for any kind of pain and our goal here, and we designed the program with the agency to be able to get a broad moderate-to-severe acute pain label, whether it's postsurgical or not post-surgical. I think you'd have to go back a good 20 years for a branded small molecule to sort of have a sense for it. Charlie, anything you want to add?

# Charles Wagner Executive

Maybe the only thing I would add is given the conversations we've had in the !eld, our con!dence in this being a multibillion-dollar franchise is greater than ever. And we are building for the long term, not trying to lower expectations for 2025. But as we enter these contracting conversations, we're thinking about the trade-o#s between value and speed, and we're building a franchise for the long term. So I think we're going to be thoughtful. We're going to move as quickly as we can.

But we want to set up the business for success over the long term because we see such huge potential here.

# Terence Flynn Analyst

And then how would you consider handling guidance at this point for the pain franchise? I know CF, you kind of have the framework laid out what we expect. CASGEVY, again, totally di#erent from pain here, again, very unique given the nature of the therapy in the market. But how do you think about expectations? Should we just not expect guidance in the !rst year for the pain side because, again, the analogs aren't there.

Again, a lot of moving pieces. Or would you consider giving guidance...

# Charles Wagner Executive

Yes, I appreciate the question. It's a little early for us to give an answer. So the good news is we're in the fortunate position where we would expect to have revenue from three di#erent franchises next year. Obviously, though, with CF and the stage of that business, it's so much larger. So we are thinking through di#erent permutations on guidance, but we'll have more to say later this year.

# Terence Flynn Analyst

Okay. Great. The other question coming up more frequently is just you accelerated the Phase II LSR data, so that's coming now at the end of this year. It is going versus a placebo. This is a disease that does not have any options.

So maybe just help us think about expectations there.

I guess, one question we get sometimes for time to just placebo response and your con!dence that there won't be kind of an outsized placebo response. But again, we know the safety pro!le from the other study, so it's more about that kind of a#ects placebo response. So maybe just walk us through kind of how to think about that ahead of this data set.

# Reshma Kewalramani Executive

Yes. So maybe three or four things that are important as we await the LSR results. So LSR is lumbosacral radiculopathy. It's the impingement of a nerve in the L5 region. That's the pain that you feel.

There have been trials that have been done, but there are no medicines that are speci!cally approved for pain from LSR. And LSR !ts into the broader category of peripheral neuropathic pain. So Diabetic Peripheral Neuropathy, the program in which we released Phase II results last year where we're in Phase III, that's one kind of peripheral neuropathic pain. DPN, Diabetic Peripheral Neuropathy, is about $20 %$ of the overall peripheral neuropathic pain market. $4 0 %$ of it is this LSR, and the rest of it is things like herpetic neuralgia or small !ber neuropathy.

So putting DPN together with LSR, that is more than $5 0 %$ of what is P&T.

All right. The Phase II trial. The Phase II trial has enrolled and dosed faster than we expected, and we have very ambitious time lines, but it has gone faster. So the data readout will be this year, and we had originally expected it to be next year. The study is -- has taken the high dose from the DPN program, so the 69-milligram dose, which is the same dose that's in Phase III in the Diabetic Peripheral Neuropathy study.

And it is a study that has the arm that is randomized to suzetrigine. The analysis is a change in the pain score from baseline to the end of the study period. And there's a placebo group, same thing, the change in baseline pain score to the end of the study period. The question you asked, Terence, about what is your con!dence level, it's the same question we got when we were studying acute pain and when we were studying DPN. And my con!dence level in those two instances was high, and it is equally high here.

And there are three reasons for that.

First, the mechanism of action. This is a very speci!c medicine that targets NaV1.8. NaV is the sodium channel 1.8. That channel is speci!cally found in C !bers of peripheral nerves only and the job of that particular channel is to propagate the action potential, which is what leads to the sensation of pain.

So it's extremely speci!c. That speci!city has led to a whole suite of positive trials with the predecessor molecule. It was called VX-150, then with a suite of studies in acute pain and DPN with VX-548. And so, I happen to be a bayesian in my thinking around probabilities and what's going to happen next. In so far as all of the trials worked before this one, my con!dence level is high.

The next part of this to think through is the selection of patients, and we've been very thoughtful about making sure that we have patients who are included in the study who genuinely have this thing called LSR and their inclusion and exclusion criteria, physical exam !ndings, et cetera, that allow us to do this. And lastly, you mentioned it, and it's absolutely true. Pain studies are hard to do because of the placebo e#ect. There is a placebo e#ect, the perception of pain in one person and what they might score is di#erent than another person. And we've really worked our way through how you should design these studies and we've done it successfully now in the whole trial program with VX-150 as well as with 548.

You put all of those things together, and that's why my con!dence level is high.

# Terence Flynn Analyst

Great. Maybe last one is probably more for Charlie before we go on to pove. Another question we get frequently is just partnering. Obviously, you guys have laid out the strategy for the acute setting. Chronic, I think there's still some debate about this is a much larger potential opportunity.

How do you think about maybe potentially partnering this for that setting over the longer term to address maybe a wider prescriber base?

# Charles Wagner Executive

I think most importantly, people tend to think of chronic pain as one thing. I think we think of it as two things, which is neuropathic pain and all other chronic pain. Neuropathic pain, we see as kind of something that we can serve with a specialty sales force, much like we see with acute. We are going to focus on commercializing in neuropathic pain. We think we can do that exceptionally well.

We have seen in some of our trials that the medicines work for other forms of chronic pain, musculoskeletal pain, et cetera. And we do think that there is opportunity there for patients and opportunity for value, we'd like to establish the value of the medicine in acute and neuropathic. And then over time, we think there will be an opportunity in all other chronic, and given that, that's kind of a primary care call point, it's likely that we would partner for something like that, but !rst things !rst.

# Terence Flynn Analyst

Have you gotten interest from folks like given the pro!le of the asset?

# Charles Wagner Executive

I mean I think the pro!le of the asset is pretty well understood at this point. So it's -- I think it's interesting to a lot of people.

# Terence Flynn Analyst

Great. Okay. Great. Moving on, pove, this is a product -- platform and a product here, as you've talked about, Reshma. One thing I think some people are trying to understand is just this asset goes after BAFF and APRIL and some of the other competitors are focused on CD38.

So why did you guys select this asset in the context of the pathway and the data you've seen? Maybe we'll start there.

# Reshma Kewalramani Executive

Yes. So povetacicept is exactly as you described, a pipeline and a product, and there are 8 indications right now in Phase II already. IgA nephropathy was just the lead indication and -- on the earnings call, I talked about the fact that we would be in Phase III in August. It's now September. So it's a good day.

The reason we're interested in APRIL BAFF inhibition is the following. There are a host of renal diseases and hematologic diseases and actually others, but I'll focus my comments on renal and heme that are known to be B cell driven. So in the basket of renal diseases which are already in Phase II, it's called the RUBY-3 program. There was IgA nephropathy, membranous nephropathy, lupus nephritis and something called ANCA-associated renal diseases. These are all B-cell-mediated diseases.

And in the heme basket, you have things like ITP, cold agglutinin disease, et cetera.

The interesting thing about BAFF APRIL is its dual inhibition of pathway. And what you get from that is inhibition of maturation, di#erentiation and proliferation of B cells which is critical in tamping down the immune response, which is the cause of these diseases. So the dual inhibition at early and later stages of B cell development versus some other approaches what attracted us to this. We also had a chance to see the Phase II data in IgAN, and we had real respect for the Alpine team. I think the design of these basket studies was very clever.

So you put it all together and it was a real !nd for us, and we're delighted with how the acquisition has gone since the announcement.

# Terence Flynn Analyst

On the other side of that, the risk bene!t, the infection risk, I guess, with the \[ plane \] B cells. Just walk us through that access. And again, I mean this is -- there's a lot of history here around this. So I'm assuming that's where you got the comfort from?

# Reshma Kewalramani Executive

Yes. It's a really excellent question because the trade-o# in all of the immunological diseases because the goal of it is to tamp down the immune system is obviously and clearly infection

and such.

So we looked very, very carefully at the IgG levels and the IgA levels, and we looked very, very carefully at the AE pro!le. The e"cacy in this case is world-class. And because of the bene!t risk assessment, we believe that this is the molecule that has best-in-class potential, not just a medicine that looks great on e"cacy or on safety. Bene!t risk is going to be important. It's a biologic.

It also has to have additional characteristics.

This one is a monthly injection. It is a low volume and those kinds of features end up being really, really important for chronic biologic administration. So the preclinical science was very, very sound. What we saw in the clinical trials data made us very excited and has these features of what is going to end up being very important to commercialize.

# Terence Flynn Analyst

Okay. Great. Maybe we'll just talk about the pivotal trial in IgANs a little bit. So you mentioned the trial is now underway. I think you guys -- on the second quarter earnings call, you gave a little bit more of the details about the trial, this 36-week interim analysis this year.

Maybe just remind us like what -- do you have a sign-o# from FDA and kind of what that bar looks like and endpoint? And then what would be the traditional approval, like endpoint, and what you need to show there, I guess?

# Reshma Kewalramani Executive

The short answer is yes. The long answer is we have multiple programs now in renal medicine by the progress of our pipeline. The -- in IgA nephropathy, it's been established and the agency has been very transparent about the fact that they would accept proteinuria as an accelerated approval endpoint. And that's exactly our discussions with them.

We've had our end of Phase II discussions, we've designed our program in consultation with them. And the high-level important points are it's 38 weeks to the accelerated approval analysis for proteinuria. The !nal analysis is for slope the change and the slope of GFR for making sure that the renal function stable is stabilized and it's -- I would say it's a fairly traditional approach for a homogeneous proteinuric kidney disease. It's a very similar approach we've taken for our other Phase III program in AMKD.

# Terence Flynn Analyst

Is $30 %$ the bar for that kind of proteinuria endpoint? Is that fair historical data out there on that?

# Reshma Kewalramani Executive

Yes. I think that, that's a very fair assessment. But if you ask me what is our data at the last time that Alpine show data was at the World Congress of Nephrology in about April. There -- it's a small data set. But at, I don't know, 24 weeks or so, it was like a $67 %$ reduction in proteinuria, and there's only like 1 or 2 people at the longer end point, but it was a 70-plus percent reduction in proteinuria.

# Terence Flynn Analyst

Great. Maybe just in interest of time, we'll move over to CASGEVY. You talked about the early momentum you've had here. Maybe just talk us through some of the remaining bottlenecks that you guys are working on here to continue that momentum. Again, I'm assuming part of it is the geographic rollout, but maybe just help us think through kind of rest of this year into next year?

# Reshma Kewalramani Executive

De!nitely. Charlie?

# Charles Wagner Executive

Yes. I mean it's exciting because we're commercializing in North America, in Europe and in the Middle East, all at the same time. We've commented that -- I think in terms of authorized treatment centers, we're north of 30, 35 treatment centers at this point on our way to 75 or so total, and we should be well close to that goal by the end of the year.

We've had cell collections from more than 20 patients. We've already dosed our !rst patient. The momentum is really strong. And the cell collections have been, again, across all of those geographies. So interestingly, with the ATCs activated, I think the term you used was bottlenecks.

We're not really seeing any bottlenecks. We've got enough ATCs activated, more and more activated every day. We have no bottlenecks in manufacturing, none in our !eld organization, and importantly, real support from payers. And that's really signi!cant.

So whether it's commercial payers, government payers, inside the U.S., outside the U.S., really strong recognition for the seriousness of the disease, really strong recognition for the value of this therapy. And so we are really happy with the trajectory at this point. We've described 2024 as a foundational year. Again, it's better, in our view, to have an outstanding !rst year. These patients, given that we can address 80-plus percent of these patients in 75 ATCs means that a lot of these patients know each other.

They see the same physicians, they see each other in waiting rooms. We really need to make sure that the !rst patients have the best experience, and we're all in and focused on that because we think then momentum will build in a really signi!cant way. So we're thrilled with where we are in 2024. We'll update on those stats, again, in the next earnings call, but we're well on our way to build a kind of a pipeline of patients who are advancing and setting us up for a nice year in 2025.

# Terence Flynn Analyst

Okay. Great. Any reason why a patient that had cells collected wouldn't ultimately transition to receive the product? I know it's a long process here. But -- are there any other things we need to think about?

Or is it -- should we just assume that $1 0 0 %$ of these people will ultimately go on to have the infused product?

# Reshma Kewalramani Executive

Yes. It's a really good question. The time line is what you have to think about. So if the patient had self-collected, the cells were edited and they're ready to be shipped back and received. Sometimes a patient just decides that the last step, although they thought they wanted to go through it, the last step is the busulfan conditioning step.

And even though they went through the process, they had their self-collected, they thought they wanted to do this. They might decide, you know what, I don't want to do this. So I think it's idiosyncratic patient-based factors simply based on where they are at that time and their willingness to say, yes, I want to go through the journey.

# Terence Flynn Analyst

Yes. Okay. Any -- just a !nancial one, as you think about the transition of this JV with CRISPR to pro!tability, have you guys given any rough bookends for when that might occur?

# Charles Wagner Executive

We've not yet -- again, just as a reminder, the economics are a 60-40 pro!t share with Vertex $6 0 %$ CRISPR $4 0 %$ . Importantly, we'll book $1 0 0 %$ of the revenues, and then the pro!t share happens as we -- they will essentially pay their share of R&D costs and then there's a commercial margin that's calculated in the pro!t shares based o# of that. So no, we've not given any guidance on that speci!cally. But look, we're in year 1, there are some costs associated with getting a business like this o# the ground. We're still conducting clinical trials in adolescents.

We've invested in manufacturing capacity so that it is not a bottleneck. And as the patient volume ramps, those costs will get absorbed nicely. So again, I think importantly, we see this as a multibillion-dollar business and one that's going to have attractive pro!tability as it scales.

# Terence Flynn Analyst

Yes. Okay. Great. Want to touch on VX-880. Again, Reshma, you alluded to this, another very interesting pipeline program here, the potential in type 1 diabetes.

The kind of three-pronged approach that you guys have taken, 880 is, obviously, the cell plus immunosuppressive approach. It sounds like we're going to get some updated data at EASD.

# Reshma Kewalramani Executive

Yes. That is exactly right.

# Terence Flynn Analyst

So maybe just is this additional patients, additional follow-up? Just trying to remind us set what we should be focused on here going into that update?

# Reshma Kewalramani Executive

So the VX-880 program is the !rst of 3 programs in our type 1 diabetes portfolio. This is allogeneic stem cell-derived pancreatic islet cell for the purpose of replacement and hopefully, a curative therapy for these patients. Where we are with VX-880 is that we have fully enrolled and dosed the original cohort of 17 patients that makes up the Phase II study as it was originally designed. We have now expanded that. We've spoken to the regulators, and we're thrilled to have expanded that by another 20 patients.

The data you're going to see at EASD, I think that's a September meeting, so later this month, is data on more patients who have longer durations of follow-up than the last cut of the data, which was at ADA in around June.

And where we are -- what we're looking to do with the VX-880 program now is complete our discussions with the regulators and plan forward for Phase III. The next program after that is VX-264, it's those same cells, which we already know work encapsulated in device so as to obviate the need for immunosuppression. And the third program, that program is in Phase I/II, it's in the clinic. The third program is a program that's in preclinical development, so it's in the lab. And what we're trying to do there is a second way to avoid immunosuppression.

And what we do is we are working to make certain gene edits so that the cells are hidden, if you will, from the immune system.

# Terence Flynn Analyst

How do you feel about durability for 880 now -- that we're getting now? I mean I think this is going to be well past 18 months?

# Reshma Kewalramani Executive

Yes. Certainly, some patients are at that point. This is a !rst-in-man study, no one else has been successful. So we don't have any analogs to look at in terms of allogeneic stem cells. But what I can tell you is we fashioned our program after what's called CIT 007, it's donor -- cadaver donor islets.

And when you look at that program, there are people who are out years, 5, 10, 15, 20 years and they're doing really well with their transplant. The problem with cadaveric islets is quantity and quality of cells, quantity, i.e., we don't have enough cadavers and quality because the pancreas in addition to being an endocrine organ is also an organ that is releases enzymes for digestion. So trying to isolate islets is a di"cult thing. Our goal here is -- no doubt about it, our goal is to have a functional cure for type 1 diabetes. It also turns out to be the \[ gaze \] and you learned this from the cadaveric islet experience.

If you need a second dose, it's doable. The problem with cadaveric is they don't have enough dose. You can't even get enough dose for the !rst dose. In our instance, if you need -- I hate the term, but people call it a top o#. It's completely !ne.

We make these cells in our lab, we have as many as you want. But our goal is to transform this disease and to deliver a functional cure.

# Terence Flynn Analyst

Okay. Great. Well, I think we're up against time. But Reshma, Charlie, I really appreciate you

24/05/2025, 22:05

joining us today. Thank you.

Charles Wagner Executive Thank you.

Reshma Kewalramani Executive Thank you, Terence.

Terence Flynn Analyst Thank you.