Vertex Pharmaceuticals Incorporated ($VRTX)

Hi, everyone. I'm Ellie Merle, one of the biotech analysts here at Barclays. Very excited to have Vertex here with us to discuss a lot of exciting news this week with the povetacicept Phase III amongst a lot else going on in the pipeline. Joining us is Miroslava and Susie Lisa from the Investor Relations team. Thank you both so much for joining us.

Maybe to kick it off before we jump right into pove after. But we've seen Vertex shift from being a cystic fibrosis biotech to a more diversified story across several verticals. Could you walk us through the strategy behind the efforts you've made so far and what's coming on the horizon?

Sure. Thanks, Ellie, and thanks for having us very much. Yes, it's a really exciting time. We have long been proud of the work we've done in cystic fibrosis, but have also long had the goal to diversify our revenue base as well as the patient groups that we can address. And I think are very pleased with the progress that we have been making, all while maintaining the utmost diligence and care towards that CF patient community and continuing to move the bar forward there in terms of our ongoing ALYFTREK launch now, which is our fifth commercialized medicine as well as having a NextGen 3.0 family of therapies already in the clinic, and we can talk more about that if there's time. But we're very pleased with the progress that we have made with our ongoing launches in CASGEVY for sickle cell disease and beta thalassemia as well as for JOURNAVX in acute pain to the point where we have built really strong foundations for these products in terms of the patient outreach and support the commercial capabilities as well as the clinical data to support these transformative therapies and have said for 2026, right, that we expect those 2 products combined to do over $500 million in revenue and have established strong basis for their growth. And then given additional targets for JOURNAVX, I think, excitingly to more than triple the number of prescriptions in 2026 versus 2025 and revenue growth should outpace that on a year-over-year basis. And then I think as we'll get into the pove data, what we are really excited about is we feel that this exciting Phase III data from the interim analysis firmly establishes our vision for renal ultimately to rival the size of our cystic fibrosis franchise. And there are 3 therapy -- 3 Phase III ongoing programs in the renal franchise as well as an exciting Phase II for autosomal dominant polycystic kidney disease. And I think this is an exciting time in renal medicine overall, and we look to be a thought leader there and expanding that. And then beyond that, all the while, we've remained very, very true and disciplined to our R&D strategy with our identified sandbox diseases where we under -- they're serious diseases, we understand the causal human biology. There are validated markers. There are efficient pathways for both clinical and regulatory progress as well as specialty commercial infrastructure. And so I think sticking true to that discipline and then just the focus on R&D, the outsized investment that we maintain, that's what enables us to continue to diversify away from CF, all while maintaining a strong outlook for growth there.

Great. Yes, certainly, a lot going on beyond cystic fibrosis. Turning to the pove data. Outside of just the top line proteinuria result, which I think a lot of investors were focused on, what are the other important data points that you think people should be focused on coming out of that release?

Yes. So I think there's a lot, bear with me. I'll try and keep it quick. But I think we were very excited by the overall, what feels to us like a best-in-class profile from an efficacy standpoint. Keep in mind, too, that we feel we definitively have an advantage from a patient administration and dosing standpoint, where we have the lowest dose of 0.46 mls in an at-home auto-injector, and it's once monthly versus peers are either higher dose and/or weekly injections that are required. And we also feel that we will have best-in-class from a commercial capability standpoint as well and there are actually a lot of similarities between the CF and renal markets and nephrology community. And so we're excited for that. But in terms of the key data highlights, UPCR certainly does grab everyone's attention, and that's where we saw a 52% reduction at 36 weeks. I think that's important because some of the peers have had primary endpoint measurements at 40 weeks and you continue to see improvement over time. So seeing that type of reduction at 36 weeks is important. From Gd-I -- on the secondary objectives, 2 endpoints there, one on Gd-IgA1 with a 77% reduction as well as an 85% resolution for patients' hematuria, an 85% rate of resolution. And those 2 were at 36 weeks. Again, some of the peers are measuring secondary endpoints at 48 weeks, so even more potential for differentiation. I think another key highlight, particularly in physicians' minds is the fact that 42% of our patients got to the KDIGO recommended guidelines of a UPCR less than 0.5 grams per gram that also compares quite favorably. And this is very much a real-world population, right? With the most recent of the IgAN studies, we enrolled the fastest. We also had the highest rates of background therapy. Nearly everyone was on ACEs and ARBs and more than 65% of patients were on SGLT2 inhibitors. We also saw that the average duration from time of diagnosis, biopsy diagnosis to enrolling in the study was 3.8 years, right? So it very much is a real-world population that high background therapy and still seeing that level of improvement on there, I think, is really significant. The other big piece of news is that they -- we announced that we'll submit our -- complete our rolling submission by the end of this month. I think that's beating expectations by about a full quarter for most. And we have used a priority review voucher. So after the FDA has 2 months, to accept the filing, consider and hopefully accept the filing, then it will be a 6-month review from there. And I think those are the key highlights. Yes. If others come up, we can bring them up later.

Yes. And I think that's particularly compelling, particularly the proportion of patients that got below 0.5 grams given that is in the guidelines now in terms of where patients should be going.

Exactly.

So I think that's an interesting from an efficacy perspective. And considering the patient baseline, which I think you appropriately called out, seems to be a more real-world patient population. A question that we're getting a lot of is on safety. Maybe if we could talk about that. I mean you have the potential to be more potent, but with the immune system that also comes at the potential risk of some more like infection risk. Can you talk through what was actually seen in the study and how you're thinking about the safety here?

Yes. We were quite pleased with the overall safety results, and it's a very, very clean profile. I think perhaps to start that the vast majority of adverse events were mild or moderate and that there were no severe serious -- no SAEs that were deemed related to pove and no SAEs that were inherent in that, right, is none due to infection. We can also confirm that there were no discontinuations related to infection. and there were no opportunistic or unusual infections either. Most of the -- we included in our release that the greater than 10% rate were upper respiratory tract infections, nasopharyngitis and injection site reactions, right? So all very common. And I think a very favorable profile, and we're excited to move forward.

And a question that we got has been on hypogamma. I guess what can you say on what was seen here and when we can expect to learn more about that?

Yes. Thanks for the question. And I think there has been a lot of discussion around this. And it's very -- I think in general, everyone cautions from cross-trial comparisons, right? And particularly when it comes to issues like infection, I think it's even more fraught with peril. And there are very different definitions across the industry in terms of definitions of what the thresholds were for hypo IgG as well as what counted as a case of it. For us, in the RAINIER study, any patient who went below a level of 300 milligrams per deciliter that, that was then deemed to be monitored. And if the patient went below 150, then treatment was discontinued or would be discontinued. We have told you there are no discontinuations through the interim analysis group. And so due to -- in order to maintain study integrity, we're not disclosing the number of that below 300 number or numbers. But we have told you all the information on infections because the so what of hypo-IgG is infection. And you're just not seeing it as we went through previously. I would say a similar question, we did disclose that there was evidence of ADAs, but the so what there is on efficacy. And as we mentioned and discussed, right, I think very, very good efficacy even with all of the background therapy. And in addition, we provided a fourth plot in the press release that shows you excellent results across every subgroup, including by race as well as by region. So you don't see any of the outliers perhaps you've seen in other studies. So I think both on hypo-IgG as well as ADAs, I know investors always want more disclosures, but we feel that we've given the consequences, the answers to the potential consequences of those, and there's nothing there.

That makes sense. In terms of pove, what I think is interesting is that this could be a pipeline and a product and has applications in a number of other conditions. Can we talk through that and sort of the rationale you see in PMN, myasthenia gravis and the time lines for those?

Yes. So in primary membranous nephropathy, I think very much akin to thinking about IgAN and in terms of that patient population. But IgAN is a little bit larger, right, 330,000 patients in U.S. and Europe and PMN is slightly smaller. There's no -- we're in an ongoing Phase II, Phase III study. There is no interim analysis or accelerated approval pathway here. It's a 104-week study, but we're underway and excited to keep progressing. And I do think as physicians are considering their choices, the thought of having to learn and be fully immersed in one therapy to treat a broader array of their patients is a potential advantage we could have. And then for myasthenia gravis, we said that we'll initiate a Phase II study in the first half of this year. And I think if you're looking for a [ poster ] trial for B-cell-mediated disease, that's probably myasthenia gravis. And you have seen data out of China that looks quite compelling. And I think the rationale just makes all the sense in the world, and that's why we're moving forward and excited for that. And there could be additional indications beyond those 3 that we have discussed.

Makes sense. And how should we think about kind of the commercial opportunity for each of these considering unmet need, patient population, but also the competitive landscape?

Yes. So I think in -- let's maybe just start with IgAN that there is a clear unmet need, right? There's 330,000 of these patients who are diagnosed today, really with no good options. You've heard physicians describe them as kind of just waiting to see how and when and how fast they'll progress. And to have a disease-modifying therapy that can stave off the need for dialysis or transplant and ideally death, right, that, that is, I think, obviously compelling to patients, physicians and to payers as well because all of those options are expensive ones. There are -- I think about 4,000 nephrologists treat 80% of these diagnosed patients in the U.S. We've had ongoing conversations with them from an access -- with payers about access since the middle of last year and continue to have those conversations. We have built out sort of the initial phase of our sales force. And now with this data, we'll look to complete that. Vast majority of the ones we have hired have nephrology experience in the community. And again, we've been in nephrology for a long time with our inaxaplin study. And I think definitely, as we saw at ASN last November, a real excitement and buzz about the innovation that Vertex is bringing to the renal community, not the least of which is helped by the fact that our CEO is a trained transplant nephrologist. So that certainly helps. PMN, similarly, I think no real disease-modifying therapies. And in myasthenia gravis, we view the opportunity as some of the existing therapies, the drawback there is that they need to be cycled on and off, whereas we don't see that need given the mechanism with pove, but we need to do the trials and move forward from there.

Okay. Makes sense. And then I guess, in terms of inaxaplin, you have some exciting data either late this year or early next year. Let's talk about that opportunity and what you're looking to see in the Phase III program.

Yes, sure. So this is a disease that has no existing therapies, nothing that addresses the underlying cause of disease. And we think that the cause is the APOL1 mutations that people inherit that ultimately, there is a second trigger, but they drive poor formation in the kidney that ultimately results with the progression of kidney disease and rapid progression to kidney failure. So what we're developing there is our molecule is inaxaplin. It's in Phase II/III pivotal development, and we expect to read out the interim results from this trial late this year or early next year. The goal is reduction in proteinuria, and we will also look at eGFR slope versus placebo. So those are the endpoints. It is clear we need to show stabilization of eGFR versus placebo as a pathway to file for accelerated approval.

And what gives you confidence that you'll be able to see the stabilization in eGFR slope?

Yes. So it's a great question. AMKD, this is really the first trial for this population. So obviously, we are the first to study this disease. But what gives us confidence is these patients, based on all the literature and everything we know about them, they progress twice as fast to renal failure and to dialysis than their peers who don't have the APOL1 alleles. So based on all of the -- everything we know about the patients and the progression of disease, there is reason to be optimistic that the curves can separate even at 1 year.

I'd also mention in our Phase II study, which we published in New England Journal that even just at 13 weeks, right, you saw a 47.6% reduction in UPCR. So we're hopeful with that sort of speed and depth of reduction that, that can lead to the endpoint in eGFR. I think admittedly, 48 weeks typically would be a short time frame for eGFR, but we're optimistic.

Great. Turning to the cystic fibrosis business, maybe just the latest that you're seeing in terms of a ALYFTREK uptake. We saw some decent growth in the fourth quarter. How should we think about the trajectory over 2026?

Yes. We would expect a continuation of the same solid trends in terms of ALYFTREK and conversions from TRIKAFTA to ALYFTREK. I would say that virtually all new patients are initiating on ALYFTREK given the lower sweat chloride that you can see with it as well as the once-daily dosing convenience as well as the fact that, that means only 1 fatty meal a day and patients have appeal there. We're also excited by the ongoing launches and reimbursed access in Europe. And for instance, just given the derivation of the disease, you actually see more of the rare mutations in Europe than you do in the U.S. And we gave an example on the fourth quarter call that there are now 1,500 patients with access for the first time in Italy given the rare mutations that are -- that can be addressed by ALYFTREK. There's also no incremental liver monitoring anywhere outside the U.S. So that's helpful for uptake outside the U.S., too. But I think continued good progress and a focus on the messaging around lower sweat chloride is better and ALYFTREK gets you there, right? And we also just published or released top line data from our study in ALYFTREK, where you see in the 12-plus population, right, about 30% of patients are getting to diagnostic levels. In the 6 to 11, I think it's about 53%. And by the time you get to 2 to 5, which is the one we just released, you're getting to north of 60% of patients getting below the diagnostic threshold. So these are kids who essentially be asymptomatic of their CF. And we've begun a study in 1- to 2-year olds with ALYFTREK. So that will continue the momentum. So we've talked about growth overall in CF from younger patients, additional geographies, additional patients with the rare mutations and then the underlying population growth, which has averaged 3% over the past 5 years due in large part to the survival benefit that you're seeing from our meds.

Makes sense. And as we think about long term and life cycle management, any thoughts on NBD1?

Sure. So NBD1, we know the CFTR protein intimately well. I've been studying it for 20 years. NBD1 is a known binding site on the protein for many years. It's been in the literature, I think, over a decade. And we have -- we are looking at NBD1, we've disclosed, but that the binding sites that we have used for our 5 commercialized medicines have been different ones. And as I mentioned, as we're getting close to now almost 2/3 of 2- to 5-year-olds getting to carrier levels of sweat chloride. I think we are happy with the binding sites that we have chosen. But we'll continue to look to try and improve until we can get virtually all patients to those carrier levels. I don't know that there's anything particularly unique, particularly given the breadth that we're seeing in terms of over 300 rare mutations, et cetera, about NBD1. But we are continuing to look to move forward. We have a NextGen 3.0 family of therapies one of which is in patients, one of which is in healthy volunteers, and we'll look to continue to raise the bar, and we'll see what others can do in terms of data middle of this year, I believe, which is on top of TRIKAFTA, which is our therapy. But as I said, we'll see, and we continue to move the bar forward. And it's a long pathway from proof of concept, if that's what you see to finding a molecule -- a combination therapy is inherently difficult and then the head-to-head studies and then just getting it down into the younger patients. It took us a decade to get into the 1-month old from initial approval.

Yes, makes sense. That's helpful context. Turning to JOURNAVX. You said you expect scripts to triple this year, which is certainly impressive growth. This is a program that I think investors should be paying more attention to. Maybe talk through some of the investments in the sales force that you've made and what's driving some of the script growth.

Yes. On JOURNAVX, we are very pleased with the momentum, frankly, entering 2026. We came into 2026 having secured the last remaining commercial PBM for access to -- for coverage to JOURNAVX. So we are at over 200 million covered lives. That's 67% of all covered lives in the U.S. We -- as you remember, Ellie, we had 550,000 scripts written for JOURNAVX in 2025 in year 1, which was pretty broad across the hospital and the retail segment and different specialties, 35,000 physicians writing prescriptions. So we were very pleased with the momentum going into 2026. And we feel strongly that now is the right time to double down and invest further behind the launch. So we are doubling the sales force from 150 to 300 reps. These reps will be active in the field in the second quarter. And the goal for them will be to go broader and deeper with accessing physicians and driving adoption of JOURNAVX. And in addition to that, we are also increasing our marketing investment. So things like direct-to-consumer, where we are launching advertising across Connected TV, Hulu, Paramount+ and the like. We have a campaign with Basketball Star, Hall of Famer, Jayson Tatum. So we're out there. We're promoting heavily, and we expect that to increase over the course of 2026. And as coverage broadens, the gross to net we are realizing on JOURNAVX will improve over 2026. So that will result in more revenue and higher revenue growth, as Susie mentioned, relative to the script growth.

One other thing I'd add is, and maybe touch on it is 2 Phase IV studies that we're excited about. One we just published -- was presented last week in aesthetic and reconstructive procedures. We'll have one next month in arthroscopic and laparoscopic orthopedic procedures, but showing really tremendous patient satisfaction as well as high, high rates of patients being opioid-free in the 14 days post treatment. I think in the aesthetic one, it was 90% of patients were opioid-free. And typically in that patient group, you see only 10% of patients are opioid-free according to the literature, and we look forward to similar results in the orthopedic one. So I think that will also help continue to fuel the momentum.

Yes. We've certainly heard very positive feedback from physicians in the aesthetic setting as well. So exciting data. As we head into 2027 and potential Phase III data for DPN, sort of remind us of the time lines and the trial design there? And what gives you confidence in potential success? Because this certainly would dramatically, in my view, expand the market opportunity given the duration of the script would be much longer than a chronic type of pain.

Yes. We are well underway with our 2 Phase III trials in diabetic peripheral neuropathy. We expect to complete enrollment in both trials by year-end. and that would set us up for results in 2027. So we feel very good about the progress of this program. There's 2.5 million patients with diabetic peripheral neuropathy in the U.S. who have a significant unmet need. The current available treatments are either not well tolerated, I would say, or just don't provide sufficient relief. And so we think we have a lot to offer here with JOURNAVX, but we'll have to read out the results and see how it plays out.

There are 12-week studies with 2 weeks of follow-up. Is that right?

Yes, yes.

Great. Well, a lot to look forward to. I think we're out of time, but thank you both so much for joining us, and I appreciate the time today.

Thanks very much for having us.