Great. Good morning. It's my pleasure to be moderating this chat with Stuart Arbuckle, COO of Vertex Pharmaceuticals. Good to see you again. We had a nice dinner last night.
We did.
Maybe to start, Stuart, I think we can have you kick it off by talking about launch prep for acute pain. We can get into other indications and then go from there. So thanks so much.
Sounds good. Yeah, thanks, Paul. Thanks for having us. Yeah, no, we're excited about the potential to launch suzetrigine for acute pain, FDA willing, next year because it's the next pillar, if I can put it that way, of our kind of commercial diversification. Clearly, we are the house that was built on cystic fibrosis, and we continue to be very optimistic about the growth prospects in cystic fibrosis. Clearly, just this time last year, we launched Casgevy for sickle cell disease and TDT, which was the beginning of diversifying on top of our CF base, and so suzetrigine will be our third kind of pillar of diversification starting in acute pain.
But as you know, we've been working in this area for nearly 30 years now, and our ambition is really to do the same for pain as we've done for cystic fibrosis, which is completely transform the treatment of the disease and serially innovate. And so while suzetrigine is a great medicine, we're very much looking forward to launching that. We are, as we do in all of our disease areas, investing in serial innovation. We're looking at additional indications for suzetrigine in neuropathic pain, for instance, where we're in phase III in diabetic peripheral neuropathy. But we also have follow-on molecules like VX-993, which have the potential to be even more efficacious than suzetrigine and can also be formulated IV, whereas suzetrigine can't. It can only really be an oral formulation.
Then after that, we're continuing to work on NaV1.7s, which is the kind of the partner channel to NaV1.8. Our belief is that the NaV1.7s could be both used as monotherapy, but also potentially in combination with NaV1.8. We're certainly pre-clinically. We've seen very compelling evidence of the sort of synergistic effects of working on both channels. We're very much looking forward to the suzetrigine approval. As I say, it's the first step in what we hope is going to be a very long journey to really transform the treatment of pain.
Yeah, excellent. So obviously, the acute pain prescriber landscape in so many ways is completely different than cystic fibrosis. Can you talk about what your goals are for 2025? And if we were sitting here next November, what would constitute a successful year?
Sure. Yeah. So the landscape for sure is very different to cystic fibrosis. So many of the things we're doing from a launch preparation are different than the things we have to do with cystic fibrosis. There are some that are the same. So what are some of the things that are different in our launch prep? Clearly, from a trade and distribution point of view, this is a very different market to cystic fibrosis. So we're going to have to be looking at being available in hospital institutions across the United States.
We're going to need to be in retail pharmacies across the United States so that if a patient presents with a prescription, the pharmacy has the product and can dispense it because if it's not there, they're going to abandon that prescription or the pharmacist is going to ring the doctor and get them to prescribe something else. So that's clearly very different than our specialty pharmacy model in cystic fibrosis. There's clearly many more customers that we're going to need to be calling on. So we have a much larger sales force in pain than we do in cystic fibrosis or in acute pain. We have about 150 representatives in cystic fibrosis. As you know, we have about 16. In addition, we're going to want to get even broader reach in the physician community and increase frequency.
So we're investing much more in digital and digital enablement, both in physicians and with consumers, so there's a lot of things that are different about our launch prep for sure. There's some things which are the same. I mean, they're the same payers, so in the commercial landscape and the government landscape, it's the same payers that are paying for CF, that are paying for Casgevy, that are going to be paying for our acute pain medicine, so much of that work, which is already ongoing, is with the same kinds of customers, and then there are some things which are smaller, so in cystic fibrosis, one of the big teams we have is our patient support specialists who work with CF patients on education and compliance support and things like that, given it's a chronic medicine.
Clearly, so suzetrigine in acute pain, you don't need that kind of support. So we have about 100 patient support specialists in cystic fibrosis. We're not really going to need any of that sort of support in acute pain. So things are very different. What I would say about the difference is it's not like these aren't paths that people have gone down before. The sorts of things like getting on hospital formularies, P&T committees, working with payers for a branded drug in a generic market. These are all processes that are very well established. Our job is to work those processes as fast as we possibly can to make sure that we have access as soon as possible after approval. In terms of our focus in the launch year, as I said, we're taking a very long-term view of our approach in pain.
So we look at year one through the lens of we're going to be in this market for decades looking to transform it. The priorities in the first year are going to be securing access because clearly that's critical to patients being able to receive a prescription for suzetrigine and then also ensure that patients and physicians have a seamless patient experience and that we get broad utilization in the first year. What we don't want is a prescriber writing three or four prescriptions. Those get denied. The patient has a bad experience. The physician has a bad experience. And they decide, you know what, this suzetrigine is just more trouble than it's worth. We're going to put in place programs to make sure that that doesn't happen.
So those two things, I would say, seamless physician and patient experience and securing broad patient access through the year, those are the two things that we're going to be focused on in year one.
Yeah. Okay. Makes sense. I guess having the product available in your local retail pharmacy or in stock in a hospital, right? I mean, the amount of just sheer number of places that you have to have access built up is a lot. And you've talked about how important it is for it to be easy for a physician to kind of get this written and have the first experience be good. So in the context of all of that, how quickly do you think you can, I guess, blanket the United States with drug availability for this to kind of have that initial prescriber experience be favorable and promote more and more utilization?
Yeah. Well, I mean, we are in those discussions right now with both partners in the trade and distribution side, but also in the payer space as well. As you know, we are allowed to engage in pre-approval information exchange with payers, which we are already doing. As I said, our goal is to secure coverage for our patients as soon as possible after approval. And we're also engaging with our partners on the trade and distribution side, both on the hospital side and on the retail side, again, to try and secure distribution as soon as we can after approval. So our job is to try and get it done as soon as we possibly can. Clearly, it's not 100% in our control. It's something we have to work on with our partners, but we are already well engaged in those discussions.
Yeah. I mean, notoriously, hospital launches are slow. I think the challenges, and this is my own experience, I was covering some of those antibiotics companies years ago, right? Where that's a different space because physicians are disincentivized from using a new drug. Nonetheless, do you feel like in the first half of 2025 at the hospital level, it's just going to be about getting on those formularies? Or do you think because of the unmet need in pain and the broad awareness around these issues with opioids that you can actually go faster than predecessors?
Yeah, certainly. Everybody is aware of the opioid epidemic, and therefore everybody is aware of the unmet need in this space for novel non-opioid medicine. So it is unlike virtually any other situation you can imagine in terms of bringing a product to the market when you're trying to solve kind of a societal epidemic, which is absolutely not a secret to anybody. But as you said, we're still going to have to work through those processes with formularies and P&T committees. There are structural impediments such as financial disincentives. That's where a lot of the work around the policy side of things is going to be super helpful to try and remove those financial disincentives to use a brand versus a generic.
That's why things like the NO PAIN Act are so important because I think they're a tailwind to try and remove the kind of barriers that otherwise would be sort of institutionalized in a hospital setting.
Yep. Okay, so in the meantime, your favorite topic. We have LSR data coming up and.
Took me 10 minutes to get onto that.
Yeah. Well, now we have 20 minutes just to talk about the bar and every single permutation.
That's good. Thanks.
But look, I'll ask you the same weighted question I asked you last night, which is that when we talk to physicians in the pain space, they are predisposed to think that LSR is one of the toughest indications to treat. The Gabapentin or Lyrica failed, right? There's just a lot of views out there that these are the hardest patients to manage. So do you feel like this is the highest bar yet for suzetrigine? Or do you continue to be super confident in the rationale and your prior successes?
Yeah. So totally agree with you. There is an enormous unmet need. Lots and lots of products have tried in LSR, and all of them, for a variety of reasons, have failed. So there is a huge unmet need, which is why it's something that we are really keen to try and solve. So what are the reasons why we're confident about suzetrigine in lumbosacral radiculopathy? The first one is the underlying human biology of pain is moderated by voltage-gated sodium channels in the pain-sensing nerves. Lumbosacral radiculopathy, by definition, is pain caused by impingement and other damage to those nerves. So you are attacking the underlying human biology unlike any other product that's come before. Most other products are working on other parts. Things like the gabapentins, things like opioids, they're working on the brain. They're not actually working on the cause of pain.
They're working on your perception of pain, so the actual underlying human biology of pain, and particularly in neuropathic pain, we think plays to what we're trying to do with suzetrigine. That's the first thing. The second thing I would say is we've run six studies now with suzetrigine. All of them have been positive in a variety of different pain states. If you really want to go back even further to our VX-150, the predecessor molecule that we used, it was successful as well. That is almost unheard of in pain that you get so many positive studies. Again, which I think talks to the fact that what we're trying to do with suzetrigine is tackle the underlying cause, the human biology of pain, not try and influence your sensation of pain.
So really, for those kind of couple of reasons, that's why we feel kind of confident to take suzetrigine into LSR, and then we've done the best job we possibly can to ensure that we are getting a population into the study which genuinely has LSR, that they don't have other causes of their pain, that they've had that pain for a while, ruling out other causes of things like lower back pain and things like that to get to a population which is as kind of pure as we possibly can, and as you know, we've said that we're on track to have the results and release them by the year end. It's a few weeks away from the year end, so we're all going to know the answer soon.
Okay. So the primary endpoint of the study is change from baseline.
Correct. Within group. Yep.
Within group, right? And in neurology studies or neuroscience studies, I know it's not CNS, but it's nervous system with subjective endpoints, placebo also usually meets this bar or often does. So in the context of that, how do we think about what is actually good data, right? The canned what is the bar question.
Yeah. So I can tell you what we are looking for. The reason why we designed the study the way we did is we like to do fast, efficient phase II studies, which tell us whether the medicine is going to work and to inform the size and powering of the phase III study. That's what we're doing. Because what we're trying to do is get to patients as fast as we possibly can. So the reason why we've designed the study the way we have is we are looking to evaluate the magnitude of the impact that suzetrigine has itself on pain. And then by having the placebo arm in there in a modern-day well-controlled study.
To give you some context.
To give us some context for what does a placebo do today in an LSR population in a well-controlled LSR population, and that will allow us to size the phase III study, so that's why we've designed the study the way we've done. The other way of doing a comparison with placebo would need a very, very large study, which would take a very, very long time, and that's not what we are interested in doing in phase II. We want to do a fast, efficient study which helps us predict whether it's going to work, whether suzetrigine is going to work in this patient population, and allow us to size the phase III study, and if everything's good, that we can move into phase III rapidly. That's why we designed it the way we did.
Is there a certain numerical margin over placebo you'd want to feel comfortable in the powering of a future trial?
Yeah. We're just not going to speculate on the size of the difference. As I say, it's not going to be powered for a difference. It really is there for context to allow us to size the phase III study. And there's 100 hypothetical scenarios, probably more, that we could all think about.
Should we go through them?
But we've only got 15 minutes left, so probably not.
All right.
We've only got a few weeks left, and we're going to know the answers.
Okay. Okay. Fair enough. So I thought one of the interesting things we talked about last night was this idea that if LSR works and you have LSR and DPN, that you can try to present this case to the FDA to get a broader neuropathic pain label. So maybe take a step back, talk about these different cohorts, what they mean from a TAM perspective, and why you think clinically you have a credible case here with the agency.
Yeah. So peripheral neuropathic pain large is about 10 million or so patients here in the U.S. who have PNP as their primary diagnosis. They may have other diagnoses, but peripheral neuropathic pain is their primary diagnosis. Diabetic peripheral neuropathy is about 2 million or so patients. LSR is about 4 million, just north of 4 million. So between the two, they account for about 60% of all patients with PNP. After that comes small fiber neuropathy, and then there's kind of a catalog of other things to trigeminal neuralgia, et cetera, et cetera, a long list of other conditions. So if we can demonstrate that we are effective in essentially two different types of peripheral neuropathic pain, our hope is that we'd be able to present a case to the agency that that should allow us to get a broad label for PNP.
Now, we will have to get the phase II results from LSR, assuming it's all as well, then we'll be able to go to the agency with our end-of-phase II meeting and discuss that with them, so I don't want to give anybody the impression that that's already decided. It's not, but I would say the one thing that gives us some level of confidence that the FDA is thinking broadly about these things is our hope that when we get our suzetrigine label, it's going to be for moderate to severe acute pain writ large, independent of etiology. It's not going to be linked to specific surgeries, particular settings of care. It's going to be for moderate to severe acute pain.
And to get that label, as you know, we did two studies, one in abdominoplasty, one in bunionectomy, and then a kind of all-combination open label.
This will be the same division for chronic and acute.
Same division. So they've shown flexibility. Again, I think because this mechanism is attacking the underlying cause, the underlying human biology of pain, and therefore you would think it's potentially extrapolatable across different indications within the same setting. So that's our goal. Our goal is to try and get a broad PNP label. Now, what I would say, the downside scenario that we don't, we've still got if we were positive in DPN and positive in LSR, you've still got 60% of 10 million people. You've still got 6 million people you'd be indicated for. Both of those independently, I think, represent a multi-billion-dollar opportunity. We know what things like Lyrica did in DPN. They were billions of dollars in just that indication alone. So it's not a disaster if we don't get PNP right off the bat. They're both very, very big opportunities in their own right.
But mechanistically, you would imagine you might be able to extrapolate it to broad PNP.
Can we talk a little bit about NaV1.7?
Sure.
We didn't get to talk about that last time.
Yeah, yeah.
I'm tremendously interested in this target because of the genetics behind it.
Yes.
And I think outside of the genetic supporting efficacy, I think also the knockout model doesn't have a phenotype. And so you have both ends of the spectrum there that are compelling. The one challenge is if you look at prior NaV1.7s, all of them ran into tox and a couple of them have run into syncope. And there's this theory that in people who have this expressed, you have to avoid hitting the target in the CNS to avoid some sort of interference of the autonomic nervous system. All theoretical, but I'd be curious, where do you stand on your confidence that this target is truly druggable and maybe talk a little bit more about your approach?
Yeah. I mean, so our approach is we're looking at small molecule inhibitors. As you said, there's a variety of hypotheses for why some of the others have failed. You've certainly mentioned one of them. Other ones are obviously given. There are nine of these potential NaVs that you can be hitting. Many of them are in different places. Many of them have different functions, and so certainly specificity and selectivity have also been challenged as well.
Maybe these other challenges are that clean. Yeah.
So that is certainly another hypothesis. And I'm not saying your hypothesis is not one, but there are a number for why these things haven't worked. And the same thing, frankly, with NaV1.8. It is also very important that you get the level of specificity and selectivity. So that's where we're kind of focused with the chemistry effort. Clearly, it is a difficult problem to crack. Many, many others have tried and failed, as you said. We remain confident that we're going to get there. And as I say, both independently as a monotherapy and also very excitingly in combination, certainly preclinically, we see synergistic effects, not just additive of NaV1.7 and NaV1.8 together. And in theory, you could get to never-before-seen levels of pain control if that can play out in the clinic. So like you, we're super excited about it.
Just so to orient people, the kind of NaV1.7 is responsible for the sort of initiation of the electrical signal of pain. NaV1.8 is responsible for the propagation of that signal to the central nervous system. So that's why these two things working in concert could be really, really important in terms of reaching, as I say, new levels of control of pain. So very exciting. We haven't cracked it yet. We'd love to be able to crack it.
Do you have an IND timing there or is it TBD?
We don't. It's still in research right now, so.
Okay. Okay. Maybe let's talk about vanzacaftor a bit.
Yeah.
Okay. So I asked you this yesterday. Any of your prior launches in CF, I mean, obviously Kalydeco is not the right analog, but I asked you specifically if Symdeko is a good analog for vanzacaftor, right? Is Symdeko improved upon or can be just in terms of the kind of market dynamics and how this might be received? So maybe use that to either agree or disagree.
Sure. Yeah. I mean, it's certainly very exciting. As you said, it's not like Kalydeco because Kalydeco was kind of launching into a.
Right, and it's not like Trikafta.
But it is. The profile overall is incredibly appealing to both physicians and patients. And let me just talk you through why that is. Because I'm not sure it's necessarily as clear on its face as to why. And it really is a kind of sum of the parts. The first one is you have to show non-inferiority to Trikafta, which we know is an incredibly high bar. And that is basically the ticket to entry into this marketplace for us and for anybody else going forward because it's clearly the standard of care. And so tick, we met that mark. That's great. In addition, we showed greater levels of CFTR function control as measured by improved reductions in sweat chloride. And CF physicians are very well aware that sweat chloride is the pharmacodynamic marker of CFTR function.
And so they translate that into greater CFTR function control, which is exactly right. The third sort of thing that I think is important is we anticipate we will have 31 additional mutations on the vanzacaftor label that aren't going to be on the Trikafta label. And that's with the Trikafta label with the rare mutations sNDA, which is currently under review by the FDA and other authorities. The reason for that is that in vitro, vanzacaftor as a triple combination versus elexacaftor can get more of these genotypes in our FRT assays, levels of control which are predictive of clinical benefit. So that again reinforces the fact that this is delivering greater levels of CFTR function. And the last thing is it's once a day. And there are many, many patients taking CF. I mean, these patients are the very definition of polypharmacy.
Anything you can do to improve the treatment burden on them is going to be well received. In addition, it's a little bit more for a CF patient with our CFTR modulators than just twice a day to once a day because these things have to be taken with a fat-containing meal. So if you're not having to worry about your fat-containing meal twice a day, every day of the week, every day of the month, every day of the year for the rest of your life, that is a significant treatment burden lifted on you. I think the sum of the parts on vanzacaftor is a super compelling kind of clinical benefit proposition for CF patients and physicians. We're looking forward to FDA approval. Our PDUFA date is January 2nd, so we might be busy over the holidays.
Yeah. Okay. Great. Do you want to talk about the pool of patients who've tried and fallen off Trikafta? And I think you said there are many reasons for discontinuations. Maybe speak to that. But do you feel like this pool of patients, there's going to be a meaningful bolus of early vanza adopters?
Great question. So yeah, so in total across all of our CFTR modulators, kind of globally, north of 6,000 patients who started on one of our CFTR modulators have discontinued over time. And that's across the entire kind of portfolio of them. As I mentioned to you yesterday, there really isn't one major reason why they've discontinued. It really is a whole litany of things. Some of it is for adverse events. It could be lack of efficacy. It could be changes in people's life situation, people getting pregnant and not wanting to take in the drug when they're pregnant. It's a whole long, long list of things. But these patients are currently not receiving any CFTR modulator therapy, which, as we all know, is the only thing that addresses the underlying cause of CF.
And if they can get on a CFTR modulator and stay on one, we know that the clinical benefits certainly at a population level are absolutely exceptional. So we do think there's going to be a lot of enthusiasm from patients who've not tried a CFTR modulator before and not been able to stay on one to try a new treatment option like vanzacaftor. In addition, I think there's going to be many patients as well who are well controlled today but are looking to kind of upgrade to something if it can deliver improved CFTR function. I remember these patients are going to be taking this for the rest of their life. Why wouldn't you want to be on the best product available?
To answer your question, so it's interesting. I've heard the skeptics on Vanza have talked about rare disease markets like hemophilia or other areas where a drug that's come along that's been incrementally more convenient. And there's been a lot of patients who don't want to rock the boat. But usually the two drugs when we're talking about other analogs, and there's no good analog, are from different companies. The fact that this is also a Vertex drug and has some of the same components as Trikafta, how much of that do you think for patients who are well controlled on Trikafta will still make them take the leap because ultimately they trust you and they trust kind of your history in this market?
Yeah. I mean, I hope there's a lot of patients who trust Vertex and the sort of innovation we've been able to bring to CF. And we know that's the case from talking to them. So I certainly think there's going to be a certain level of confidence that this is a medicine that's been brought forward by ourselves. And I think the convenience benefit is certainly one of the benefits that they potentially will see from vanzacaftor. But it's not, as I was trying to communicate, it's not just a convenience.
Yeah, I get it. You have the sweat chloride.
But this does have the potential to deliver improved levels of CFTR function. And if you're a patient or a parent, why wouldn't you want your child or yourself to be on the best available medicine given that you know you're going to be on this for the rest of your life? I think there's also other things and things like hemophilia with titration and worries about kind of.
Sure. It's not a good example, but there's analogs of kind of the same drug. Yeah, anyways. So interesting. Anything you can say on pricing?
That we'll comment on it when it's approved.
You don't want to announce it at the Stifel Conference?
I wasn't planning to.
Okay. All right. Fair enough. Okay. Great. Anything else on Vanza?
No. Looking forward to it. It's going to be our fifth CF medicine or combination of CF medicines and just the latest in our kind of ongoing journey to develop medicines that treat the underlying cause for all people with CF, including those who aren't responsive to CFTR modulators and to continue raising the bar every time as part of our kind of serial innovation strategy. And we're not going to stop until we've got medicines that get all patients to CFTR levels of sweat chloride because we believe that that is what patients deserve. And we believe that's what's going to be the end game in CF is getting all patients to CFTR levels of sweat chloride and then hopefully, if we can, treating them early enough in life that you prevent the kind of CF even developing as we know it today.
That's always been the goal. Vanza Kafta is just the next step on that journey.
Yeah. Okay. Maybe I'll turn it over to you in the last two minutes because there's many other directions we could go. What would you like to talk about?
I guess the last thing I would want people to take away is we are in this new era of commercial diversification. CF is the foundation and continues to have great growth potential. We're super excited about the Casgevy launch and where we are with that. Looking forward to suzetrigine pain. But one of the really notable things I think, and I mentioned this to you yesterday, in the third quarter alone, Vertex put three medicines into phase III studies. So whilst a lot of the focus is on CF and on suzetrigine and to a certain extent Casgevy, three new programs went into phase III just in the third quarter alone to add to inaxaplin, which is also in its phase III program. So the three that went into phase III were povetacicept in IgAN, following our acquisition of Alpine earlier this year.
Our phase I/2 study with VX-880 in type one diabetes converted into a phase III study, which I think is incredibly exciting for type one diabetics. And then the last one was obviously suzetrigine moving into a phase III study, phase III program in diabetic peripheral neuropathy. So that is by far and away the most productive quarter we have ever had in terms of putting programs into pivotal development. And so while a lot of the focus is on the short term, we think that gives us incredible growth prospects for years and years to come. And as we've said, just like with NaV1.7, there is a bunch of stuff in earlier research that we're excited about as well. So Susie always teases me. I always say there's never been a more exciting time to be at Vertex.
I think that's probably the last message I would leave you.
All right. Great. Perfect.