Vertex Pharmaceuticals Incorporated — 2024 Q1

Yes. Geoff, this is Reshma. Let me take those questions. On the vanzacaftor triple, if you go back and look at all of the CFTR modulated labels, you'll see that we always have sweat chloride in the labels, and they are reflected because it is indeed a pharmacodynamic or PD marker. So I fully expect that the sweat chloride data from the vanza triple studies will be reflected in the label. Obviously, we are just at the point of having submitted the filing, so we're not at the point of label negotiations yet. But if history serves as a guide, I expect the sweat chloride will absolutely be in the label.

Yes. So on the acute pain side, Geoff, I think that the most important data are going to be the primary endpoint data, and I'll ask Stuart to comment on that in a minute. And with regard to securing reimbursement and ensuring that there are no barriers to prescribing a non-opioid, we see that as a very important place for policy. Stuart?

Yes. Thanks, Reshma. So first thing I would say, Geoff, is remember, we are seeking a broad moderate to severe acute pain label so that the product could be used, if the physician decides and the patient wants to, for any type of acute pain, and so we're not really looking for a label that's looking to niches or pre-position us relative to other agents that are out there. We want physicians to have the broadest possible ability to use the product in the patients they see fit.

Yes. Thanks for that question, Jess. So just to set the stage, we see 3 distinct areas in pain: acute pain, neuropathic pain and then everything else. And in everything else, I would add, musculoskeletal pain. It's the kind of osteoarthritis kind of pain. We fully intend to serve all patients, and I fully do expect that our NaV1.8, and when the time is right, the NaV1.7 or the NaV1.7, 1.8 combinations, our pain assets, will serve patients with musculoskeletal pain.

Sure, Salveen. Let me ask Stuart to comment.

Yes. So Salveen, all of the stakeholders that you described are going to be important in making decisions on the use of a new medicine in the institutional setting. So administrators are certainly going to be important, but as are our physician advocates who are going to advocate based on the efficacy and safety of the medicine.

Yes. Evan, just to set expectations, we're not going to comment very specifically on patients and exactly where they are in the cell collection process in each region, but I will ask Stuart to give you a little bit of color commentary on what we're seeing.

Only that we are expecting the momentum to build based on all of the feedback that we've got and the trends that we're seeing in activations and cell collections, as Reshma said. We're delighted to have had 5 cell collections already.

Colin, let me break that up into 2 questions. One on inventory, which I will ask Charlie to comment on first, and then I'll come back on 993 and 973.

Colin, in my prepared remarks, I mentioned that we saw some benefit in the first quarter from phasing of international channel inventory, so I assume that's what you're talking about. That benefit was on the order of $75 million to $100 million in the quarter, and I expect that to begin to reverse in the second quarter.

On 993, 973, Colin, this is all part of serial innovation. 993 is a little bit further ahead than 973 in terms of the preclinical package, the manufacturing and all of the things we need to do to get our medicines ready to go into Phase II. That's why that one is ready to go. 973 is just a little bit further behind.

Yes, on VX-548, fall meetings, shall we say. You should expect more data on 548 with those Phase III results. certainly not only in Congress form but in publications. So I'd say fall meetings. And let me ask Stuart to comment on CASGEVY in the Middle East. It is a really exciting opportunity for us.

Yes, super exciting opportunity for us, Terence, which is why we provide a little bit more color on it. Specifically to answer your question, we don't provide pricing data at an individual country level, but suffice to say, the price we are receiving in the existing reimbursement agreements that we've signed there reflect the transformative value of the product and the lifetime benefits that patients can accrue from it. And that's going to be the same kind of philosophy we're going to have everywhere around the world where we're commercializing CASGEVY.

Yes. Phil, I will ask Stuart to comment on both CF in Brazil. You know that we have regulatory approval and reimbursement there as well as formulary discussions on suzetrigine. But just to make sure we are on the same page, the formulary discussions are separate from our discussions with policymakers.

Yes. So just to add to that, Reshma, what I would say, Phil, is that the policy initiatives that we've seen so far are really looking at trying to reduce financial disincentives for patients and indeed for institutions to selecting a branded non-opioid in a market which is obviously currently dominated by generic opioids. And so that's why things like NOPAIN, which is providing an additional payment above the DRG in the outpatient and ambulatory surgical center setting, is important there.

I can't really speculate on exactly what's going to happen with, for instance, 2,000 institutions. But my hope would be that, that's not what's happening. I don't think it's very reasonable to expect a patient to have to step through a therapy which has significant side effect liability, including addictive potential, when there is a product available, which has very good efficacy from a pain control perspective and has an excellent safety and tolerability profile, including lack of addictive potential. So I don't think that would be something that we would -- certainly wouldn't be advocating and I don't think would be particularly medically reasonable.

Olivia, this is Reshma. Let me take 1 and 3, and then I'll ask Stuart to take the question on where are we exactly with paying commercialization. On number 3, again, just to set expectations on CASGEVY. We're thrilled with the number of ATCs, 25 since approval, which has been in just the last few months, and we commented on the cell collection, but we're not going to comment any further on exactly where each one patient is in their journey.

Yes. So the recruitment of our teams is going very well. Obviously, we are in the middle of our rolling submission here. Obviously, once we've completed that, we'll get an indication from the regulators on when we could expect our PDUFA date to be, and we are going to be launch ready.

Debjit, let me take both of those. On DM1 or myotonic dystrophy type 1, we actually haven't had a chance to talk about it extensively. But this is a program that is in Phase I/II in patients. So we are going to have the opportunity in this study to not only assess safety, but to assess efficacy as well. With regard to what the agency might want to see for the endpoint for approval, the real answer is I don't know yet because we haven't gotten to that phase in the clinical trial.

One last quick question, please, Chuck.

So just 2 from me. Just a follow-up on IgA nephropathy. Have you thought any more about how you might highlight having [ BAFF ]? Because in addition to APRIL, I think that's one kind of key differentiator of this program. And just wondering how you're thinking about how you could differentiate on that point. I don't know if there's biopsies or some kind of different points that you could really highlight the potential benefits of BAFF.

Let me take the IgAN question first, and then I'll ask Charlie to comment on CF. On IgAN, you are correct in pointing out that it's a dual inhibitor. It's an inhibitor of BAFF as well as APRIL. And this is one of the most attractive features of povetacicept is this dual inhibition. Yes, preclinically, we can certainly share when we have information, and you'll certainly see all of this with the fullness of time, the inhibition of BAFF and the measurement of that, and how we can show that preclinically. We can also do that with APRIL.

Yes, Liisa. On the quarter, I wouldn't read too much into sequential quarter fluctuations. We saw strong volume growth in the U.S. year-over-year. As we normally do, we see some seasonal gross to net in the first quarter, and the benefit of the price increase really isn't fully reflected in the quarter that comes throughout the balance of the year. So all of those factors affect the comparison. But overall, very, very strong year-over-year growth in the U.S. and outside the U.S.

Thanks. Chuck?