Thank you. We're ready to go.
All right.
All right. Fantastic. We'll jump right in. I want to do R&D and commercial. Do we have a preference where we should start?
Up to you.
It's up to you.
OK. We'll start maybe a little bit on the R&D side, and we'll come back to commercial, then probably go back into R&D again.
OK.
Maybe in no particular order. Let me start with the cadence trial. Clear success. It looks like there were these questions around whether it was enough to warrant an FDA submission or at least a regulatory conversation. It does not look like it met that bar. Was there a certain number you guys were expecting or a certain endpoint that would have warranted that? How should we think about that?
Yeah. We are very excited about the cadence results because these are patients that do not have any possible, any current therapy to improve their outcomes and their ability to engage in activities of daily living. These are patients who have got pre- and post-capillary pulmonary hypertension caused by heart failure with preserved ejection fraction. It is a really discreet but very important population. The results were really quite good. We are very happy with them. This was a proof of concept study. It is not a regulatory, it is not a filing study. It gave us rock-solid evidence that we can move on to phase three. We think this is really going to be important for patients. We look forward to seeing the results being presented in upcoming meetings so that everyone can assess it. Our steering committee has been super happy about it.
We are going to head to phase three in 2026.
Got it. Is this a launch which is post-2030?
I don't know. The reason why I don't, I don't mean to not answer the question. It's just we have to figure out what the primary endpoint is going to be for phase three. That requires discussions with our steering committee, our regulatory agencies, and so on.
I see. I see. Is it fair to say that there is a signal on time to clinical worsening?
We have not disclosed other endpoints. I would tell you that we are confident that we can move to phase three.
Got it. When I did some checks on this, one of the feedbacks I was hearing quite often was part of the reason phase two took so long to recruit was because the inclusion was very restrictive on the wood units involved, more than four. Would Merck look to relax that?
You know, one of the axioms that I learned through bitter experience is don't get a phase three signal that looks really good, and then go ahead in phase three and change everything. Because that just doesn't make sense, particularly when you have a new biology like the story here. I actually think that the reason why enrollment took so long to begin with is because no one looks for these patients at present because there's nothing to give them. I recall back in my days with hepatitis C, the moment we started to see patients to see the promise of the new therapies, everyone came out of the woodwork to be retested and be ready. I see this as a similar sort of thing. Once you have something that you can offer to people, then people are testing. We'll test for it.
For me, we saw that in the last months of enrollment, all of a sudden there was a lot of interest once they saw the results of ZENITH and STELLAR. They said, maybe this is good for my patient. All of a sudden, patients showed up. We had a big acceleration of enrollment. I see phase three enrolling quickly, even with this.
Got it.
Great.
Chirfi, maybe just taking that enrollment to the commercial side, I guess one thing that confused me on cadence was it was about 160 patients, but it took 120 sites to deliver 160 patients. Does that form a very tough commercial uplift? Or do you think it'll be very different once the data are out there?
Yeah. The CpcPH population we estimate to be roughly the same size as PAH. You are thinking about, you are looking at 50,000-60,000 in the United States. As Eliav mentioned, the diagnosis rate is lower because physicians have not been looking for it. We think that, again, post-phase three data, once people start to see the presentation next year or the phase two, more physicians will be sensitized and look at those patients. We do not anticipate a different commercial model to what we have with PAH. We will be able to execute this.
Got it. Your confidence on WINREVAIR sotatercept trajectory right now remains good. I know there were some questions a couple of quarters ago on whether rate of patient adds was slowing. It sounds like things are pretty smooth.
Absolutely. Our confidence is growing because with the data, with ZENITH and Hyperion now, what you're seeing is in the U.S., to stick with the U.S. for a moment, the majority of our patients have come from the more severe PAH cases. About 75% of those patients are on WINREVAIR in the U.S., and those are the triple therapy patients. We are seeing an increasing willingness by physicians to treat the less severe patients, and the data from Hyperion in particular is giving confidence. We are going to see steady growth, 500-600 patients steady every month coming into treatment with WINREVAIR. We are launching outside of the U.S. and are very encouraged by the early signals from Japan. We are going through the reimbursement process in Europe. You know that takes longer, typically. The feedback has been tremendous across.
Fantastic. Fantastic. Which takes me then to another important launch for Merck next year, PCSK9. I think Peter would tell you Reed has a lot of questions on this one in terms of is this a real launch or not. Obviously, the Merck opinion is very different than the street opinion on this. Maybe this is a question first for you, Chirfi. I'm sure Rob has a number out there for you to deliver on this. Is the feedback you're hearing from AHA consistent with sort of the perception that the broader organization has?
You know, we are not surprised by the feedback. I was at AHA.
Sorry, which one? The investor feedback or the doctor feedback?
AHA.
A doctor feedback.
Doctor feedback.
OK.
Thanks for clarifying. Thanks for clarifying.
You're like, I told you it's bad feedback.
Thanks for clarifying. I mean, we're really excited about the opportunity for obicetrapib. I mean, this is potentially a game changer. There's a cardiovascular epidemic going on. Despite all the tools that are available, the injectable PCSK9s have not really had the kind of impact that was anticipated, given how powerful they are, really. The whole mechanism is just such incredible. To be able to deliver a PCSK9 antibody efficacy in a pill form, and I summarize it as 60, 50, 50, 30, when you think about the efficacy of obicetrapib. 60% reduction in LDL cholesterol, 50% reduction in non-HDL cholesterol, 50% reduction in ApoB, and 30% reduction in Lp(a) little. That's the profile that was presented at AHA. That was really surprising to the scientific community. Not to us, but to the scientific community, certainly.
The AE profile is comparable to placebo. Think about that. That is a really, really big deal. We think that we now have a tool that will allow us to democratize access and to really, really drive LDL lowering in the U.S. and around the world.
I want to come back to access because I've been getting questions on it lately as well. Just before that, the feedback on food effect, feedback on sort of drug-drugs, like you can't take multiple drugs together. Like how?
Yeah. No, thanks for the question. Drug-drug interaction does not appear to be an issue.
No drug-drug interaction. You can take it with you. Can you take other meds with it, like your blood thinners and all that?
Yes, yes. That's a big deal. That's a big deal.
No issues there.
That's the big deal. The food effect in the study, Eliav can talk to it, but 97% of patients in the program were able to follow the regime. You take it in the morning, 30 minutes later, you go about your breakfast. Not an issue at all. The scientific community was ecstatic.
OK.
For us, for me, what was really interesting was the lack of any, it was kind of a let's talk about how we're going to implement as opposed to worry about these sort of things. The lack of DDI, consistency of effect, it was really exciting for people.
Got it. Peter, I think there was a comment shared on the transcript recently. And Chirfi, if you could chime in as well on access. There's this perception that you guys are looking to come in below what the current PCSK9 branded pricings are. I just want to make sure I understand exactly what you guys were saying.
Yeah. We've not been that specific. We've just said we're going to price for access, for broad access. We've not been specific with respect to what that means in terms of gross or net prices.
I see.
We do not anticipate price to be a barrier. I mean, we are going to price appropriately for value and for access. We really want to drive rapid access. I mean, just to be clear, I mean, we are going to need guidelines to be updated. As you think about the models that we are working through internally, we're going to need to activate the inertia that exists in the space, ensure that guidelines are updated so that more patients can benefit from the power of Enlisted Tide.
Interestingly, the Vesalius study results are I think we're a major recipient of the benefit of that, being able to show tremendous reduction in cardiovascular outcomes in patients who are high-risk primary or primary prevention patients is going to be very, very useful. It's the place where cholesterol management is done. I think that that's going to be very useful for us.
Right. There is another oral cholesterol launch next year as well. Is that factoring into your expectation somewhere? Do both of these launches just do well in both new cholesterol offerings? I realize that is a different mechanism, but a lot of LDL reduction from New Amsterdam.
Yeah. I mean, obviously, as you said, it's a different mechanism of action. I think the excitement really is around oral PCSK9. It's such a powerful, we believe we'll have the most powerful LDL-lowering oral agent, either on the market or in development, period. We'll be well differentiated.
OK. Fantastic. Maybe perhaps then moving on to some of the other programs, I want to start to get into oncology a little bit. TROP2 ADC, your expectations in the EGFR mutant lung and HR-positive breast, especially in light of some of the underwhelming findings from the Gilead side in both those indications, just in lung broadly as well as HR-positive breast as well.
Sure. You know, ADCs are very unique. Each one of them is different. They're different in every element of the—so with Gilead, of course, the antibody is the same. But we have a very different linker. We have a different dosing strategy, a very different development approach, et cetera. I don't think you can read through positively or negatively from one to another. We've chosen a very specific dosing strategy and a specific approach that leverages the reliable efficacy and the easy-to-detect-and-treat safety profile of sac-TMT. The idea here is to have a workhorse drug that's available for both the NCI Cancer Center and the community practitioner oncologist. That's why we have a broader spectrum of diseases that we're evaluating. That's why we're putting things—a lot of things—with Pembro. That's why we are very GYN-forward, maintenance-forward, et cetera.
I think that all this is a very differentiated profile. I would not read too much on what Gilead's done to address what we have in our pipeline. What I would, though, say is.
Would the payload doesn't matter, in your opinion, for lung setting?
We have our payload is really quite effective in lung. And you know how I know that? I know that because there's two studies now that are floridly nicely positive with Kelun-Biotech in China. The first is OptiTROP 4, which was actually presented and is published. And then very recently, OptiTROP 5, which was presented in top-line results by Kelun-Biotech. To me, that study is a very significant study because it's sac-TMT plus Pembro. I think that these data really validate why we think sac-TMT is different and that right sweet spot for patients with good activity, in some cases biomarker-defined, a safety profile that's easily manageable, long durations of therapy. Again, it allows us to in settings where that benefit is not clouded by having to go up against platinum chemotherapy, which is really great. It's good chemotherapy and on a background of Pembro.
Fantastic. Fantastic. Is there a possibility that we get some sort of an interim look on your EGFR mutant lung study and/or perhaps even the HR-positive breast study next year?
We do not share when our, we always have interim analyses in all of our studies. The PCD dates are the ones that investors typically look at. We do have interim analyses with our event-driven. I really cannot say exactly when and where. Remember, we have 15 phase three studies that are ongoing, 10 of which are in novel settings. They are all enrolling like nobody's business, which is always a leading indicator, for me, a leading indicator of enthusiasm. They will come and they will come.
Right. Fair to say there haven't been any interims passed on those because it's too early for that.
It's early. We do things like futility, but that's not really an efficacy. Those are easy-peasy ones.
OK. Got it. That would have been a big surprise if there was a futility.
Yeah. Got it. Yeah.
OK. OK. Eliav, I know I've talked about this with you a couple of years now. The BTK inhibitor, Lilly's on the market now. Merck is going to market at some point. I guess when would that be? Could there be some sort of readout possible in 2026?
So look.
CLL?
What we've done with Nemtabrutinib is gone for that long pass. That's going to just get us to the touchdown earlier than everyone else. What I mean by that is to take everything and put it on front line.
OK. You did not do the refractory for.
We have refractory, but it'll come right at the same time, the front line, because that's where the action is. That's where patients will get benefit. You want to be able to give people a drug that you can use for long periods of time, and you won't get mutations. So Nemtabrutinib has got the highest barrier to resistance because it's got a little bit of other non-BTK activity. What we've chosen to do is to take it right into the front line. Unlike the other studies, which is front line plus, so not really front line and not designed for the hard endpoints, we have a much larger study that's enrolled. Now we're following patients up. It's going to be mostly against Acalabrutinib, very little Ibrutinib. It's going to be a very straight-up comparison. We'll see what happens.
I'm confident that Nembutal will be that we'll be able to see the results and be able to show benefit. If our hypothesis is right, we'll be able to demonstrate non-inferiority and potentially superiority and lack of resistance. I think that's the key. Puretone had shown some data on what the resistant profile is. We looked at our data, and we saw that our drug would have been able to overcome those resistances where Puretone's resistance doesn't remain. I mean, it becomes inactive.
Got it. I guess how do you think this trial could differentiate over Lilly's pirtobrutinib 313?
Oh, because it's straightforward, first line. I mean, it's not a, and the endpoints are different. We start with non-inferiority, but then we go to superiority, and then we go to.
Could there be a clinical profile difference?
Yeah. Maybe. We'll see.
OK.
That depends on the phase three trial. I really can't. I mean, we put all of our efforts into doing that with the idea that there would be a different clinical profile. We chose something a little dirtier because we thought that when I say a little dirtier, I mean a little some more other receptors that it binds, tyrosine kinase inhibitors that it also inhibits, with the idea of having a little extra efficacy. Now, the trade-off is whether there's going to be a safety profile difference. We don't know. The data look pretty good so far, in blinded fashion.
Got it. Just so I'm clear, the Bruin 313 for pirtobrutinib, that was a clean first-line study, no?
Not exactly. It was a smaller study. It didn't have the long-term outcomes.
You mean on OS?
Yeah. Right.
Got it. Excellent. Maybe moving on to a program everybody cares about a lot, which is PD-1/VEGF.
Oh, that one.
I guess let me ask you this. If it shows what the other PD-1/VEGFs have shown, which is about a 50%-60% response rate, given what we know on overall survival data for the rest of the programs, is Merck going right into some sort of phase two registrational, or is this going to be more slower than that?
The challenge with PD-1/VEGF is to show that PFS translates to OS. It's the age-old question. We've had a little initial possibility in China. We'll see if that's really true. The issue with that is that the delta between the PFS hazard ratio and the OS hazard ratio is pretty gargantuan. You were at something at 0.5 and then something at 0.78, which was kind of you wonder why. We have to wait and see. For us, it's a disciplined approach. We have MK-2010 that's from LaNova. It's very active. It looks good. ORR is a good marker for choosing dose, but it won't tell you if you're going to ultimately improve overall survival. That's where the discipline comes in. You'll see some of those.
Apropos of sac-TMT, it'd be very interesting for investors to look when Kelun-Biotech finally presents the results of OptiTROP Lung 05 to compare that to Harmony too and ask the question, how do the two compare and what does that mean? We are interested in PD-1/VEGF, and we are interested in a disciplined way. I think we have to say the proof is in the pudding. Not fall into the pitfall that we fell in because I can tell you it's me. I was the one that invested in Pembrolizumab and had a success rate that wouldn't get me anywhere near the big leagues.
It sounds like you're much more guarded on PD-1/VEGF this year than previously.
No, no. Yes.
Has it always been like that, or do you feel like that even more after this?
It has always been that way.
You're more open about it now?
I feel like I'm waiting all the time. It's a struggle. Oh. No. No, not quite.
Can I ask you a controversial question then?
Yeah.
There's an IOIO combo, which had a second interim OS of 0.81. We know PD-1/VEGFs have a second interim OS of 0.78. That first IOIO of 0.81 was PD-1 Tijet, and the 0.78 is PD-1/VEGF. The perception from the street is very different between those two combos. I guess how do you think about that?
Beware.
OK. OK. Let me take it to another extreme then. Is it possible that these PD-1/VEGFs are just a high-dose PD-1?
Possible, but not quite because they also have the AEs profile of VEGFs, some AEs profile.
Sure. My point is, could the efficacy simply be the higher PD-1 driving it versus KEYTRUDA?
I'd ask the other question a little different question. I'd say if you take KEYTRUDA and you add Avastin and then you compare it to PD-1/VEGF, is there any difference in efficacy? That would be an interesting question because the concept is that by somehow having it on the same molecule, you've done something really biologically different. There's a daisy-chaining concept that people are talking about. There's the increased internalization. There's the being able to intensify the immune modulation or something of that nature. Yet there's been studies that have looked at PD-1 and VEGF, and you see PFS benefit. We just don't see much of an OS benefit is all.
Got it. It sounds like you want to see a definitive OS signal before you commit any significant resources here.
We're going to commit it in a staged way. I don't want to talk through all the different if/thens. Some of it has to do with the drug. Some of it has to do with the drug plus other drugs that we have in our pipeline.
Eliav, could you remind me the trial that LaNova was running was, I think, 200+ patients, but it got cut into half right ahead of their sale.
Yeah.
What happened there?
Because we took out the drugs that were the combos with drugs that we did not buy from them.
Oh, I see.
They're arms with other LaNova products. We didn't need that. We're going to globalize after this trial.
Got it. Do you have a US IND on this drug?
Not yet, but it's coming.
OK. Why the delay? Because it sounds like there's enough data to warrant it.
Oh, because we got a lot of stuff that we were able to do in China.
OK.
Yeah. Right now, we have a pretty vast footprint there. And phase I data, hopefully, the U.S. will change its point of view, make phase I easier in the United States. China is easy to work.
Got it. This is a question for Chirfi then. If the Summit Akeso programs have an overall survival of, let's say, 0.84 final OS, do you think that type of profile warrants a potential KEYTRUDA life cycle management within Merck where you could do a big switch over to an internal program? Is that threshold enough to do that?
It's very difficult to comment. I mean, you have to look at specific tumor types. You have to look at the standard of care per tumor type. I mean, that's what will drive adoption ultimately. It's difficult to give you.
OK. Let's say lung in particular, if there's like a 0.84 hazard ratio, could a Merck's in-house PD-1/VEGF effectively replace KEYTRUDA in lung with that type of hazard ratio, or is that not enough?
Again, I would reserve my answer on this one. I would not.
The base case plan for the company is not to sort of plan some sort of switch internally to an incremental program?
Yeah. Not a wholesale switch. This would have to be really tumor dependent.
I see. Peter, I think you were going to say something on this.
No.
OK. OK, great. One more on an IND topic we discussed last year, the oral GLP from China. I feel like that's been in the preclinical for a while. It looks like there wasn't enough preclinical done on the Chinese side before it was brought in. So I'm just curious.
Hold on. It's coming.
OK. All right. I almost get a sense sometimes when I listen to Dean that the interest is much more on making a cyclic peptide, which is a true sort of oral synthetic peptide rather than a small molecule. This may not be the top priority for oral GLP. Is that true, or?
No, I don't think that that's necessarily true. I think what Dean is talking about is the power of macrocyclics to be able to have antibody-like effects like we've seen with enlisted types. I think he's really excited about the technology. No, we wouldn't have bought MK4082 if we weren't interested in MK4082.
Got it. OK. I want to transition to ophthalmology franchise. I want to talk about immunology as well. John Reed is in the audience. We'll talk about J&J pipeline.
Yeah, I saw him.
Competitive feedback. Let me start with iBio for a quick second. Sherify, how big an indication is that? With two shots in the eye, can you just frame that for us?
Yeah. We're really excited about the iBio acquisition. The program is advancing really, really rapidly, which, as Eliav mentioned earlier, is always a sign of enthusiasm in the community when you're enrolling very rapidly. Just for context, obviously, anti-VEGFs are the standard of care in DME as well as with AMD. What we have, the insights we're getting from the community, is that up to 40% of patients are really not well controlled or not respondent at all to anti-VEGFs, standard of care. There is an unmet medical need here. There's a need for new MOAs. This is what really the iBio acquisition affords us. MK-3000 is a WNT agonist, a new MOA. Then you have Tispectus, which is a bispecific of TITU and VEGF.
The combination of those two really will address this high unmet medical need that I just talked about.
Are docs comfortable with two separate shots in the DME setting?
There is a trend in this community towards personalizing the treatment.
I see.
This is as you do your programs, as you do your studies, you typically have your more frequent injections. Then over time, we've seen that with all the retinal disease, all the launches in retina over the past number of years, over time, with additional data, the frequency of administration goes down in the real world. The same will happen here for MK3000 and Tispectus. At the end of the day, it's about the efficacy. It's about the new MOA that we're bringing to market. Really, really exciting.
Is this a multi-billion opportunity?
Oh, totally, yes.
Just real quickly, we're talking about one injection. We're not talking about.
No, the VEGF would still happen, no?
No. The WINT is being administered separately as monotherapy.
As monotherapy?
Yeah.
These are naïves as well?
Naïves and people who have failed.
And infiltrated.
Yeah. I see. There is no concurrent VEGF injection.
There's like a small arm of patients. I think for people who might benefit from VEGF, that's where Tispectus or 8748 would be.
Got it. OK.
It's only going to be one shot at a time.
Eliav, when I looked at the prior data, I think that was the AMARONE study, the confidence intervals looked very, very wide. I wondered if that was just like very high dispersion around what different patients were doing, or was that just like very tiny n?
It's a small end thing. I think that the results were actually pretty consistent. The CSD results were quite consistent across the board and over time in that 12-week study. I remember it's just a 12-week study, so it's not a one-year study where eventually people who are slower responders eventually get there. No, we're not worried about that at all. Both the BRUNELLO trial is nearing completion and BAROLO afterwards. I think we'll have good results and good data on WINT.
OK. It was not like patients with low CSTs did better and high CSTs did better. It was fairly consistent.
It was fairly consistent across the board.
Got it. What about the, and I've been burned by this on a couple of companies I cover in the retina space, but can you speak to intraocular inflammation, vasculitis?
Nothing yet.
That community is very intense, even on one case. Nothing, no observations.
Not yet.
OK, got it.
I mean, clinical studies go on.
Got it. What about rescue criteria? How does that work in the setting?
The protocol does have rescue criteria for people. They have recommendations for different kinds of progressions that occur, both in terms of what they see in the eye and in drops in letters. At the end of the day it is up to the physician to figure out what she or he wants to do with that patient. They do have some rescue events, some rescue methodology that is available.
Got it.
I don't know what the numbers look like simply because it's blinded.
Got it. Peter, would you remind us the timing on this readout for next year?
Ophthalmology is toward the end of next year, the first trial, right?
Yeah.
Yeah.
That's DME.
Yeah. Yeah. That'll be the BRUNELLO trial.
DME.
DME.
The Tispectus is the year after, correct?
Phase two Tispectus will be next year as well.
Yeah. Phase two Tispectus is next year. OK. Makes sense. OK, great. Perhaps we can just keep moving here. Oh, and maybe just a quick reminder. What about AMD? Is that a consideration for Merck as you're going into retina?
What, AMD? Oh, very much.
That's with the Tispectus only, not with the first.
We're doing it too.
Oh, is that right?
Yeah.
What is going to happen with the VEGF injection there then on AMD? Will that be concurrent, or how is that going to be?
No, no. The way DME is a good de-risking because it is a slower progressive disease. The data look good, then we will go on to AMD.
OK, the AMD study is still monotherapy.
With WELIREG, yes. And the VEGF Trap, it should be that's going to be the first indication.
And Umar. This is a large category, as you know, Umar. We are going to study both assets in both indications.
Is there very high interest from the retina community on a new mechanism? Are you hearing that?
Yeah. Absolutely.
Very interesting.
Look, VEGF is really important and has worked very well, but there's a lot of people who are failing.
Yeah. I mean, 40% is a big number, right?
OK. The first commercial positioning is VEGF failures for the launch in DME, and then you perhaps pursue that in AMD. Even though that's not what the trial is.
I think that makes sense if I were a doc.
Yeah.
I was just going to add, thank you for asking about ophthalmology. We've called it out as one of the areas in our pipeline that is underappreciated, along with HIV and just the overall breadth and depth of the pipeline, including oncology. We've gotten a little bit more attention on ophthalmology recently, but it's a good discussion to have.
Yeah.
Got it. Again, late next year, I think you said, for the readout, for the phase two.
Yeah. September, I think, 26 is the primary completion date. The Tispectus phase two is April of 2026.
Outstanding. OK, great. Maybe just you happen to mention HIV. I want to move on to immunology in just a second. On HIV, the monthly prep obviously looks the idea of a pill once monthly for prep looks very interesting. I have noticed, at least sort of going through the prior presentation, there were a couple of cases of CD4 drops, which I wonder if that was the CMAX issue. Could you speak to that?
Yeah, it's not a CMAX issue. I mean, this was drops within very tight criteria that FDA asked us to use. There were no clinically significant issues. The FDA has kind of allowed us to move forward now.
OK.
Yes, what happens is that you have these people who come up with way high CD4 counts, and they're probably you just measured them in some, I don't know, for some reason. And then it goes down from top end of normal to normal.
Got it. OK. Makes a lot of sense.
No, there were no clinically meaningful reductions.
Yeah. On that note, I think the excitement around our HIV pipeline is really the opportunity to establish a new anchor treatment with Islatravir, which is really a first in a new class of NRTTIs. For years, the field has been looking for one because right now it's integrase that is the anchor of treatment. As patients get older, you get concerned about long-term effects, especially cardiometabolic issues associated with integrase inhibitors. Finally now there is the potential to have a new anchor around Islatravir for both treatment as well as prep, to your question. Really, really exciting.
Right. Sherify, I guess this is one molecule I've always had some amount of confusion on. Because of that legacy Gilead trial where Islatravir was probably driving some of the CD4 drop problems, I think you guys lowered the dose since then. Wouldn't some of those legacy issues carry over commercially? How would clinicians perceive that?
I mean, the data is so clean. I mean, you've seen that this is the switch data. And then we've announced the naïve data just in the past week or two. Let's wait and see what the label says at the end of the day. But we're confident that the profile is going to be a very, very compelling one.
Would you remind us, Eliav, what was the dose when the Gilead combo was being studied? What's the dose now?
It was 0.75 qDAY and 20 milligrams qWeek. Now we're at 0.25 qDAY. We're not doing a qWeek for Islatravir. I mean, the qWeek for Islatravir is 2 milligrams. It was 60 milligrams for qMONTH Islatravir, but we're using 8527. qDAY was 0.75 down to 0.25. qWeek was 20 down to 2.
The 20 down to 2 is really where you brought the CMAX way down.
Yeah. I mean, the issue was, so the issue was we wanted to have something that was so very super forgiving that you could forget for a couple of weeks and be covered.
I see. So there's some two bar.
We were a little piggy.
OK, got it. OK. Now, I do want to be clear, though, on 8527, which is sort of the mainstay for a lot of the future combinations as well. There is a grade 4 CD—sorry, there's a grade 1 CD4 drop, but you're saying the thresholds are not as clean.
Yeah, it's fine. It's going to be the reduction. This was a reduction, and then it went back up afterwards. I mean, these patients, none of this is worrisome to us, wasn't worrisome to FDA, didn't have any issues for the community. Look, we'll see what phase three shows.
You said that 8527 is the mainstay of the future combinations. I don't know what you mean by that.
Oh, sorry. No, I'm sorry. I was referring to the HIV PrEP version.
Yeah, for prep.
That's the prep.
Exactly. Islatravir is the foundational for the combinations.
Again, as I mentioned, the grade 1 results were, as I said, minor. It went back up in the next measurement.
Got it. OK. Let's transition to immunology. I guess my first question is really, and this is not because there's J&J in the audience, but my question really is, there's a perception that Merck doesn't have the type of commercial infrastructure from a rebates perspective in immunology that J&J, AbbVie, Sanofi have. Does that curtail Merck's ability to launch TL1A and/or continue to build it out?
This is a new MOA, right? One thing that we know about the space, and we learned a lot from J&J from our collaboration in Europe for many years. I was head of the Netherlands for a number of years for Merck, or MSD as it's called there, where we had the J&J collaboration with Remicade, SIMPONI, and did a great job there. It was the number one drug in the industry at that stage for a number of years. We have learned a lot through that collaboration. Coming back to the U.S., we believe the opportunity to bring a first in a new class, TL1A, that has both anti-inflammatory and antifibrotic benefit will be very, very meaningful, especially in IBD, where you have a recycling of patients typically through MOA after MOA. A number of patients, a great number of patients never achieve remission.
They do need this new approach. We think that the commercial case is going to be very compelling. We're not really concerned about some of those contracting barriers that you referenced because of the unique MOA and the benefit that this will bring to patients. What I will also add is we're so enthusiastic about Tulisokibart that we're not limiting ourselves to IBD. We have the two phase three programs ongoing that Eliav and the team are driving. We have four phase two programs in addition in rheum and derm indications. We're thinking big around Tulisokibart. This is why we've announced $5 billion plus. I should have mentioned also in the case of HIV, $5 billion plus opportunity.
There is a series of $5 billion-plus commercial opportunity for a number of these new categories that we are really, really excited about.
Got it. On the UC trial, what's the efficacy expectation, Eliav, if you want to hit for that $5 billion plus?
No, it has to be differentiating. Look, we have the phase two results that showed a delta of pretty substantial.
Mid 20s, I think.
Mid 20s, yeah.
26?
I think.
Do you want to hit that at least?
We want to be able to, the study, it will be successful if we're successful, but I think being in the mid 20s would make it an important addition.
Placebo rates are going up, I feel, in general in UC.
I mean, when you go from phase two to phase three, you can. I mean, there's some studies and this is true, by the way, across immunology. If you don't choose the right patients and you're not careful about patient selection, you end up with individuals who have very mild disease. Given the fact that the disease goes up and down and up and down, you have placebo rates. We've done a really good job. One of the things you're right, we're re-entering immunology from the MRL side. What we did is we had an en bloc resection of the people that did a lot of AbbVie's drugs and moved them down to Merck. There's a lot of.
R&D or commercial?
R&D and commercial.
Yeah, we have some commercial as well.
Yeah.
We've hired a few from J&J as well.
All right. So we basically have an AbbVie UC crew that is on the show for us.
On the non-UC indication, what's your expectation on the HS trial? I believe that's next year. Should we comp it versus what a TNF does, or should we really comp it versus the real bars with IL-17?
You have to do it against Bimzolux, against IL-17s. I mean, that's the new standard. We can't do something inferior.
Does Merck have any visibility on either the HS trial or the SSC ILD trial as of right now on the TL1A?
It's blinded, so no.
All blinded. Yeah.
Time will tell.
OK, excellent. Excellent. Which brings me to the last point. A lot of the other immunology players are very quickly moving to combinations now going forward. Because Merck is focusing on sort of new mechanism, I guess how do you balance that from a combination perspective? Do you need partners? How does the immunology build-out look like, truly?
Yeah. We do think combinations are going to have to be done rationally. Here, I think, hearkening back to the oncology experiences, getting the right combination is important. One of the things with TL1A, because it's a new MOA, is to understand the phase three results and be able to build on that basis. We're interested in combinations. There are generic drugs that are available out there. There may be partnerships that we do. We also have drugs in our phase one pipeline that may be of interest.
Monospecific drug?
Yeah. Yeah. We will be able to think about combinations and see how that goes.
Did you think about bispecifics? There's a lot of Chinese bispecifics available, for example, in Merck's BD in China.
Sure. I mean, I think you can look at that. I mean, again, the one thing that I—so this is not an immunology specific thing, but this is how some of my concerns about bispecifics as a general principle is that they may be great on efficacy. But you have an AE event that is related to one of the arms, and you can't just chop it off and say, oh, we're going to stop that arm. You either stop the whole thing or you live with the AE. We have to be careful about that. It's easier to develop because it's a single product, and you don't have to do contribution of components. At the same time, it reduces your degrees of freedom to pull back if you have a problem that's related to a particular MOA.
That said, we always look at we have a very active BD arm in China. If there's something interesting.
Got it. I guess, Eliav, from your seat, what's the overall conversation like with Rob and the rest of the team internally on whether enough exists now to manage the rookie KEYTRUDA or more still needs to be done?
Oh, I think, look, from my point of view, we're always looking for good science and for good data and good products. Our perspective is longer term than two, three, four years, five years from now. I've been at Merck for 30 years, so my horizon's a little longer than others. I wanted to be I want to when I go to Happy Acres Retirement Park here in Florida, my hope is that I will have left Merck in a good position for the next 30 years.
All right.
Umar, on that point. Rob has been clear that even post the Cidara Therapeutics acquisition, we're still on the hunt for great science to bolster the pipeline and bolster the long-term commercial opportunity we think we can achieve. I guess what's exciting is we've highlighted over $50 billion of commercial opportunity by the mid 2030s from the existing pipeline. We've only added to that this year with Verona and now with Cidara . The pipeline is advancing, and we're starting to see a lot of de-risking events. 2026 sets up in a very exciting way. You talked about immunology. We have a readout in ulcerative colitis late next year. You talked about ophthalmology readout in September. Back to Islatravir and HIV, the Islatravir and lenacapavir once weekly treatment trials read out early in the year.
Everything is starting to de-risk, and there's a lot more visibility to this opportunity we've been talking about now for a couple of years.
Peter, remind us again, KEYTRUDA, LOE. What's the latest you guys are saying?
Yeah. So the composition of matter patent for KEYTRUDA will expire toward the end of December 2028. There are a couple of additional patents we've identified. It's NR10K that extend out to, I believe it's May and November of 2029. One is a manufacturing patent. One is a method of use patent in oncology, which we will defend. We'll have to see what the outcome of that is. The potential is it could extend well into 2029.
Got it. Chirfi, from your perspective, any switch over to KEYTRUDA subQ, does that sort of dampen the slope down or not necessarily?
What I can tell you is that the feedback so far is very positive for QLX. It's still early days in the U.S. We just received the approval in Europe last week for subQ KEYTRUDA. We are confirming what we have said, which is that over a period of 18-24 months, you're looking at a 30%-40% adoption rate of QLX. This is an injection that you administer in less than a minute for the Q3 week dose and less than two minutes for the Q6 week dose. It's really, really convenient for both patients. It also helps the institutions manage their flow and their resources. We're really excited about the opportunity to provide that value. We will be competitive.
We intend to, we've priced it at parity with KEYTRUDA IV, as you know. Beyond the LOE period, we do intend to compete and make sure that we maintain broad access to QLX. Yeah. The LOE on QLX extends out to 2039, so we have a long period of time where we can have exclusivity.
Got it. Excellent. Maybe just in the last few seconds, number one, Verona without a DPI, do you think it's still competitive? And then also.
Absolutely.
Gardasil single dose, do you expect any impact?
Who knows? Who knows? The U.S.?
Yes. We have been clear that today's FDA has made it clear that the current evidentiary standards are insufficient for a label change. What happens with ACIP depends on ACIP. I think they have other fish to fry at this stage.
I think we can do another 50 minutes on today's FDA.
Yes.
We should leave it right there.
Thank you so much.
Thank you guys so much for making time.
Thank you. Thank you.