Listen, thank you guys for being here. Apologies, I'm a couple of minutes behind. Pleasure to have Merck Management join us. This is our last fireside of this conference, at least-
Okay.
From my end, so really looking forward to it. Peter promised it'll be action-packed, and so let's jump right into it. You know, I think it'll be a great idea. Maybe let me turn it over to you, Peter and Eliav, and to kick things off, maybe frame for us what's on top in terms of priority list on your mind, and we'll jump right in.
Sure. This has been a tremendous year for Merck, and we're looking forward to 2024. You know, the things that are top of mind for us are the continued news on KEYTRUDA, especially in early-stage cancers. You're gonna see a large number of phase III starts for all of our antibody drug conjugates that we have partnered with Kelun and with Daiichi Sankyo. A large number of efforts in precision medicine and oncology, as well as, of course, V116, the filing, and then hopefully, if all goes well, the approval of that. Sotatercept should be commercial or entering the commercial space, and we're looking forward to seeing that. There may be additional data coming from the ongoing studies that are event-driven, like the ZENITH study.
And, as we've talked about before, our oral PCSK9 MK-0616 has started Phase III programs, including our cardiovascular outcome trial. We have Phase III start for MK-7240, formerly PRA023, our TL1A antagonist. And then, of course, continued work on MK-6024, which is our compound for NASH, and it has some weight loss benefits as well. So, a lot going on, a very diversified pipeline, a very busy year going forward.
Excellent. I know, you mentioned KEYTRUDA, and I want to go through each of those, but, maybe just before we get into the more product-specific stuff-
Sure.
Peter, can I just start by asking, I know there was a fair amount of confusion on it a few weeks ago around the margin profile, what Merck is saying, whether the commitment to the margin target stays fully intact? Could you just remind us on that?
Yeah, no, thank you, Umar. So from a margin standpoint, we continue to point to the achievement of additional margin expansion. We've been on a, quite a record of margin expansion over the last several years, including in 2023. We expect further margin expansion in 2024, driven by product mix, so as KEYTRUDA and GARDASIL continue to grow strongly as we expect, that's a benefit. And we also have the roll-off of some significant royalties, both for KEYTRUDA and GARDASIL. KEYTRUDA rolls down from 6.5% to 2.5%, and on global sales, and GARDASIL, there's a royalty that we pay to Glaxo that's now 7%, that will roll down to zero. So we'll benefit from that, and we will continue to tightly manage SG&A, but making sure we invest in our growth drivers.
R&D, well, we will continue to invest, and we've expanded our pipeline pretty dramatically, so we'll continue to ensure that we fund those programs, so you'll see R&D continuing to increase. As we look out to 2025, we have had a target for 43%+ operating margins, and we continue to believe we'll achieve that. What Caroline has said, to the degree the pipeline continues to expand, we're not gonna forgo necessary investments that would fully optimize those pipeline assets and lead to better long-term growth. But right now, as we stand, 43%+ is something that we would continue to point to.
Okay, excellent. That's very helpful. And maybe just one more as a quick follow-up on that. I know there's Keytruda growth, a fair amount of growth still modeled in. I think, Ali, you mentioned about some of the additional indications coming online. There's underlying momentum, and ex-US launch is ongoing as well. If I look at consensus numbers, you know, Keytruda is being modeled in from in going from about $25 billion to perhaps $35 billion over the next five years or so. I know you guys have clearly expressed enthusiasm on the momentum continuing. Could you just expand on expectations on Keytruda? Because that's critical to some of the margin expansion as well, obviously.
Yeah. So I'll start from a commercial standpoint. Ali, if you have anything to add from a clinical perspective, feel free to, but we continue to expect strong growth of KEYTRUDA, and we don't give product-level guidance typically, but as I just suggested in your prior question, we do think that 2024 will be another year of strong growth for KEYTRUDA. Albeit, I mean, we've had exceptional growth for KEYTRUDA over the last year or two years, and the third quarter annualized run rate was $24 billion plus. So the types of percentage increases that we've seen in the last year or two are would be difficult to achieve, but I think consensus has already reflected that as they, as they've modeled out 2024, and we think that's appropriate.
Right. I think the point that was made previously was: Don't expect 20% plus type of growth going forward. But conversely, wouldn't EV-302 just create a very significant tailwind into next year, especially given the first line, especially given the duration that we saw? There's a, it seems to me that there's a realistic chance Keytruda just vastly outperforms numbers into next year. It could actually approach meaningfully north of the types of 10% type numbers.
Well, I mean, it's a great. The results speak for themselves. I think it's outstanding results, and so, you know, we really look forward to having those data come through, and I think, everyone that we've talked to, including the regulators, are very excited about the results, so I think that's really great. And KEYNOTE-671, KEYNOTE-564, those are two other ones that I think are really important. For the first time, there's overall survival benefit for interventions in the perioperative state, and they're all both with KEYTRUDA, and they're both only KEYTRUDA, not no other.
of the IO compounds that have been there. So I think that there's some really exciting momentum from that. You know-
Okay.
Tell you about the commercial stuff, but-
I mean, I think we are excited by KEYTRUDA's move into earlier stage cancers, as Eliav suggests. So there's a lot of opportunity for continued growth. We've pointed to early stage representing over half of KEYTRUDA's growth as we look out to 2025, and to represent 25% of global KEYTRUDA sales in that year. So the early stage is important. Certainly, bladder, lung will become increasingly important as well, some of the women's cancers that Eliav mentioned as well.
Got it
continue to be very confident with the growth of KEYTRUDA.
Makes sense. As I start to transition to pipeline, I thought maybe since we were talking KEYTRUDA, let's start-
Sure
. with the oncology pipeline.
Great.
There's broad buckets. I think of it as IO, IO, where we could have new IO modalities, including the PCV, including TIGIT. We could have ADCs, and then some small molecule efforts, unless I missed any other major chunks.
That's pretty good.
So on the IO, IO side, Peter would always tell you, TIGIT's always on top of my mind. Is the, is the Moderna cancer vaccine on top of Merck's mind?
Look, we have a broad portfolio. Each one of these is exciting, and we've invested quite a bit in it. The INT or V940, I think is a really big opportunity because it's very unique, and it's got the ability for durable, long-term, drug-free effects. So like every immunotherapy of its sort, you know, the expectation here is that there'll be benefits even after the medicine, the medical therapy is done. And we'll see how that goes. There's gonna be further cuts of the data going forward for the phase 2 study in melanoma. You've seen the melanoma phase 3 program start.
We're gonna have a heavy jump into lung coming up, and there'll be several other studies that we'll initiate in 2024. We have done a really nice job. Moderna has done a really nice job in building the capacity ready for clinical trials, so that's really great. TIGIT, there will be a presentation of KeyVibe-002 in about a week at the ESMO IO conference, which data are still embargoed until about six tonight, and then you'll be able to see what all the hoopla was about. So, that'll be exciting. And then, you know, of course, the first-line lung and the adjuvant melanoma program continue at pace. You know, it's just they're big studies, and they require both enrollment and follow-up, so-
Adjuvant melanoma, we're talking about the PCV, right?
Both. KeyVibe-010.
KeyVibe-010.
Yeah.
Oh, so you're talking about-
Yeah
TIGIT?
Yeah. So you know, yeah, the. So with the PCV, with the INT compound, we, you know, phase 3 starts. Phase 2 should be in 2024, for TIGIT. KeyVibe-002, you know, will be presented in a week. The abstract should be viewable later on today. And, you know, the phase 3 program continues, and, you know, we'll, it's just a matter of now enrollment and time. Protocol completion dates are later, are not next year, but the year to follow. But, you know, there's interim analyses, and we'll have to see how that goes.
Got it. Okay.
Yeah.
Anything notable on the KeyVibe-002? We should keep in mind it was a trial of triplet versus triplet PD-1 chemo TIGIT-
Right
versus just, PD-1, sorry, versus just PD-1 plus TIGIT versus chemo. We know the doublet was dropped.
Right.
We know the triplet was moved forward. Data tonight, you said, exciting data, but also this is not a first-line trial, which is-
It is not.
Anything else notable we should just know about the trial design?
Well, I think that the key there is to ask the question about to try to figure out, are there ways to gain early looks at whether TIGIT added to a strong PD-1 has benefits? And, you know, there's been. This study doesn't directly look at that because there's no pembro-only arm, but at the same time, these are people who are all been experienced with who've had PD-1s, and we know what their objective response rates, which are usually single digit to the very low teens. And so I think, you know, it provides a piece of data.
We've seen with the TIGIT compounds, however, and we have to acknowledge that there have been phase 2 studies that have looked good, and then there's been phase 3s that have been more complex. And so, you know, my, the way I see the compound is you will wait to see for phase 3 and, and go from there. We have a very robust program across the lung space, which is where we think this might be useful in melanoma. So I think that's, those, those two sets of tumors are really important and have the best opportunity for showing incremental value that's of sufficient size to be meaningful for patients.
Makes sense. Eliav, also, I think the other aspect of this TIGIT trial, which is particularly relevant, is, so, A, you mentioned these are PD-1-experienced patients. The other dynamic is, they're not selected for PD-L1 highs or lows. These are all comers.
Yeah.
Again, there's prior data from Roche focusing on PD-L1 super highs only. There's other datasets suggesting the benefit did continue. There's no reason why a TIGIT should work only, only in PD-L1 highs or-
No, I think, you know, we'd be careful about post-hoc analysis. I don't know what to make of and small datasets as well. If you look at what we're doing in our clinical trials program, we are essentially following the paradigm of where pembro has been approved. So pembro is approved as monotherapy in people with a TPS greater than 1% PD-L1, as monotherapy, and so we have a trial of tigit plus pembro against pembro. The study is large enough to look at the greater than 1% and greater than 50% separately. We have a study of pembro tigit with chemo versus pembro with chemo. So the standard regimen against the standard regimen, plus pembro in first-line non-small cell lung cancer.
We've got a Stage 3 study, KeyVibe-006, and then we've got studies in small cell. So, you know, we'll see how that goes. And then again, KeyVibe-010 is a study in adjuvant melanoma in patients with Stage 2 and 3. Each of those studies is every one of these studies is characterized by the fact that that pembro is foundational for that tumor, and that's the front. That, that, and so we're just adding TIGIT on top of that.
Got it. One last.
Yeah.
KeyVibe-002, primary endpoint was PFS, not ORR.
Mm-hmm.
We should expect, at the ESMO IO presentation, both the ORR and PFS.
We have everything.
Have everything.
Yeah.
Okay, got it.
Including some OS data.
Got it. Excellent. Maybe perhaps starting to move on, on the Merck... Sorry, on the Moderna PCV program-
Sure
... V940. One of the questions, and I remember having some discussion with Peter on this, too, there was a presentation at ESMO, which dug into data breakdown by BRAF mutation.
Mm-hmm
... BRAF mutants or not wild type, and then further by, I forget now, it was the ctDNA status.
DNA, yeah.
It looked like the benefit was coming from one of the two subgroups, and even within that subgroup, in ctDNA. I guess I, I was just thinking out loud about how should we think about that as— 'Cause there's been always questions around how robust is the signal?
Right.
It looks very good overall, but then the fact that it's driven by one subgroup and not totality makes you wonder, could it be a false positive for it?
No, I don't, I don't think so, because I think we have like everything with the small Phase 2 studies, confidence intervals are very large. And then there's things that are that favor the-
You mean baseline?
Yeah, the baseline things that are favor the-
In the subgroups.
Among all the different parameters that might impact presence of ctDNA, different PD-L1 status, whatever, all these different things, there is imbalance between the groups, as you would expect in a phase 2 study that's so small. But things that a priori you'd think would favor control versus favoring the combo, pretty much evenly distributed. It's really hard to tell. But, you know, like, it's fair to say phase 3 is where we prove efficacy. You know, we're very excited about this. Obviously, we've invested quite a bit, not just in clinical trials, but also in the setup for manufacturing.
And, you know, we think that notwithstanding some baseline imbalances that favor one arm or the other, the overall picture is one that's very promising indeed.
Got it. Maybe... Okay, anything else on IOIO before we transition on?
I think that's it.
Okay.
Yeah.
On
ADCs?
On perhaps ADCs, because there are several things to go through there. Obviously, there's the collaboration that was announced with Daiichi recently. One of the questions that came up was: What was the primary basis of that deal? There were three programs that came in. My understanding is, it was the, perhaps the B7-H3, which was really the impetus behind it. I don't know to what extent that's true, realizing that HER3 was more further along.
Well, I think each one of these assets is really exciting. And I think Caroline had said that she hopes that we have all the—we pay all the milestones, so that we—so that, because that would mean the best benefit for patients, everything will work out great. So B7-H3 is exciting because of the small cell and some potential in prostate. And there are other things. Obviously, we're just at the beginning of the investigation for that. I really like the HER3 ADC, because I think that it has opportunities to both to be active in various forms of driver lung cancer sort of settings.
And here, I mean, things, we know the EGFR mutant, but we're also looking at other driver mutations like KRAS, and also interested in other cancers. So I think that there's a really nice opportunity with post-rituximab that we're really looking at. And during the due diligence, we were really excited about that as well. CDH6, I think, is topical because of today's news about the Immunogen acquisition by AbbVie, because it's about ovarian cancer at present. The early data as presented look very, very promising indeed. It's phase 1, so, you know, we're just beginning the investigation there.
But I do think that we have a strong history in ovarian cancer, and a really great basis for, and a set of trials that I think will serve us well, to help position CDH6 as-
Right
... as an essential medicine in that treatment.
So maybe, working off of that CDH6 ADC, I realize, the efficacy was clearly very intriguing.
Mm-hmm.
It also is clear that a couple of higher doses were dropped because of therapeutic index reasons. Do you think at doses that are realistically possible for an extended interval dosing, we have the right therapeutic index, and we have encouraging efficacy at those doses, which are realistic?
Yes, because, you know, the dosing starts, the activity starts at 4.8 MPK. And we're going, I think, 5.6 and 6.3, I think, 'cause there's three arms. And, you know, one of the things that has been very useful in our collaboration is that, our colleagues in Daiichi have learned a lot about the therapeutic index and dose selection based on their first two ADCs. And I think that they're much more sophisticated in the modeling and the approach to, choosing the sweet spot for, the next three. And I think we're not gonna have the kind of ILD issues that we see. Of course, you know, at higher doses with all of these drugs, you will reach a point where there's toxicity.
But, you know, what's interesting about CDH6, just as an example, is that the activity well below the ILD at doses is pretty exceptional. So, we're thrilled about this. And by the way, the activity was in an unselected population. Don't need to know about folate receptor alpha status, so I think it's gonna be a very key part of future therapies for ovarian cancer.
Got it. HER3-ADC, this was being filed in EGFR mutant lung cancer?
Correct.
If you and I spoke a few months ago, I would have said, "Oh, your TROP2 ADC is going into that indication." I guess, how are you guys thinking about that? Or do you intend to have two different programs for EGFR mutants?
Yeah, I think, I think we will. I think that there's... You know, while for the most part, the six ADCs are unique in their own areas, there are a couple of areas of overlap. I think it's okay because there's enormous opportunity for in this space. Because, you know, we already see that once patients fail, you know, successive rounds of EGFR inhibitors, they- the cancers are really they're very, very short time to demise. And so I think that there's a lot of opportunities there, both in terms of, you know, looking at TROP2 levels or HER3 levels, or looking at, you know, sequencing the the ADCs. So I actually don't think that that's gonna be an issue.
Both agents are very active, and I think we'll be able to provide options for people with somewhat different AE profiles. So we'll see.
Got it.
Both of them are gonna go forward.
Got it. So I realize the TROP2 ADC, which you guys got from the Chinese partner, Kelun-
Kelun
as well as your some of the newer stuff that you got from Daiichi, including the HER3. They're both topoisomerase-based payloads.
Mm-hmm.
But within that, you could have differences in potency on the exact type of payload. So my understanding is Daiichi's exatecan, which is-
Right
... less potent, much less potent than irinotecan. Can you remind me, is the Kelun TROP2 irinotecan?
No, it's a derivative of belotecan, so-
Belotecan.
So again, with and you have different DARs, and so, you know, there, it's all... it's very hard to do cross comparisons. But, I can tell you 2870, again, is has been exceptionally active for us, we're really excited about it as well. We've seen two clinical studies already entering clinicaltrials.gov in Phase III. They've already started, we've started enrollment. And then, next year, there should be a pretty substantive number of trials for 2870 moving forward.
Got it. Excellent. Anything we missed on ADCs just before we move on?
No, I think, MK-1200, darolutamide in 18.2 ADC is moving along, very quickly. And again, that's a unique profile that'll be-
Got it
you know, exciting as well.
Got it. One minor question I forgot, and I just got an email about it. On TIGIT, a couple of your competitors have talked about how Merck has lowered the dose. What's the, what's the back-
Yeah
... backstory there? I, I meant to ask that.
There isn't, there's no backstory. I mean, you know, we never reached MTD. So, you know, we went all the way up to 700 milligrams. There's no reason to have it... You know, there's complete saturation of the receptor based on our modeling at 200. There wasn't a safety issue.
Okay.
We just reached kind of the plateau. There's no reason to go higher than, you know, full saturation.
Okay, so all the trials are using 200 now going forward?
It is, yeah.
And the one that's being reported in lung right now-
Hundred.
the KEYTRUDA, that's also 2- they're all 200. Okay, got it. Final point on oncology, just before we graduate on small molecules, a couple of programs high on my mind, HIF-2 and the BTK. We can discuss any of the programs you'd like. On HIF-2, where do things stand? I feel like there was a lot of interest in this. I realize the initial approval was in a more, 2, what, a mutation selected, was a much more smaller subgroup. Do you see a path now to a much broader approval, and when would that be?
Yeah, so you know, LITESPARK-005, which is our first study in all-comer renal cell cancer, read out positive for PFS. And achieved priority review, and we'll have a PDUFA date in first quarter next year. And I think it's a great example of how HIF-2 alpha can be an excellent anticancer drug outside of the germline VHL setting. Renal cell is gonna be where the main focus of activities are, because there is a lot of somatic mutations of VHL as well, that is, you know, associated with carcinogenesis. So, we have studies in the front line, we have in IO failures, we have in the adjuvant setting.
You know, this kind of builds on the enormous body of data with KEYTRUDA in the renal cell space. There's just, we'll have offerings across the different levels of disease for clear cell and non-clear cell, and I think that's gonna be very important. We do have trials going on now with the HIF-2α in patients with other kinds of mutations. Those data are cooking and may very well provide an additional area for use of this drug above and beyond renal cell. So there's a lot still going on with belzutifan, where we really are first and only.
Got it. Peter, I see very modest growth in consensus numbers on the HIF-2, $200 million-$300 million. Has there been much discussion on this, on sort of the momentum into a potential broader approval next year?
Among analysts and investors, not a lot-
Yeah.
No. So we have-
Okay.
It has not received a ton of attention. We've consistently said we see strong expectations for WELIREG longer term, and believe it can be a blockbuster.
Got it.
Yeah, I think it's kind of-
Next year, this PDUFA opens that up-
Yeah
... is how I would think about it.
Yeah, I think so. And look, you know, the VHL data were objective response rate data based on, you know, a single arm study. So obviously, you know, people thought to themselves, these are for people with a specific genetic defect. I think that this is, this is a breakthrough, what we see right now, in the sense that, it opens up a much broader patient population. I look at this kind of like Prevnar, you know, it's a drug that is always under the radar screen, and yet it makes quite a bit of impact, and therefore, money.
Got it. Excellent. Finally, BTK. I feel like we've seen LOXO continue to be very active at ASH meetings with data updates, path to approval, et cetera. There was sort of a big readout data sets that Merck went into a big quiet zone for a while. I know you guys started to come out last year. But if we do some of the data comparisons versus data being reported by LOXO, I kind of get a sense, broadly speaking, mid-50s for you guys, versus anywhere from 60s-80s for LOXO, depending on how you look at in CLL, et cetera. How are you thinking about that? Is there baseline differences that explain some of those discrepancies?
There are actually. I think there are different patient populations. You know, we can talk about the cross study comparison issue and all that good stuff, but the specific elements are they looked at and had a very large number of patients who were intolerant to BTK inhibitor to BTK to the irreversible ones. We focused all of our attention on those with C481S and related mutations. So we had more mutant patients. The first sets of data from LOXO, they had a median prior lines of therapy of 3. We had 4.
So it's, it's-- I don't think that there's that you know, these cross study comparisons are like to like, I think it's apples to oranges. As a measure of our commitment, you will have seen that we have a fairly robust Phase III study, including a study that LOXO has not done, which is their first line study that just popped up on ct.gov, which is called BELLWAVE-010. So, I think you'll see here that we have a lot of confidence, and put money behind this. After you're right, there was a quiet zone, it was mostly we're just ensuring that we got the dose absolutely right, got to that sweet spot, and took our time to do so.
But I think we're in the right position now, and it's gonna be an interesting next few years for the field.
Excellent. Maybe that might be a good point now to transition then towards some of the stuff beyond oncology.
Mm-hmm.
Unless there any questions on oncology in the audience, and I'm happy to make it interactive. Okay, sotatercept,
Yes.
Obviously, there was a big hit in the trial that came out.
Mm-hmm.
Stellar was stellar, is what I call it.
Yes.
But I feel like amidst all the discussion on PAH, there's almost a non-PAH or a different type of PAH, where nothing is approved.
Mm-hmm.
The Group Two trial, which I think is a full new indication.
That's right.
Where are we with that? Could you also remind people how is that different from the standard PAH?
Sure.
Because it's more like a HFpEF than not.
Yeah, yeah. So, there are different groups that WHO classifies PAH pulmonary hypertension into different groups. PAH is the idiopathic, genetic associated, specific pulmonary vascular issue. Group Two is what we're talking about with this trial called Cadence. It's in patients who have both pre and post-capillary pulmonary hypertension. So they have heart failure, usually from HFpEF, and their response in the pulmonary vasculature is overexuberant. It's really quite dramatic, and you have substantial increase in pulmonary arterial pressure above and beyond what you might expect due to pulmonary venous congestion. The reason why it's taken a while to enroll that study, because there's nothing for these patients, so it's not like they're warehoused or pre-identified.
A lot of the work that we're doing now is actually to do the right kinds of right heart caths and screening patients so that we can identify the patients. This is true in a variety of diseases where there's zero opportunity to help these patients, so you end up with, you know, having to start the screening process to bring out the patients. But once there's something that will make a difference for them, then the docs will have a reason to do the screening. So, you know, Phase II is always a for these kind of new indications, where there's not much out there, takes a while. And we'll get there. We have a PCD next year.
you know, hopefully the results will warrant further study.
Got it. Excellent. Recruiting, could you remind us how is that tracking in the Group 2 trial?
It's just, it's been slow, slower than we expected, but again, this goes back to this whole business of, you know, it's not like there's a whole warehouse of patients waiting for something because there's no, there hasn't been anything for them. So there's no reason for docs to pre-identify them as a patient population. So we have to go and screen for them, and that's why it's taking a little longer. But we have a lot of really great sites, and I think we have slow and steady wins the race kind of thing.
Okay, excellent. Any questions in the audience? Oh, it's up. Oh, I thought it was going to be out at six. Okay.
Yeah, I just realized the poster schedule for, if that's for population, so the actual results, what's that saying? The coverage makes sense, but what's on top of the-
Yeah, this is not this was.
PFS?
Yes, PFS.
Okay.
So remember, the study was a Phase II trial. We weren't really planning on looking at it from a statistical significance point of view. The poster, you'll see some interesting results on the shape of the curve and what we anticipate will be, you know, the overall view. I think that these results, again, in second line, are encouraging to us because we have... It's not a filing study, right? And it was just designed as a signal finding evaluation. They're encouraging for us because, again, it just shows that when you add the TIGIT to the docetaxel, you get a pretty substantial improved outcome. And again, you know, this is small numbers of patients, hazard ratio of 0.77.
It translates to a trend in OS, good enough for us for what we were looking for to confirm the investment for the first line. Yeah. Now, there's, you know, we're already in first line, so we might as well.
Got it. Okay. Anything else in the audience? Can we perhaps transition then to some of the other parts of your business? I know, so, I want to talk about pneumococcal vaccines, obviously. I want to talk about the oral PCSK9, as well as a broader cardio strategy. Let me just hit up on a couple of questions that-
For sure
... came in from the audience as well. One question was: Can you ask about other oncology modalities like T-cell engagers, cell therapies, interest in those?
You know, I know where we wanted to go is we want to go to places where we can do the best benefit for patients and and leverage the huge infrastructure that we have here. We've chosen at present not to go into cell therapy, although we have some collaborations going on. We're always looking for exciting opportunities, and so there are some interesting T-cell engagers or other modalities that we have going forward. We'll definitely-
Internally?
I'm talking about externally.
Externally.
Yeah. So we have a collaboration with Dragonfly and TriNKETs, you know, it's an NK cell engager work. And as I mentioned, and as Peter noted, we're always looking for new agents, and we're modality agnostic. We just haven't been in cell therapy because the infrastructure for that is a lot. We already have seen that in something less complex like the INT, cell therapy is an order of magnitude bigger than that.
Okay. Another one that came in is, broadly speaking, you have an oral PCSK9. You have a GLP-1, I think, which-
No, we have the NASH compound, the GLP-1 GCGR.
GLP-1 GCGR.
Yes.
It doesn't have an A1c benefit. It has a weight loss benefit.
It has the most important thing, it's got a NASH benefit.
It's got a NASH.
But that's outstanding and much, much more robust than semaglutide or any other drug.
Mm.
But it has also about 10%-12% weight loss benefit. So it's a really good drug for NASH-
Right
and we're looking forward to evaluating it there. I think, you know, we have a whole cardiometabolic program, and I think that, you know, our focus here is NASH as the anchor around which we build other things.
I guess the question that comes up is, to the extent you have a injectable incretin-
Mm
you have an oral PCSK9, I would have thought they might even be interested in expanding the oral PCSK9 to beyond, let's say, oral GLPs, maybe oral hypertension molecules. There's, like, orals in development that are novel programs. Is there-
Sure
going down those directions?
So, the macrocyclic platform that we've built, I think is really useful, and we're very interested in looking at a whole array of things where there's injectables, because we really think that oral administration democratizes access. And so, but the key has to be something that's differentiating and is valuable. We've seen that there are orals, you know, obviously RYBELSUS, and then orforglipron is out there. If we're looking at the developments, we're thinking about second and third generation sort of things. What are the things that are missing in the current therapies? They're amazing in terms of weight loss. It's been really beautiful to see the field grow, but we have to think about long-term durability and tolerability.
We have to think about whether the kind of weight loss that is being affected is the right kind of weight loss in the sense of, you know, muscle wasting versus fat. I think that there's still opportunities to improve on these, and I know that all the companies, including the leaders-
Are there pockets out there which could do this without hitting muscle?
There might be opportunities. I mean, I think that there's a lot of—there are some groups looking at myostatin, some people are looking at other, a completely different mechanism of action. I think the problem with, as you know, with muscle wasting, sort of, issues with these drugs is that if people go off drug—First of all, you lose muscle, and you, you know, it's not what you need when you're, especially as you grow older. The second piece is that when you get off therapy, then you have a real big jump up in weight because muscle is where there's a lot of energy sink, in just in the resting state.
So people are in a much lower basal calorie use, and so you get this kind of overshoots of weight gain. So it's not such a good idea to have that if you can get around it. I think everyone's looking for that secret sweet spot, but we're I think the data aren't quite there yet. There's a lot of opportunities in the basic space to think about it.
Got it. Maybe I realize we're short on time, so I want to be respectful. Pneumococcal vaccines, this is the last question from my front, unless there's anything in the audience. Obviously, Merck's been able to go beyond just the PCV20, based on V116, which doesn't have a lot of the shared serotypes, et cetera. Is there a future program where Merck could deliver all the 13 shared and an additional 11, have something well into the twenties on one vaccine, which works in infants and in adults?
Well, they'll the reason to do that is because if the biology is the same or the epidemiology is the same, and it's not. So, we're perfectly comfortable, as we have now, with separate vaccines for babies and for adults, and so we'll continue to build the adult platform. For babies, of course, we've talked about V117 and the growth of the new, more, you know, the franchise, and we have V117, which has more types that are going to be added on. So we're not shy about adding on to the pediatrics, but we would do that in the context of what makes sense-
Got it
for pediatric disease. So I'm not, I'm not worried about having a vaccine that has multiple, more types than 15, which is what we have.
Got it.
But it just has to be the right ones. It may not be the same as V116.
Does V117 have to be beyond PCV20 to be competitive commercially?
I, you know, I think it depends how the field goes because, you know, remember, there's a lot of excitement, but then there, you need to get the pediatric data. You need GSK Affinivax, the Sanofi has something.
Right.
You know, I'm sure that Pfizer is going through. So we'll just have to see what transpires. But we're planning to go and to add more types and to do as many as we can that makes sense, not just to say, "Oh, you know, X is greater than X minus one," but to really hit the important ones that cause both invasive pneumococcal disease, pneumococcal pneumonia, and otitis media in babies. But the point is that the epidemiology, the types included, have to be what's relevant for the kids. And adults, they get their own vaccine because they have different disease. That's just the way it is.
Excellent. Unless you have anything else, we're gonna go ahead and wrap up at least my HealthCONx for 2023. All right, excellent.
All right.
Thank you for joining us.
Well, thanks for having us.
Great seeing you all.
All right.
Thank you.