Pleasure to have Amgen Management with us today. I feel like between Sean, Mom, and myself covering Amgen for, like, 14 years now, I have not seen this type of setup come up in terms of P ipeline readouts for Amgen in a long time. I'm very curious what's on top of your mind. Peter, why don't we jump right into it?
Great, Umer. Well, thank you for inviting us. With me today, Paul Burton, our Chief Medical Officer, Justin Claeys, our Vice President of Investor Relations. So we're delighted to be here, and strong execution driving innovation at speed and scale. So three points to make there, following up on what you shared with the group. We've closed Horizon. We've added rare disease business, demonstrating our willingness to pursue the best innovation, whether it's internal or external. And second, to your point, driving our pipeline, rapidly advancing a number of first-in-class, best-in-class medicines through our Organic Pipeline, including three Breakthrough Therapy Designations, two of which came in the third quarter. And then finally, our volume-driven growth, evidence of the value physicians are seeing in prescribing our Innovative Medicines to seriously ill patients. So what did that do?
That resulted in 4% revenue growth in the third quarter, 6% non-GAAP EPS growth, and our volume growth was 11% worldwide. Underneath that was 12% volume growth outside the United States, inside of that, 27% volume growth in our JPAC region. We updated guidance to $28.0 billion-$28.4 billion on revenue for the year. Remembering that Horizon comes in effective October sixth, the close date. We raised the bottom of the range on EPS, raised the midpoint, we're now at $18.20-$18.80 a share for 2023, and increased the dividend 10% to $2.13. But to your point, record sales of seven brands, both Evenity and Blincyto, greater than 50% growth year-over-year in the third quarter.
Repatha, workhorse, cardiovascular, 31% growth year-over-year in the third quarter, 44% volume growth. Now, let's turn to the oncology pipeline. We've got Dr. Burton with us today, and I'm sure you'll have a lot of questions around that. At ESMO, we talked about Tarlatamab, a positive, potentially registrational enabling medicine for small cell lung cancer, breakthrough therapy designation. We announced top-line results for Lumakras and Vectibix. Vectibix is our medicine in colorectal cancer, and that combination is for metastatic colorectal cancer. And then finally, Blincyto, moving that into earlier lines. And Blincyto, we like to remind our colleagues that that's the first BiTE, the first bispecific T-cell engager for B-cell in the new indication of B-cell acute lymphoblastic leukemia.
We're very excited about that for patients and moving that, working with regulators and moving that into earlier lines of treatment. And let's finish up in that pipeline with Xaluritamig for prostate cancer. Again, another bispecific T-cell engager. So both Xaluritamig and Tarlatamab are bispecific T-cell engagers showing unequivocal activity in solid tumors. Very exciting for patients, and of course, you know, good news for the oncology pipeline. And let's just finish up on 193, AMG 193, first-in-class MTA-cooperative PRMT5 inhibitor, and we've seen activity in 6 solid tumors. The 4 late-stage programs we have, we certainly will talk, I'm sure, about maridebart cafraglutide, now known as MariTide, formerly AMG 133.
Okay. I was like, which drug is that? I was like, I've never heard of that one.
We've all stipulated to MariTide now.
Okay.
I think it's because they got nervous when I showed up and started talking about maridebart cafraglutide, 'cause they figured at some point I'd trip on that one, but I haven't yet-
Okay. too much. But that's the obesity drug, and it, We just finished up phase two enrollment, and look for top-line-
Excellent
Data in the back half of 2024. Number two, Olpasiran, Lp(a) molecule. We think it's a first-in-class, best-in-class, good data so far, but we'll see what happens in the investigation. Phase lll Cardiovascular outcome trial on that, rapidly enrolling. Three, we've got indications we're exploring on Tezspire, including in-
Right
COPD. And just finally, to wrap it up, Rocatinlimab, first-in-class OX40 monoclonal antibody, being studied for severe atopic dermatitis, of which we think there's about 30 million patients around the world, maybe 10 million or so, which are addressable. We're excited. We, we like what we see. First and foremost, Umer, is always starting with the patients. So at Amgen, we're now up to over 26,000 colleagues, with those who joined us from Horizon, and we're working hard advancing that pipeline organically.
Excellent. There's a lot to unpack there, so I wanna go one by one. Peter, maybe just to kick things off on the... Because it's a big R&D year coming up, there's an expectation for some R&D increase into next year, and very much more modest is how consensus is thinking about it. How are you thinking about sort of... This is not necessarily a 2025, 2026 guidance per se, but how are you broadly thinking about the R&D resource allocation that Amgen would have to do to fund some of the pipeline developments?
I think that's a really fair question, and I think this year, we've increased our guide for non-GAAP R&D. I think we've increased it up to about 10% year-over-year, and that's indicative of what we see, Umer, in this pipeline. We think it's very important to expand and accelerate in these opportunities that we have in front of us. So we-
You're not gonna underfund just for any ratios?
We recognize this. We guide, and have guided, and are maintaining that guide of roughly 50% operating margin in 2023. But we realize, and we've shared this with investors, and we wanna make sure our colleagues understand, that when there's opportunities like we have right now, we're going to address those. We're gonna do everything we can in prioritization and productivity to reallocate that money from other functions into research and development. We're good at that at Amgen. Certainly, generative AI and so forth offers us opportunities to do that, but we realize it's very important to fund these and move them along, and we are committed to that at Amgen.
Got it. Okay, excellent. Excellent. So that's number one. The other one is from a SG&A perspective... Again, I'm just thinking broad strokes right now. Obviously, 2023 to 2024, there's the Horizon SG&A, which gets added on. But beyond that, consensus is generally just assuming flattish, in part because of some of the Prolia, Xgeva expectations that are modeled in the way they have been. Is there any broad strokes on SG&A medium term as you think about any pushes and pulls to think about?
Just think about this year. I think this year we're also-
Mm
Anticipating OpEx overall up about 10%. I think we said about half of that is Horizon.
Right.
As we go through the year. So we always watch SG&A very carefully. What I would say on that, Umer, and this is a really good question, is that we see an opportunity here to continue to invest in some of the in-line portfolio too, which comes through there. We've indicated to investors, in fact, at the end of the second quarter, with Repatha and even Otezla, that we're in the market, and we're investing in those 'cause we think we're in a position of strength to go at those, in terms of the capital that we have to invest in those. We expect those investments to continue into the first half of 2024, and we think those are really important also.
And as long as we're kind of on the expense side, I would just drop down into OI&E just really quickly for a minute, and we guided to about $700 million or so in the fourth quarter. And we see that, and as we indicated, we believe that run rate will continue in 2024 in OINE. And we've looked at a few of the models out there, and we've seen that. We don't think everybody's recognized that yet, but our capital structure's a little bit different right now. You know, we expect it in the year with, you know, a significant amount, more debt than we did when we started it. We raised about $28 billion to fund Horizon. So it's important to remember that's coming into the non-GAAP OINE in the fourth quarter and also into 2024.
So that's how we think about the expense structure. At Amgen, we'll always continue to be as efficient and effective as we possibly can. And number one, capital allocation in the capital hierarchy is innovation, both internally and externally.
Got it.
You know, and so we'll, we'll remain committed to that.
Got it.
Peter, I wanted to just pick up on one point.
Please.
I think it's important. So, you know, and I know, Umer, you've been following this for a long time, so you might recall that, you know, almost 10 years ago now, we, we did a business review in 2014, and we talked about, you know, significantly increasing our margin into 2018. And one of the elements of that was this idea that Peter mentioned of a, of a productivity program across the company. And so, you know, really, that was in anticipation of an environment where prices would be going down over time. So then you have a bit of a conundrum, right? How do you grow the business? How do you invest and grow volumes while you're facing reducing prices?
So what the company did, again, a long time ago, and has been executing on, is this, this idea of a productivity program, where each year, leaders look across the business. They figure out a way to, you know, streamline processes to get, you know, more done for less. And as Peter said, AI provides kind of a nice, you know, lever in that regard as well. So just wanted to... You know, it's something that maybe goes a little bit under the radar because it's not, it's not really sexy. It's just blocking and tackling, but, you know, that's what'll frees up resources and allows us to really, you know, plow money back into the business.
Got it, got it. Very helpful, very helpful. I wanna tie this now towards the bigger picture as well, but just before I do, historically, I remember one of the points I've discussed with you, Justin, with Arvind, has been, on average, Amgen would do about $4 billion worth of buybacks. Obviously, there's some leverage right now, and the Horizon deal is just getting closed. That's not something that's anytime soon. But Peter, how are you sort of broadly thinking about that? Again, this is not a 2024 question, but medium term, when, when could Amgen be in a position to start getting back in that direction again?
Well, prior to going as Vice President of Investor Relations, Justin was a treasurer, so I'll suggest to him that-
All right
He cover that capital structure question, which we thoroughly interrogate all the time. It's a very fair question.
Yes, Justin, you're giving me flashbacks to when we were meeting with the rating agencies and staring into their eyes.
Well, if he was meeting with rating agencies, Umer, he'd have a tie on this morning-
That's right
... just so you know.
Yeah. No, it's... Thanks, Umer, and, I mean, I guess the first point is that I think Amgen has quite a track record of returning capital to shareholders. And, you know, it's been obviously share repurchases in the early days of Amgen, and then a blend-
Dividends
... of dividends, you know, going forward. You know, at the time of the Horizon announcement, we obviously wanted to be thoughtful, and we wanted to be helpful to our Investors of how to think about the capital structure. We knew this would be an important question. So the first thing we did is we actually laid out, how we think about debt and leverage. So we shared our 2022 debt-to-EBITDA ratio, which was 3.2, which we hadn't previously provided. And then, what we committed in the various communications is that we would return to that same debt-to-EBITDA ratio by the end of 2025. So that kind of frames up the deleveraging period-
Got it
... if you will.
For the next couple of years-
Yeah
... repurchase is not the first priority?
Yeah, and I would say that maybe the way to think about it is, you know, our practice has been year by year to give guidance on share repo. So we'll obviously, you know, have more to say on our earnings call for next year on that.
Got it.
So just last point, Umer, you know, we did also say at the business review last year that we would have a payout ratio of greater than 60% through the decade, and that would be in both share repo and dividends, and that certainly holds. You know, we're on a good track to meet or exceed that.
Excellent. And as I sort of bring it all together, then, the big lever from a P&L perspective, and again, I have a lot of R&D-specific stuff to get into, but just to round out the P&L, the biggest lever now, in my opinion, is obviously the Prolia, Xgeva, where, in my opinion, there's a very extreme position being modeled per consensus, which is the Amgen 10-K, which guides to the very first patent, which is 2025, and that's what's being modeled in for erosion. Over the years, I've always learned Amgen, Amgen, and Amgen's lawyers, so I realize there's patent estate all the way out to mid-2030s on Prolia Xgeva franchise.
I realize there's only so much you can say on this broader topic, but I can already see in court dockets that you guys are fighting this pretty hard against the biosimilar players that are going after this opportunity. How are you guys thinking about as a base case, what a realistic launch scenario could look like? Because to me, 2025 seems very unrealistic.
Well, this is a really important question 'cause it's the bone franchise, and we believe in the long-term growth outlook there, Umer. We feel good about progress that we've made in the bone franchise. And each year, as you said, you know, we provide the disclosures in the 10-K. I would encourage our colleagues to look through that thoroughly. Our outlook assumes multiple entrants after the LOE in 2025, so that's how we think about it. But I would add to all of you, Evenity is coming on very strong. And so when we think about Evenity, as I mentioned earlier, greater than 50% growth in the third quarter, year-over-year. This is a bone strengthener.
You know, I think in the United States, you know, we see, just so I get the numbers right here, we see about 3 million patients in the U.S. treated for postmenopausal osteoporosis, about 40% at a high risk for fracture, and only 6% of those right now are on a bone strengthener. So we feel great about Evenity, and, you know, we see that as a key part of our franchise, you know, through the end of the decade and beyond. And we see Prolia is continuing to be an important component of our bone franchise going forward. But we don't anticipate pulling a rabbit out of the hat on this or anything along those lines. We think good, steady growth.
You know, we'll play really hard on Prolia, 'cause we think it's really a terrific medicine, but Evenity's coming on strong. So the bone franchise is very important to us. We'll continue to invest in that, and, you know, we're looking forward. I think this year we're going to deliver Prolia to over 7 million patients around the world. So what a fantastic medicine for those with osteoporosis disease.
Got it. Excellent. Peter, I'm forgetting this. I don't know if you were at Amgen when the 2030 guidance was given out, but consensus is-
Mm-hmm.
Forget how much it's off. It's nothing like the Amgen expectation on 2030 from an EPS perspective. I realize when that guidance was given out, some of the key drivers of that were very different than the drivers that we're about to talk about on the pipeline front. But... And again, pipeline evolves, data evolves. As we sit here today, where do you see the biggest disconnect between consensus is just flat on EPS, and you guys are talking about a potential 50%-75% higher EPS. Where do you see the biggest disconnect?
Great question. So I went back, and I keep at home-
All right.
... the mountain slide. For those of you that's been described as the mountain slide, the lasagna slide, the spaghetti chart, any number of various descriptions. At the end of the day, it's really the components of what we talked about in February 2022 on our growth trajectory to 2030. So we've said all along, you know, we feel we're on track to meet our 2030 objectives, and that horizon is additive to that. So I wanna make that very, very clear. The first part of the chart was the pipeline, and it was LUMAKRAS, TEZSPIRE, and the rest of the pipeline. So as we sit here today, and you know, I think we'll probably spend a significant amount of the time-
Thirty-two minutes
... Dr. Burton, on the pipeline and the wonderful news there for patients first and foremost, we feel really strongly that the pipeline's, you know, continuing to evolve in a very positive way for patients, and as a result of that, for shareholders and going forward. Biosimilars, we talked about a 2021 base of about $2 billion, more than doubling that by 2030. That continues to be a strong area. We think buy and bill is a good place for us there. We'll continue to focus on that. As we say about biosimilars, it's new molecules and new markets that we'll go into that'll continue to drive that. Umer, Repatha. Okay, Repatha grew again, 31%.
It printed a great quarter, but the most important thing is cardiovascular disease is the number one killer on the face of the planet. We've got 90% coverage now with, with payers in the United States. We feel this is a really important advance going forward, and we're working really hard. We're inflecting into the primary care physicians now out of the cardiologists, not out of, but in addition to the Cardiologists. Otezla, even though it's, it's had some challenges here and, and a little bit of a, a flattening, if you will, with, some of the competition coming in, both from the free drug, from the topicals a little bit earlier in the year and, and the other, free, oral that came in with some free drug there. We are confident on Otezla. We're spending on it.
We think there's a great opportunity between the mild and the severe indications there. It's the only systemic that is available for that, so we continue to invest in that, so we remain confident in that. The rest of the currently marketed pipeline that we had back in 2022, Blincyto, I mentioned, is up 50%. We'll talk... You'll talk with Dr. Burton about moving that into earlier indications. The HEMONC portfolio, I believe, was up about 16% in the quarter, year-over-year. And so we've... You know, Tezspire grew rapidly, I think, in the third quarter, it was up to about $161 million of product sales, so there's a lot of really good news. We like breadth and depth. You know, it's going well.
And then we have a portfolio of other products. They're declining a little bit, but as we shared at Business Review Day, the decline in biologics tends to be, you know, a slower erosion than others. So we like that profile, too. It adds cash flow that we can then reinvest into the pipeline. On top of all that, rare disease business, and we feel good about that. We like that as the fourth leg of the stool, so we think that's additive going through to 2031 and beyond. So we like the picture. We think it's an execution story now. We think we've got the cards in hand, and it's time for us, and we've always been really good at execution, and we're doubling down on that-
Got it.
and gonna work really hard for patients and shareholders.
I don't know this, and I don't recall seeing this, but I'd be curious, is there any management compensation tied to the long-term EPS targets and the 2030 guidance targets?
We have our... And again, you know, it's in the proxy that we tend to have three-year-
Got it.
on our long-term investment.
That 3-year is kind of backing its way towards the 2030.
Keeps rolling. Keeps rolling.
Okay.
I can assure you, we think at Amgen really in four timeframes. So just to take one more minute, then I'll let you get to Dr. Burton. We think about the current year, and we focus on that, and we need to achieve that. We think about the forward 12 quarters, because all of you ask us, you know, what's gonna happen, you know, with, with maybe expiries and significant events in the next three quarters, so we next three years or forward 12 quarters, if you will. We think about through 2031 now, and then we think beyond that. In February 2022, we talked about BioNext we talked about our targeted protein degradation, our induced proximity platform, and moving that forward. So we think about those four timeframes. How do we allocate capital?
How do we manage the business? We're always thinking that way. It's really important. That's how the top of the house thinks at Amgen, and when we think about that, we're always fully committed first to patients, and then, of course, to creating value for staff and shareholders after that. But that's how we think about it, Umer. We always think long term, but at the same time, we hold those, if you will, as, F. Scott Fitzgerald said, those opposing thoughts in our mind to make sure we're allocating capital and managing the business for all four of the timeframes.
Excellent. Fantastic. Well, maybe that's a good segue, having now laid the sort of broad strokes around the P&L, to transition to R&D side of it. AMG 133, I still don't know what its actual name is, but that's all I know. But your GIPR antibody, the first question that's coming up, and maybe this is where I want to kick things off, is... And we'll talk about efficacy, we'll talk about the durability and all those things, but a question that's percolated in a lot of investor conversations has been around bone density changes, especially as it relates to... And I don't know where this has come up very much, but there's a couple of preclinical papers that surface quite rapidly if you Google this, and which talk about GIPR.
Agonism would be associated with bone density preservation, but antagonism, which is the Amgen approach, would presumably have a theoretical risk of bone density changes. And it's actually created a little bit of a question mark that heading into the phase II readout next year, there's some risk around bone and fracture and things along those lines. So I'd be just curious how you guys are thinking about that broadly, and to what extent do you have any visibility on a pooled, blinded basis on the ongoing study?
Okay, very good. So, AMG 133, as Peter said, maridebart cafraglutide.
All right.
So we call it MariTide, for obvious reasons.
That's so good.
... internally. Subcutaneous injection, molecule given every four weeks, combines two parts, right? As you say, GIPR being antagonised. So let's take the first part around fractures. We have not seen any fracture risk in preclinical studies at all. Now, clearly, we need to assess that in larger human studies, which we're obviously doing, and we'll pay careful attention to that. But I can tell you that through the deCODE part of Amgen, which, you know, is our very powerful human data engine, that we acquired some years ago, we've been able to do huge individual human-based studies, 350,000 people, where we can look at individuals who have that variant, who don't have GIPR. So it kind of parallels what we're seeing with the molecule - what we're doing with the molecule in real life.
When we do those analyses, we don't see any increased fracture risk, and we can even, and have, enriched that analysis population for people with post-menopausal osteoporosis.
Oh, interesting.
So we can, we can really tailor the analysis to address that question, at least in the real world, to the best of our ability today. Is there a fracture risk? There does not appear to be one. Now, maybe just on the interim, should we talk about the interim analysis?
Yeah.
So we've done a—maybe just stepping back briefly, we've done a phase I study, as you know. When we take MariTide, we looked at a range of doses from 140 milligrams out to 420 milligrams. At day 29, we saw a 5.3% reduction in weight loss. At day 29, that's impressive, right? Out at day 85, we saw a 14.5% reduction in weight loss. So even in phase I, it shows, you know, clear, what we believe is to be differentiated and impressive clinical effectiveness. We're in phase II now. That's a study that's already enrolled nearly 600 people, and it includes people who have diabetes and those who don't have diabetes, so it's broad.
We have an unblinded data monitoring committee who review the data frequently, and the message has clearly been: continue the study as planned. So that's very reassuring... We will, Uma, to your point, perform an unblinded interim analysis next year. That's planned, and it's important because it will allow us to then really think about the phase lll design. One thing I would make a clear point for people to take away is, I don't think there should be an expectation of a rapid phase lll start following that interim analysis. We're doing the interim, we want the study to maintain its rigor, so we won't be talking about the data openly at that time, publicly, 'cause the study will be ongoing. And it's not a go, no-go decision point.
It really is, let's see now what a larger population of patients shows us, get as much data as we can, and then use that in a very data-based way to inform phase lll study design, which we'll do internally. We know it's fast-moving as a space. We believe we have a molecule here with clear, differentiated effectiveness. We want to go quickly, but we want to go rigorously and thoughtfully as well.
Got it. Okay, makes sense. And the phase lll gating factor being you need 52-week data, is that what FDA requires? That's why interim could not inform the phase lll initiation.
I think the interim analysis will certainly inform our phase lll design around-
Doses and all that.
Yeah, doses, dosing frequency. You know what, I think... Look, what is important, are a few things. One is, I would say we're really at the infancy of weight control as an industry in our understanding, also of what people want. So velocity of weight loss, magnitude of weight loss, and durability of effect are clear. We want to be able to balance all of that across a broad patient population. And, you know, we also recognize that these are gonna be very large studies. Peter mentioned that, they're gonna be big studies to do. We're gonna have a very large safety database that will then continue into the real world. So I think the goal of the interim is to get as much data as we possibly can, to then design a robust, large platform of studies, as we go forward.
Got it. Can we speak to the weight loss kinetics, data from data seen to date? I ask that in particular because there's a lot of question marks around what's the sort of peak weight loss you guys can get to? I know there were, I think it was three injections, and you got to mid-teens. But the question really is, we saw Victoza, we saw Ozempic and Trulicity in the mid-teens, we saw Mounjaro approach about 20, and we now have Cagri somehow approaching mid-20s. Could Amgen be competitive with that mid-20s bar? Do you anticipate that to be something that the phase ll should be able to show us?
Yes. Yes, we do. I mean, again, look at day 29, just over 5%. That's, that's important. By day 85, over 14%, as you said. You know, we're exploring different doses, different dosing regimens, duration of dosing. So, so yes, we believe that we have a differentiated and, and highly effective molecule here.
Just to add one point there, Paul. So, you know, when we think about the potential differentiation or the applicability of MariTide, obviously, weight loss percentage is one component, but we think there's, you know, many other factors that are important. I mean, as Paul mentioned, the dosing. You know, we're studying. We had monthly in the phase 1, we're looking at different dosing options in phase ll. To the extent that there's challenges in, you know, real-world compliance today with existing therapies, that could be an important feature as well. So obviously, while we know that there's a lot of focus on the weight loss percentage, we would maybe encourage folks to not look solely at that parameter.
Mm-hmm.
That makes sense. That makes a lot of sense. Remind me, I was looking back at the phase 1. These were non-diabetics, is that right?
Yes. Principally, yes.
These are non-diabetics. So when we talk about mid-twenties weight loss, are we referring to obese? Because I know obese always track a little ahead of diabetics. Could diabetics get to mid-twenties as well on weight loss?
Look, I think, honestly, we'll have to wait and see the data. It's. I would think it's feasible, but we'll have to wait to see the data.
Okay. Is there any reason to expect A1C, for whatever reason, not being as competitive on this, or no reason to think that?
No. No, I think, you know, when we think about the breadth of the people that we'll really want to study in phase lll, there's a couple of groups to go after. One is people with obesity and an important medical condition, for example, heart failure, where you can target a study to look at a heart failure endpoint. Can you improve outcome by obesity management? The other is to take an obese population who have coexisting comorbidities, like, you know, prediabetes or a raised A1C diabetes, sleep apnea, things like that. Can you, as corollary collateral impact, you know, improve those outcomes?
Right.
I think we can. You know, I think there's certainly opportunity to do that.
Got it. So, in the ongoing trial right now, and it's clear we talked about the weight loss aspect of it, I know you referred to various dosing regimens as well. So my understanding is there was only two cohorts, A or B,
Yeah
... in the ongoing study.
Diabetic and non-diabetic.
Okay.
B is diabetic.
So embedded within each cohort is different doses and different regimens.
Yeah.
Is that right?
Yes, that's right. Multiple arms. So we'll be able to study a broad range, and, you know, as Justin mentioned as well, we are gonna look at less frequent dosing, you know, whether that's in the initial setting or as we go out.
Got it. And when we think about less frequent dosing, I remember there was the graph you guys showed where you dose till day 90, and then you put out values, 3 follow-ups until day 210. I don't know if they were exactly at a one-month follow-up or a little longer than that. But the first time point after day 90, when the drug was off.
Yeah
... it was about a month after? The effect was very much sustained, which to me implies that every two months could be possible. The second time point after, which would then imply two months after the last dose, I noticed it was starting to tick back up. So that implies to me, perhaps quarterly may not be possible, at least for induction, for maintenance, it may be. I'd be curious how you guys think about the possibility of a quarterly regimen.
You know, look, I think, compliance, adherence, perseverance will be important. But balancing optimal dosing regimens with clinical benefit is key to us. Peter mentioned that, right? We think about the patient first, and what can we do?
Just the general caveat, too, obviously, the phase I data was exciting and informative, but, you know, pretty small patient numbers there.
Yes, yes.
You know, we'll have a lot more information-
Yeah
coming out of phase II.
Yeah. Maintained out to day 150, you know, I think that's an important takeaway. Let's see what the bigger, bigger, clinical experience in phase II now gives us.
What commercial feedback are you guys hearing on this broadly, if you can have a quarterly, incretin?
Yeah, I mean, I think,
I don't think market understands the potential for that right now.
Yeah, it's a question we get a lot: Is there room for a third player, and you know, how might MariTide fit in with the other options? And we do feel like the different dosing profile could be a differentiated you know, point about MariTide.
Yeah.
Is there YTE substitutions on the FC? Is that how it's doing it? Or it's not half-life related, it's just the continuity of the weight loss?
I think it's yeah. I mean, look, I think, to be honest, answers to questions like that, I think will also come out of phase II. Again, I would say, I think we're really at the infancy of understanding how these medicines, molecules will work in patients, how they bring about their differentiated effects.
Got it. But the half-life of the antibody was sub-1 month. That was clear. So I always assumed it was not some YTE-
Yeah
-substitution or anything like that.
No, that's right.
Okay, it's just the PD effect-
Yes
could help it last.
That's right
two or perhaps three months.
That's right.
That could also differ between induction versus maintenance?
It could, yes.
Okay, that makes sense. That's very interesting. That I actually did not appreciate that much. There was one moderate AE in phase I, literally one on the 140 and the 280 doses. Do we know what that was, if it was anything of relevance to know?
No, I mean, I think the important point is that the unblinded data monitoring committee continues to look at data safety and the effectiveness as well.
Okay.
The study should continue as planned.
Anything on cardio stuff? 'Cause we know heart rate elevations, arrhythmias are something that's been known with,
No, nothing
-incretins.
Nothing really to comment on at this time.
Could that conversely be a differentiator? 'Cause I know it's been a common finding with other incretin programs.
Potentially. Again, I think let's look at the full data set when we have it, as Peter said, next year, and we'll know more.
Okay, got it. Very interesting. So maybe that's a good segue then into the mystery oral. We have a hypothesis on what that is. One of my colleagues is here. We were looking through some of your patent filings, so we're not going to put you on the spot on whether it's a delta-5 desaturase or not. But what I can ask you is, in the ongoing phase I, it seems like one cohort was dropped in the single ascending dose. And to me, if somebody ever asked me if a fifth dosing cohort is dropped in the SAD portion of a study, I'm always assuming an MTD was hit, perhaps. But I know this question came up on the last earnings call as well. How are you guys characterizing sort of the progression of that phase I?
Look, you know, we do phase I studies to dose range and find, and, you know, I've been doing drug development for a long time. What I've learned is that you have to be adaptable, and we had cover of the doses that we wanted to explore. And, you know, you do a phase I study to get a sense of, is the drug generally safe? Does it have effectiveness? And that's what we're doing. So, you know, we'll, we'll, we'll. You know, we may drop doses, arms, we may add arms. That's just the nature of drug development. I don't think there's anything else to read into it.
I guess, how, as you're thinking about, broadly speaking, about this oral in development, it doesn't have to be a 15% or 20% weight loss. Is that a framework you guys are running with as well? It could be a 5%-10% weight loss and just be additive to some of the oral glips that are being in development. Are you thinking of it like that?
Justin might want to comment as well. The one thing I would say again is I really do believe we're at the infancy. We're right at the takeoff. You know, what do people out there in the real world want in terms of weight management? And how does that change if you have important comorbidities, severe diseases? I think there's, you know, there's plenty of room to think about all sorts of different weight loss strategies and management approaches with medicines that are, you know, less profound, greater, different durations, and balancing that will be, I think, the most important thing.
Yeah, totally agree with that, Paul, and I think you've said it well. It's not a single parameter that we're solving for-
Sure
... it's the whole, the overall profile of the program. And given, you know, how heterogeneous... I mean, if you look at the patient numbers, they're staggering, right? So we have to believe that there's going to be many subpopulations who might have different solutions.
Interesting. Different subpopulations, so with different comorbidities-
Yeah
and how some of these programs could be positioned for that.
Yeah.
It doesn't even have to necessarily be an oral for all obesity, for example.
No.
I mean, if you look at some of the numbers, I think, you know, one that we've seen that's in the public literature is over 650 million obese people in the world, right? So obviously, that's not going to be a disease for all those people.
I see. I see. And if I may just expand on that just a little more, how much visibility from a safety and the trial progression perspective do you guys have right now, knowing that it's phase I, so this is not necessarily some double-blind, randomized trial per se? How much visibility do you have on that right now?
... Well, look, we obviously scrupulously monitor and oversee the study constantly. We look at blinded clinical events and safety events as well. It's, you know, it's as David Reese said, it's a phase one study. It's, you know, we're trying to get a handle on how this molecule performs in people. So, you know, we intensely follow it, but, you know, can't really comment.
Got it. From a safety perspective, at least, like I said, where I kind of started this conversation, that one arm is dropped. It could be for any number of reasons, but it's not simply assuming that, oh, it's because there's a clear DLT or MT, that can't be a base case in interpreting something like that, that there's, like, a safety observation in the works.
Well, look, as I say, you know, we do these studies to dose range and to dose find, and to get a sense of are we covering the target sufficiently? And, you know, that's what we wanted to do, and that's why we made the changes.
Got it. Got it. Got it. In terms of prioritization, I gotta believe at some point, you always sit down with Peter, and you're like: "Well, you know what? We're gonna invest in R&D," but even then there's limitations to the directions we can go. Is there, like, a blank check on anything obesity program-related, or is there a prioritization, or is there populations that happen to be selected? How are you guys thinking about that as you're having some of these discussions?
I'm glad you asked that question. I was thinking about that earlier when you asked the question about how we are viewing R&D investment in the next couple of years, and we would just view this as a situation where, really, for patients, we need to explore as many indications as might make sense. So we are viewing this as an area where we will expand and accelerate as we need to.
Got it. So the bar could be different in terms of-
The bar could absolutely be different.
In terms of willingness to allocate?
That's correct.
From an internal perspective, is it fair to say 133 is the flagship program internally, and then oral evolves, depending on how it does, maybe position in certain populations? In an ideal world, if you had an oral combination partner with it, it could be perhaps positioned for all, but is 133 is the mainstay, oral maybe for subpopulations?
Well, I think right now we're focused on 133, but we really see this as, as we've said previously, too, Umer, as a platform opportunity. And I think what Justin said, and what Paul mentioned, too, you know, there's many subpopulations, there's many aspects to this, in terms of comorbidities and so forth. So we wanna be flexible and adapt to the situations. And as we, as we've said, you know, we're prepared, number one, capital allocation invest in the best innovation, internal or external. So we're going to push ahead on this in a very-
Right
... strong way. I would say right now, MariTide or AMG 133, is really on the top of the priority list, making sure that we, fund that and accelerate it a- according to what Paul and, and our-
Got it
... development group and so forth, come to us with in terms of, of the ideas that we need to pursue.
Got it. So, Peter, obviously, you approach these things from a CFO perspective, but also a bit from biz dev perspective as well. But I'm just curious, between yourself, David Reese, Paul, has there been a conversation that, look, in first half next year, we have this non-incretin oral data in-house? Maybe there's a possibility for an external transaction, where we have some sort of a collaboration or something of that sort with an oral GLP, and that's like a fixed-dose combo of sorts, which we could structure into a larger program. Has there been considerations along those lines, or is that not a direction you guys are going down?
I would click up one notch on this and just share with our colleagues, and with you, Umer, that we're always focused from a business development perspective with a very wide aperture.
Okay.
So we're always thinking, you know, "How should we pursue, what's out there?" And when you think about, business development opportunities at Amgen, we're, structurally agnostic, whether it's collaboration or licensing or, acquisition, we're structurally agnostic. We've got a really strong program there. So it's really, David Reese, Murdo, myself, you know, Paul, we all participate in how we're looking at opportunities out there, and that's led by Rachna Khosla, our Senior Vice President of Business Development, been with the company over 10 years and does a great job with her group of, you know, seeing what's out there in terms of opportunities and integrating that into our internal thinking. So it's a very. When we say our first capital allocation is the best innovation, internal or external, we really mean it, 'cause we wanna find the best out there-
Right
... obtain it, and bring it in.
Makes sense.
We just want everybody to rest assured that's how we're viewing this opportunity.
Makes sense. Paul, I'm sure you've looked at some of the datasets that are emerging for oral GLP's. There's some one-off ALT observations. Companies are reasonably comfortable with that, regardless, they're dosing through those. Do you think there's scope for differentiation with your oral on safety versus some of the other oral obesity datasets that we've seen over the last couple of years?
Yes, I think is the simple answer. Again, you know, we're early. We're only in phase one. We still have a long ways to go, I think, to increase that dataset and really understand. And again, I go back to that point of we're right at the start here. This is... Justin said it.
Right.
It's such a huge-
Right
... unmet need. Obesity alone, obesity with comorbidities, severe disease. So many, I think there's so much optionality here.
Yeah. And so comorbidities, one of the ones that comes to mind, obviously, especially with this type of mechanism for your oral, could be more liver fat or NASH-like indications with obesity, things along those lines.
Yeah, I think as Peter said, look, we think very, very broadly about the opportunities here.
Mm-hmm. Okay.
Whether that's NASH, NAFLD, you know, any combination of-
Makes sense
... stuff. Yep.
... Okay, excellent. Maybe then transitioning past obesity, 'cause you have a little bit of other pipeline as well. As much as that's the only one people are gonna care about now. You have a phase III trial of an OX40 program. Not surprisingly, you get almost no questions on it. I know one of your competitors is very focused on that target as well. They're a little behind, but one of the differentiations I did notice in the emerging data for your phase II program, in your phase II data, was there were more...
There was, when I looked at that safety table, it reminded me of the safety table for a COVID vaccine in terms of the fever and chills, and I'm curious, to what extent is that, a true patient observation in—how important is that to a patient experience?
Yeah.
Could that be a very important commercial differentiator, you guys versus competitors? Because that's clearly something they're going to lean in on a lot.
Okay. So maybe just 30 seconds on rocatinlimab. So it is our OX40 antibody. It's been in phase II. We're studying it principally in atopic dermatitis, Peter mentioned earlier. In the phase II study, the EASI, the Eczema Area Severity Index, came down by 60%, so it clearly is a molecule with, you know, with important, strong efficacy. We're in now this 7-program ROCKET phase III platform, looking at adults, adolescents, combo therapy, monotherapy, you know, combination with steroids. And where does it fit in? It fits in, I think, in there's a lot of people who are taking IL-4/IL-13 inhibitors, JAK inhibitors. They have tolerability issues, they're not all patients response. So there's a clear area here where rocatinlimab could sit.
You're right, in the phase II study, published in Lancet, that fever and chills were the higher rates of adverse events, most common adverse events. One thing, though, from that study that, as a physician, is important to me, is that the rates of adverse events leading to discontinuation, 21% in the placebo arm, 9% in the rocatinlimab arm. That's, that's important, you know. So it says that people will take the medicine and stay on it. We've enrolled over 1,500 people, so I think, you know, physicians and investigators are voting with their... You know, voting there to say, "Look, this is a tolerable, manageable medicine." So we see it as an issue, you know, fever and chills, something important. We'll obviously, we scrupulously monitor safety.
We'll report it. We'll discuss it with physicians, patients as they think about it. But we don't think it's something that really needs to be managed into phase III or, you know, overly rotated on.
Got it. Okay, so there's not some. And you guys do have, presumably, some blinded visibility, pooled visibility on the phase III ongoing study.
Yeah.
Was there any changes as it relates to any pre-medication or something to manage some of these fever chills in the phase III?
No. I think, look, I think in general, they're relatively mild, and they're generally manageable.
They're day one only, kind of like-
They're early. Yes, that's correct. That's correct.
The other observation, what stands out to me in your OX40 data set, is once the efficacy is kicked in, especially in the responders, even if you pull the medicine, it just stays for six months, which is highly unusual. Maybe it speaks to the T-cell mechanism.
Yeah.
But the obvious question I had was, I don't know if we ever figured out how much OX40 do you need to take before which you can pull it? Why couldn't it be after, let's say, three or four injections? Why does it have to be six months' worth of injections?
Mm.
Because if T-cells are cleared out from the inflamed skin side, presumably that's done by 1-2 months, and it could be done much sooner.
Mm.
Is that being experimented in the trial? Because it could have very clear commercial ramifications as well, right? Because if clinicians find out, "Well, I don't need to give it for six months before I turn it into an every six-month regimen.
Yeah. So look, I'd say a few things. You know, we did the phase II study. We studied a, a broad range of different doses, different dosing, frequencies. I think we've been able to come up with a dose now, or a, a regimen that is effective and, and works, and, you know, changing that would not be a good way to go forward. I think we've got an effective medicine, an effective molecule, appears to show benefit. We're in these studies now, and we see a clear pathway, to potential approvability. Obviously, it'll be a review issue with regulators, but, you know, we want to get this molecule, this medicine, to patients now quickly and address the unmet need.
That said, we are studying, though, the opportunity to go to less frequent dosing after the initial 24 weeks of therapy. So it may be that, you know, when we have a dosing regimen that appears to work, do that for those load, monthly dosing, and then we can begin to transition dosing out later.
Okay, got it. What about Dupixent experienced or Dupixent refractory? Is that a population that's on your mind?
Yes. They were in phase II as well, about 15% of the patients-
Experienced?
... Yeah, had been on biologics, primarily Dupixent. So I would- we would imagine that that proportion of people would probably be in this phase II.
There's not a dedicated phase III per se or anything like that?
No. No, there is not. That's correct. You know, across the several thousand people we'll have, there will be some good experience there that we can report on, and it might be, honestly, that this is something we then address with a real-world evidence approach and post-approval.
Got it. DLL3, I know the data was very interesting.
Yeah.
It got a lot of investor interest. On one side, it's very late line, like third line plus. On the other side, there's a massive amount of chemo shortage. So I'm thinking realistically from a commercial perspective, I understand it's supposed to be in super refractory setting, but with so much chemo shortage, there's generics getting pulled into Congress on some of those fronts. Are you guys ready and prepared for a launch, where demand might perhaps outstrip what you might have initially thought about in a super third, fourth line setting?
So I know we're getting close on time. So tarlatamab, DLL3— a remarkable molecule. We presented the data at ESMO. It was published simultaneously in the New England Journal of Medicine. In, as you say, in late-line patients with small cell Lung Cancer, as a ex-surgeon seeing those patients, we know in the real world, survival is maybe 3-5 months. Tarlatamab, in the data we had, over 14 months, almost triple survival. I mean, that's remarkable. It speaks to this whole BiTE platform. Peter mentioned it. We started with Blincyto. This is now the first time a BiTE's gone into solid cancer. We have Xaluritamig as well in prostate. Really remarkable. The Blincyto roadmap also says, look, the earlier you can get into treatment, potentially, an even bigger benefit you can provide to patients. We've seen that with Blincyto, with the E1910 data.
So your point is a good one. Can we pull back into earlier lines because we can provide more benefit to patients? We think so. We have ongoing studies, the 304 study in second line. We're doing even earlier line studies. I think the question from a chemo shortage and implications there, honestly, we might, I think it will be a review issue with regulators here in the U.S. and around the world. We're sensitive to it. We understand it. Just, if you were wanting the same thing about the launch, but—
Yeah, I mean, certainly from a launch point of view, we'll, you know, promote in the approved indication, as Paul said, wherever that. You know, we're in those discussions now. But of course, from a preparedness standpoint, you know, we have our operations team is great at looking at a whole range of scenarios. So I think, I don't think it's so much an issue of supply, it's more about-
Got it
Y ou know, where we land from the approval.
Yeah, maybe just one comment. I know we're out of time, but I'd just share with all of our colleagues at Amgen, it's every patient, every time. We've never stocked out of anything, and we don't intend on doing that. I've had an opportunity in the last couple of weeks to visit our new facility in Ohio that'll be up and running and licensed in the first part of 2024, and I had a chance last week to go to Singapore and see our facility there, our kind of manufacturing of the future facility. Every patient, every time. Supply is always first and foremost at Amgen. We intend on being there for patients, as we have been for almost 40 years.
Excellent. I had some other stuff on the agenda, but I realized I need to be respectful of time, so I appreciate you guys being here. Good luck into all the data next year, but I also, most importantly, appreciate you clarifying some of the questions around, especially obesity, which were not so clear, I feel.
Great to be here, Umer. We always appreciate the invitation.
No, this is-
It's great to see you.
Excellent.
We wish everybody great health in 2024.
Excellent. Thank you, guys.