Good afternoon, and welcome once again to TD Cowen's 45th Annual Healthcare Conference. We're delighted to have with us again this year Eli Lilly. Joining us from the company is Jake Van Naarden, who is President of Lilly Oncology. Thank you so much, Jake, for being with us.
Thank you. Thanks for having me.
While we're going to spend 95% of the time in this session on oncology, I'll start out with a more broad question, and that is, Jake, what are the key upcoming pipeline catalysts for Lilly overall as an entity?
Yeah, so I think, you know, in the late phase portfolio on the R&D side, there's probably a handful of things I would highlight for the remainder of this calendar year. I'm sure most people are waiting on the readouts of the Orforglipron program. This is the small molecule, oral small molecule, GLP-1 non-peptide agonist that we initiated a pretty broad program around.
And we can talk about the studies that are reading out this year. The first study will be in type 2 diabetes. The second study will be in obesity. I think those are, and there's more coming after that. Those will be really important readouts, I think, for this medicine and for this class, especially, you know, for an oral small molecule that we can manufacture at scale.
I'll come back to maybe that medicine in a second as I maybe run through some of the other catalysts, and we can then talk about Orforglipron a little bit more. You know, just sticking with the chronic weight management portfolio, we'll also get the first readout from the Retatrutide program. This is the triple-acting injectable incretin.
The first study there is in patients who are overweight and have osteoarthritis of the knee. So, you know, in that study, we'll be looking, of course, at changes in weight, but also pain scores associated with the osteoarthritis. I think at the most recent earnings call was the first time we talked about that study actually reading out, you know, this calendar year.
So, you know, that's a medicine that we think can offer like a real step change, actually, in weight loss and outcomes for, in all likelihood, higher BMI patients who can't get to goal on medicines like Tirzepatide. You know, this is a medicine that, you know, we hope will allow them to get to goal with a higher frequency. So, you know, there's a big phase three portfolio there too, and that's the first study to read out.
And then on the oncology side, I'll just highlight, this is a big year for the Jaypirca pirtobrutinib program. This is the BTK inhibitor of ours that's on the market today and a fairly narrow indication. And, you know, there are five randomized studies that we started for this medicine, but only one of them has yet read out. At least two others will read out this year.
One is against chemoimmunotherapy in newly diagnosed CLL patients. The other is a head-to-head study against ibrutinib in CLL, both pretty important studies for evidence generation and hopefully label expansion of that medicine over time. So it's going to be an exciting year on the late phase side. And of course, on the early phase portfolio, we've a lot going on across our therapeutic areas.
And the hope is by the end of the year, we know a lot more about what those medicines are and can accelerate their development, particularly in oncology, where, you know, we put a lot of medicines into the clinic over the course of the past year and expect to do so this year too. So maybe I'll pause there. I don't know if, did you want to talk a little bit more about Orforglipron, just given the focus on that medicine?
Sure. There's tremendous focus among investors on that medicine. And so we kind of look at it in two buckets: efficacy and safety. And there seems to be less concern about efficacy, that that's pretty much not going to be an issue. But safety is a bit more of a concern. So why should we not be concerned about the safety profile that comes out of these trials?
Yeah, so I think maybe just take a step back and we can talk about, like, what do we think this medicine is based on the data we've generated in phase 2. I think we've been pretty consistent over time that, you know, this is a single-acting oral incretin, and the profile that we observed in the phase 2 looks very semaglutide-like.
That's what we expect out of these studies, and so I think as you think about what to expect, at least in these first two readouts on the efficacy side, both for A1C as well as weight reduction, like, you got to look at the sort of right comparable studies from the semaglutide program. The first diabetes study to read out is a 40-week endpoint. Of course, the time in which you look matters a lot in these studies.
And so in that, and we know that patients with underlying diabetes experience less weight loss than those without diabetes when they take incretin medicine. So, you know, that's a study where the prior semaglutide studies would suggest call it a 5%-7% body weight loss at that 40-week time point. And then in the chronic weight management study that'll read out a few months after that, that's a 72-week endpoint.
And again, in patients without diabetes, you can look at the comparable semaglutide studies there. You can also even look at 5 milligrams of Tirzepatide and SURMOUNT-1 there. You know, those are settings where the comparable studies would suggest roughly a 15% weight loss at that moment in time. Of course, these studies remain blinded. I don't have information you don't have.
But based on what we learned in phase two and the precedent studies for Sema and Tirzepatide, that's what we expect. On the safety side, you know, I think the sort of common side effects that patients experience on incretins, notably the GI side effects, I think those, I think, we are unlikely to be surprised by when we unblind these data.
What I think is the risk, I think that's yet to be discharged on safety is just uncommon idiosyncratic things that happen when novel small molecules are put into large populations. And I don't say that because, again, I know anything. Like, we remain blinded to these data, and to the extent that there are uncommon things that occur, even on a blinded basis, we wouldn't actually know about that.
It's sort of an unknowable component of any new small molecule administered to large populations that until we discharge the risk, we haven't discharged it. You know, we'll all be paying close attention to that, you know, when the diabetes study first reads out.
Okay. Questions from the audience on Orforglipron or any of the three key events this year, Len?
I was wondering, as I see the GLP-1s over the next five years, my concern isn't about the arguments that some have whether the weight loss was 18% or 25%. You know, the upper end may only be for a small percent of patients. But I'm looking at the orals, especially yours, perhaps being used for some patients as maintenance therapy once they've lost the weight that they wanted to lose on the injectable.
Do you see that as being a potential significant component? Because you don't need to lose more weight, you just want to maintain it. Or an oral drug, people who either want to take an oral, they don't want to take injections, or for economic considerations, it might be less expensive.
Do you mind paraphrasing the question?
Sure. The question from the gentleman in front was about the sort of use case of Orforglipron as a maintenance incretin after achieving a certain amount of desired weight loss on one of the injectable drugs. Yeah, that's absolutely something that we foresee as a possibility. In fact, we're running actually a clinical trial transitioning patients who've chosen to transition off of the injectables onto Orforglipron. So we're studying this exact phenomenon.
And I think, I don't know that that will be something that everyone wants, but there will probably be some percentage of the population who wants that. You know, the addressable population for chronic weight management in the United States alone is about 100 million people.
So the notion that, like, assuming that we surmount the access barriers that currently exist, the notion that like 100 million people are all going to choose the same thing, I think is not realistic. Patients are going to choose different medicines and regimens depending on their comorbidities and depending on their lifestyle. So, you know, our job is to generate as much data as we can for all of these different patient segments and enable access broadly. And that's what we're trying to do.
Let me just follow up on something you said earlier. So when we were talking about safety, you said the GI side effects are unlikely to be of a surprising nature, and that's very understandable. But I think investors might be worried more about the rate of those GI side effects as opposed to the side effects themselves. So based on related studies, what would you say would be a reasonable or a likely nausea rate or other GI safety issue rate of AEs?
That's a good question. I don't know if I would guide to like a specific number because this is a, that's even sort of more imprecise, so to speak, than talking about weight loss percentages. But I do think that, you know, we have commercially successful injectable incretins like semaglutide and Tirzepatide that have different rates of adverse events. And yet these are, in general, pretty well tolerated medicines that patients really like.
So I think that if the medicine ultimately delivers on a semaglutide-like profile, I think, you know, we've said that in the context of both safety and efficacy, at least as it relates to like the GI side effects that are most talked about. And remember, you know, the titration schedule that we ultimately deployed in the phase three is different than what we used in phase two.
We learned from that to try and ameliorate some of the side effects that we saw in phase two. We've had a lot of experience, of course, over time with various titration schedules. I think, you know, if you rewind the clock on like the Tirzepatide experience, I think when we modified that titration schedule going into phase three, there was a lot of talk of like, wow, you guys are exploring so many different doses and it's such a long titration.
Are you sure patients are going to want to do this? Like, isn't there a simpler way? I think that turned out to be the right course. And ultimately, patients and physicians are fine with it. And I do think we've mitigated some of the GI side effects that we might have otherwise seen. So, you know, we've done a very similar thing with the Orforglipron program, and we'll see how that plays out. But I feel reasonably optimistic about it.
Okay. Other questions? Yes.
May I just elaborate on a different question for maintenance dosing? GIP antagonist versus GIP?
You're saying a GIP-only medicine?
GIP antagonist versus, yeah, only for maintenance.
Sort of a different idea entirely. I mean, we're not exploring sort of that specific concept.
Other questions? Okay, let's dig into oncology, and let's start out with the drug that you mentioned, Jake, and that's Jaypirca. So you mentioned that there are several readouts coming in 2025. Which of them is the most important relative to ultimately building and establishing this brand even further?
I think that this is an interesting medicine in the sense that it's entering into a relatively mature space. There are, you know, three covalent BTK inhibitors largely competing for new patient starts and newly diagnosed CLL. Our medicine works when those medicines stop working. And it works for a pretty prolonged period of time, and it's because the binding mechanism of the drug is completely different.
And so our initial focus with this medicine, for as long as we've been developing it, was really in that sort of second line and beyond treatment setting. I think, you know, we can deliver a lot of value for patients and for the business by utilization of the drug there. And we're not yet there even today. Even today, we have a label that's much more confined to patients who've not just been on a covalent BTK inhibitor, but also venetoclax.
That's a pretty niche indication. Today, the NCCN guidelines actually recommend the drug for a broader population. And so, you know, the guidelines are a little bit ahead of the label as of right now. That's not that uncommon in oncology. So I mentioned that to say that, like, we're all on a sort of stepwise journey here.
And there are some physicians that want to use the drug in newly diagnosed patients. And there are some physicians who want to use the drug in second line. There are some that want to wait and use it in third line. Our job is to generate all the data to get all of these indications on the label so that physicians can use it however they want to.
I think if we fast forward five years, my guess is that you're going to see like a lot of different treatment patterns as to where this medicine is used, but that like most, if not all, patients with CLL at some point see this drug in the course of their journey. So to answer your question more pointedly, it's sort of the sum of them all rather than any given one of them that like I'm most focused on because
I just want to get to the point where we have all the labeled indications and the entire pivotal program has read out, and then we can walk into physicians' offices or I can meet with physicians at medical meetings and sort of say, okay, like which of these regimens is most interesting for your patient population?
Do you want to treat with monotherapy Jaypirca in the first line? Do you want to treat with a combination of two years time-limited Jaypirca plus venetoclax and Rituxan in the second line? Are you interested in Jaypirca plus venetoclax for a year in the first line? That's a study we're running with the German CLL Cooperative Group. So we're just trying to cover all of our bases of regimen and line of therapy.
Okay. Ultimately, do you see the need to, in the first line, do you see the need to run against the current incumbents head-to-head?
We're running a study against Ibrutinib. That study is going to read out this year. I think that will generate important evidence that can be compared to Ibrutinib, but also people, I'm sure, will cross-trial compare to other studies that have compared their drugs to Ibrutinib. That's natural, despite the caveats that you have to apply.
Now, if you're asking, do I think we need to run a head-to-head study against the other two, interestingly, in mantle cell lymphoma, we actually are running a head-to-head study against dealer's choice of covalent BTK inhibitor.
So admittedly a different disease, but we actually are going to have a decent data set of pirto versus Acala and pirto even versus Zanu in the context of the mantle cell phase 3 that we're running. And I think in all likelihood, people will do some read-through from that to CLL. I think that's sort of natural, despite them being different diseases.
Okay. And do you see the BTK degraders as meaningful competitive threats to Jaypirca?
Not yet. I think those medicines look pretty good based on their phase one data sets. They actually remind me a lot of the phase one data set that we had for pirtobrutinib about five years ago, and so they have an efficacy quotient in patients who've relapsed on pirtobrutinib that's good if it's an important option for those patients after pirto.
You know, we don't have one of those medicines, and I think the companies that do have to figure out sort of how to make them more broadly relevant, if at all. You know, when I talk to physicians about that class, I think at least today they see them as, you know, post-Jaypirca medicines.
Okay. Let's dig into Verzenio, very important oncology asset for sure. I have to admit, it really does look like ribociclib has a lot of momentum. So how does Lilly maintain its franchise here and not lose too much share to the competitor?
Yeah, I'm not particularly surprised at the velocity of Kisqali's uptake since the approval in EBC. Remember, the same dynamic happened when Verzenio was first approved in EBC. I think that's somewhat natural for a class that's this mature. These medicines have been on the market for a long time. Most prescribing physicians have used all three of them plenty.
And of course, in the adjuvant setting, we're only talking about two of the three, but the point still holds. And even so, in the case of us with monarchE, in the case of Kisqali with NATALEE, these adjuvant data sets were in the public domain and sort of broadly discussed and debated for a long time, even before the EBC approvals from FDA. So I don't think it should come as a surprise that you see like a brisk uptake really immediately post-approval. We saw that with Verzenio.
They're experiencing that with Kisqali. When I look, when we look at the sort of new patient start data, it looks to us that currently they're getting about 15% of the, call it jump balls for the patients that overlap between us. That's a number that's not that surprising to me. I think these medicines are different.
They have pretty different side effect profiles. Neither one is squeaky clean, but as a result, have different patient populations for whom they address. Of course, Kisqali is three years long. Verzenio is two years long. So patients on Verzenio can move on with their life sooner. I think that's compelling to a lot of men and women in this treatment setting. So there's different choices people will make.
What we hear pretty consistently is that, you know, for the Verzenio high-risk population, Verzenio remains standard of care for a variety of reasons and that Kisqali is broadly being used in the population that's non-overlapping. I think the sort of new patient start data actually fall right in line with that. And of course, it's still early days. So we'll see how that evolves over time.
Okay. What are the pros and cons of initiating an early breast cancer trial in the N0 and the N1 patients?
You're talking the population that NATALEE studied that's not in monarchE?
Yep, yep, yep.
Like for Verzenio right now?
Yep.
It's a pretty late life cycle to start a new adjuvant trial for Verzenio studying that population. I don't think that's high likelihood. I mean, Verzenio is likely to be an IRA negotiated product in the next couple of years. And the, you know, U.S. patent expires in 2031. So the timeline of running adjuvant studies like that is probably in the rearview mirror for Verzenio alone.
That having been said, now I'm switching gears a little bit, but you know, for imlunestrant, our oral SERD, EMBER-4 is the adjuvant study we're running for that medicine. And that is a study that actually has inclusion criteria from a patient population perspective that are much more similar to NATALEE. So, you know, we learned from the NATALEE experience in the way we designed EMBER-4.
Okay. I do want to get to imlunestrant, but let me ask one more on Verzenio. And that is that, and I've asked you this question in the past about these novel CDKs like the Pfizer CDK4. And in the past, when I've asked you that, you've responded, well, Verzenio is the most selective of the CDK4/6 inhibitors for CDK4 already. So the advantage of a pure CDK4 is not that great. Is there any change in yo ur view in that regard?
Not particularly. Again, I think actually like the CDK4 phase one data sets that I've seen are compelling. They look pretty good. The problem is that like it's not sort of 2014 again. Now the CDK4/6 class exists. Some of these drugs have prolonged overall survival. They've all prolonged progression-free survival.
In oncology, you have to run a head-to-head study and win on efficacy with a compelling hazard ratio. And so that's hard when the sort of only modification you've made is minor. And so I think like to me, that's why we haven't entered this space because I think winning a study like that is pretty difficult.
Okay. Questions about Verzenio before we move on to the SERD class? Yes.
Last night at dinner, you were pretty adamant that you don't think the overlapping population with Kisqali will change much from this 15% that you've cited so far. We had Novartis here earlier. They're pretty adamant that they're going to go after that and see significant growth there.
Why do you think they're wrong? How are you going to hold them off? Because they only pointed towards cardiac risk factors as a reason for choosing Verzenio. Is there anything else we're missing there?
All I can do is reflect what physicians tell me and us when we interact with them. And it seems as though, at least in this treatment setting, they're interested in being more splitters than lumpers. And we'll see whether that changes or not. But I think the treatment regimen length is a big thing for patients and providers, and especially if they view the efficacy as broadly similar.
There actually is some false equivalence there even being applied, but okay, like we do have a more mature data package than they do, and we always will because of when it read out. There are some physicians who see that for what it is, and there's others who look at the two efficacy quotients and say, they're sort of very similar. But, you know, I think Verzenio has known GI tolerability issues.
We've tried to manage those with dose reductions, and some physicians use different kinds of dose titration schedules to manage that. Okay. I think Kisqali has cardiac monitoring, and I think there's a lot of physicians in the real world who've had rare but real liver enzyme issues that like force patients off the drug and like cause real problems.
I think for the physicians who have that like once, they sort of don't want to do it again. And you saw that even in the context of the NATALEE study itself. So again, I don't want to make too forward-looking predictions about how that 15% will evolve because I don't know. But what physicians tell me today is that these are sort of two different populations that they're thinking about.
So let's move to the SERDs. In what ways is Imlunestrant different than other SERDs in development?
So I think that, you know, there's the medicines themselves, and then there's how the medicines are developed. On the medicines themselves, you know, there are, I think, differences in particular on the safety side that we've seen over time.
There are certain SERDs in development that have either ophthalmic toxicities, cardiac toxicities, changes in lipid levels, you know, these types of things, which by the way, the field doesn't even understand why many of these things even occur. But, you know, imlunestrant doesn't seem to have any of these issues.
I know we don't tend to talk about sort of tolerability as sort of a main driver of oncology programs, but in this context, when like the main reason this entire class was invented is to change outcomes for patients in the adjuvant setting, you know, patients in the adjuvant setting take endocrine therapy for five to 10 years. It's a pretty long time.
If the medicine is intolerable, then they're not going to be able to stay on it. If they're not going to be able to stay on it, they can't get the efficacy. You know, we've always been very focused on the tolerability profile of our medicine.
It was one of the bigger learnings, actually, from the phase 3 EMBER-3 study that read out last year. It was just seeing the tolerability profile of the agent in a sort of rigorous phase 3 study. We had phase 1 data many years ago, but, you know, you always look to a phase 3 for sort of a more rigorous determination.
That was a big sigh of relief. In many ways, it sort of surprised us on the upside as to how well tolerated the agent was in that setting. Then on the development side, you know, we've developed our medicine in the metastatic setting in combination with CDK4/6, Verzenio. I think that led to, I think, a pretty differentiated set of outcomes that have excited clinicians now, admittedly, in second-line breast cancer.
And then, you know, our adjuvant program is differentiated on the basis of both design and timeline. We're running an extended endocrine switch study. So this is in the adjuvant setting after the CDK4/6 period. We are patients that enter the study get randomized to switch from their aromatase inhibitor backbone to imlunestrant or stay on the aromatase inhibitor.
And so, in a way, it's sort of a pure SERD versus AI comparison. And we think we know from historical studies that in a SERD versus AI comparison without CDK4/6 in the backbone, the SERD wins. And so that's the basis of that experiment that we're running with the EMBER-4 study. Pretty big swing. If that study hits, that'll be a very, very important new medicine for us. And, you know, in the meantime, we hope to be launching it in metastatic disease later this year.
Speaking about EMBER-4, do the results of EMBER-3 and the fact that it didn't reach significance in the overall population concern you at all about the probability of success of EMBER-4?
Not really, actually. In fact, sort of the opposite. And this goes back to what I was just saying a second ago. Like if you look at EMBER-3, remember the comparator in that study, and this is really important, the comparator was fulvestrant, another SERD. The comparator in EMBER-4 are aromatase inhibitors, not a SERD.
And so in the context of EMBER-3, what we saw is that in the ESR1 wild type population, the comparison of imlunestrant versus fulvestrant has a progression-free survival hazard ratio of about one. They look very, very similar. You might say like, well, Jake, isn't that a problem? Well, in the context of the adjuvant design, no, because there we're comparing to an aromatase inhibitor.
And if historical studies are right and fulvestrant beats an aromatase inhibitor and imlunestrant looks similar to fulvestrant, then imlunestrant ought to beat an aromatase inhibitor too. So if anything, like the randomized data we got from EMBER-3 furthered my conviction in the likelihood of EMBER-4 working.
Okay. Sure.
Are you referencing the FALCON data? Is there anything else that shows efficacy of a SERD versus AI?
That is the main body of evidence, in fairness. And we only have a handful of these experiments that have been run, right? You have FALCON without CDK4/6. You have PARSIFAL with CDK4/6. You know, I think many of us in the field have made our judgments rightly or wrongly on the basis of those two seminal experiments.
So I guess how does the PARSIFAL study impact your thinking? We're talking about FALCON right now. What were the basis for comparing the SERD to AI? As we move to the adjuvant setting, as we move earlier, the potential for SERDs, how does PARSIFAL impact your thinking?
PARSIFAL was hugely impactful into how we were thinking about the development program. You'll note that I think we're the only company with a novel SERD that chose not to run a first-line study because there you have to run concurrent CDK4/6. PARSIFAL would suggest that that's a study that won't work.
Obviously, like we'll see later this year, I think, whether we were right or wrong because some of the competitor studies will read out and we'll find out whether or not that was the right conclusion to draw. It also impacted our development thinking for the adjuvant setting because, as I mentioned earlier, EMBER-4 isn't running concurrent with CDK4/6. It's actually running after the CDK4/6 period. We did that very deliberately, in part because of PARSIFAL.
We're down to only a minute left. I thought one of the most interesting points at dinner yesterday evening was your identification of things that could be game changers to Lilly, and Lilly's already pretty much a game changer, right, but could put the company on an even greater trajectory, and you noted three things, and what jogged
my memory is one of them was EMBER-4, which we've already discussed. The other two were Lp(a) and Alzheimer's disease prevention, so maybe you could just spend in our last few seconds, just spend a moment as to why you view those, or Lilly views those as game-changing events.
Yeah. So, you know, as it relates to Alzheimer's disease prevention, I think we know that Alzheimer's disease remains a public health epidemic, a leading cause of death in this country, a huge cause of morbidity to families that have a loved one with this disease. And, you know, yes, we have, you know, the launch of Kisunla as an example in symptomatic disease has gone, you know, somewhat moderately.
I think as we transition the medicine to preventing the occurrence of symptoms of this disease with a blood test as the sort of entryway to getting the medicine, I think we'll be having a very, very different conversation with patients. I think that that looks very different than like slowing the course of the disease that is otherwise progressing.
And by the way, all of the evidence we have from both the donanemab studies as well as even the lecanemab studies, which suggests that the earlier you go, admittedly in patients with symptoms, the larger the effect size you observe. Of course, patients who have amyloid pathology in the brain but no observable symptoms, which is the population in TRAILBLAZER-ALZ 3, is an even earlier version of that same biological idea.
So that gives us a lot of conviction that this study will have a big effect size. And of course, you know, in the context of preventing a disease, we also need to observe a safety profile that's amenable to a positive risk-benefit quotient. That has yet to be borne out. So we need the study to read out to prove that to us.
Patients with preclinical, is what the term is, preclinical Alzheimer's disease, presymptomatic, tend to have lower amyloid burden in the brain. We know amyloid burden does correlate with the onset of ARIA and these amyloid-related safety events with the amyloid-lowering agents. And so we're hopeful that patients with lower amyloid burdens in the brain will experience meaningfully less safety issues with the medicine.
But if we can deliver a medicine that can prevent the occurrence of this disease, I think that'll be a big game changer for public health and, you know, Lilly as a follow-through to that. And then, you know, Lp(a) is, in many ways, I think it's like the highest profile unaddressed underlying cause of excess morbidity in cardiac disease. And there's a lot of genetic evidence to suggest that lowering this will have an impact on patients' cardiac outcomes.
Of course, cardiac disease remains one of the biggest killers globally, including in the United States. Still a lot of unknowns here. We don't know like how low do you need to go, how long do you need to keep it low, what will the effect size be upon the intervention? So, you know, today the evidence around Lp(a) is a little bit more correlation than causation because none of the actual drug intervention studies have read out yet.
But I think the genetic risk combined with the correlative studies we've seen, I think are about as tight as one of these ideas gets. And now it's just a matter of seeing whether or not that translates into a big effect size in the context of these outcome studies. And, you know, excited about the work we're doing in both primary and secondary prevention there.
We do have a cardiology panel ending today, and Lp(a) will be a topic. Thank you so much, Jake. This has been a wonderful conversation and lots to look forward to.
Thanks for having us, Steve.