Good morning, everybody. My name is Alex Hammond, and I'm the Senior BioPharm Analyst here at Wolfe Research. Thanks for joining. With me, I have Regeneron, I have Justin Holco, Global Oncology Hematology Commercial Business Unit Lead, as well as Izzy Lowy, Clinical Development Unit Head. Thank you, guys. I'll obviously Mark Hudson from IR as well. Thank you, guys, so much for joining us. Thanks, Justin. Oh, no, Mark has something to start off with.
Yes, yeah, yeah. Thanks for having us, Alex. It's good to see everyone here, too. Let me start off with just our forward-looking statements, as we always begin our presentation with that. I'd like to remind you that remarks made today may include forward-looking statements about Regeneron, and each forward-looking statement is subject to risks and uncertainties that could cause actual results and events to differ materially from those projected in such statements. The description of material risks and uncertainties can be found in Regeneron's SEC filings. Regeneron does not undertake any obligation to update any forward-looking statement, whether as a result of new information, future events, or otherwise. Alex, take it away.
That was impressive. Thank you. I guess, looking forward, we think one of the most important readouts for you guys is your PD-1, LAG-3, and melanoma. Can you kind of walk us through the confidence there from a trial readout perspective?
Sure, thank you. First of all, thank you for having us, and it's a pleasure to be here. Before I start, I was just, it's really exciting for us at Regeneron to be, I think now, comfortably viewed as a serious oncology company. That was not always the case, I think, with the development of Libtayo and its success in a number of different indications, more recent success with some of our bispecifics in hematologic malignancies. As we believe that the next big thing for us will be the readout of our LAG-3, PD-1 combination study. When we set out to develop our LAG-3 antibody, did a number of clinical trials in first-in-human studies, and were struck to find a very high response rate in a cohort of PD-1 naive patients. We repeated it twice.
We basically, it is at the end of the day, it's a single-arm, three-part cohort of 98 patients enrolled separately. Over time, what we've seen was a superior response rate coming up to close to 60%, with a PFS that, over time, as we've continued to follow, has certainly outperformed what the competition that was available. We decided to embark on a phase three study to actually really test it. The study is designed to be testing two different doses as part of our obligation to satisfy the Optimus requirement of the FDA to demonstrate contribution of dosing. Since cemiplimab, Libtayo, is not approved as a monotherapy in melanoma, we needed to go up against another one.
We chose pembrolizumab because, basically, it was a Q3 regimen fit, basically, with our study and would facilitate blinding across the study so we could do it properly. It also, the study contains a calibrator arm for cemiplimab so that we know, so we can demonstrate contribution of components. It's basically testing two different doses of fianlimab, 1,600 milligrams every three weeks, 400 milligrams every three weeks, both of them in combination with cemiplimab, Libtayo, versus pembrolizumab, Keytruda at the standard dose. When I've seen a lot of stuff percolating out in the literature, reviews saying, oh, they're worried that there might be an unexpectedly long PFS for the control arm.
Basically, what we can tell you is that although the label for the PFS for pembrolizumab is in the order of four to five months, and that was the expectation across multiple different trials, and certainly, that was also the area of how nivolumab performed in the relativity study, we took a conservative approach. It set up our study so that we are actually powered to win if pembro surprises and is in the high mid-teens, mid-single digits in terms of PFS. We do believe that, certainly, compared to nivolumab, we are very well poised to beat what we saw in what was seen in that study. I think there also, I'll just proactively comment that I've seen some comments about recent studies where the PFS on pembrolizumab was in the teens.
I'd point out that that study, the IO Biotech study in particular, was one in which we feel that the patients were very cherry-picked. They had a much lower, for example, rate of brain metastases and adverse base characteristics compared to what is in our study, compared to what was in RELATIVITY-047, and compared to what was in actually the most recent study conducted, which was the LEAP study, which was a trial of pembrolizumab and lenvatinib versus pembrolizumab, where the blinded independent review of PFS for pembro was 4.5 months, 4.6 months, something like that. We are waiting for events to come in. We believe that this is because the test arms are performing well. We will not know until we know.
We think that the way the events are coming in now, we should get a readout by the end of the first half of next year. What is also important about our study is that when we set it up, we set it up so that we could also get a survival readout in this that would be powered for that, even if we were just relatlimab-like. We think we are in as strong a position as possible within the realm of dice of clinical trials to be set up for success. We are just adjusting to events as they come in. It's not the first time studies have had slow amounts of slowing of events that ultimately prove to be a good sign. That's kind of where we stand.
I don't know if there's other specific questions you want me to address on it. I mean, why?
You covered a lot of ground.
Yeah, I did. I usually do. I would also just say, why do we think people ask us also, why do we think fianlimab is different? OK? One thing is that we were able, there are differences in terms of the molecule in that our molecule does have an FC that was engineered to be inactive in terms of engaging antibody-dependent cellular cytotoxicity and cellular phagocytosis. We have seen pre-clinically that there are clear differences between that and the competition. Whether or not this has, we have also noticed that we have been able to dose higher doses, particularly in combination with chemotherapy, which is particularly important in some of the other indications we are testing, and not encounter toxicity. Is that the reason? I am not 100% sure, but it is a phenomenon that we are seeing.
As it turns out, because the timing is such that we will probably read out in the first half of next year, we also expect to have a potential for a substantial readout in our adjuvant study during that period of time as well. It will be an interim analysis. It may not be mature enough, but we will certainly have some initial analyses. I cannot, it is like a pregnancy. I cannot make it go any faster. We are sticking with it and trying to get through to the end and cautiously optimistic.
If there's anything I've learned from Regeneron, it's very much that not all monoclonal antibodies are made equal.
Correct. I would grant you that.
I guess, what is the bar of clinical success here? We've heard management talk about this high teens, but it seems to have changed to maybe more mid-teens now. How are you thinking about this from a PFS perspective?
You mean in terms of the success of the fianlimab arm?
The fienlomab.
Right. As I said, even if our data is not that, if there's a surprise and it's not that differentiated from relatlimab, we expect to have OS data in our to be part of the study. To achieve that, we're powered, we think, to achieve that, and that's important also. Yes, over time, with five-year follow-up, et cetera, you start to see the OS emerging as well. Unfortunately, it doesn't end up getting into the label because it wasn't something that they were able to achieve at the primary readout. It's also important in other jurisdictions, like Europe, for example, as well. We think that even mid-teens will be good because it'll be superior and because we expect to have OS with it.
You don't expect the OS at the initial readout in the second half more so?
We will be having an interim analysis of OS at the readout of PFS. It is possible we'll have it then, but it may require a little more time to mature.
A little more seasoning. Got it. Thank you. How should we think about the commercial opportunity as well, assuming that you hit on OS, particularly as you can likely market in Europe as compared to some other assets?
Sure. So strictly speaking, the metastatic melanoma market's probably around $4 billion-$5 billion globally. Within the metastatic space, it's a pretty fractionated market these days. You have some monotherapy utilization. You have immuno-oncology combinations, some of which come with a little more toxicity, and then the aforementioned LAG-3 and PD-1 combination. If we do see that differentiated PFS come in and potentially even OS, that's a significant opportunity for us. If you'll recall, we're already the global leader in non-melanoma skin cancers. To be able to add melanoma to this portfolio would really be a significant opportunity for us across the vast majority of skin cancers. We're really excited to see this readout, just as excited as everybody else is. If we see something that looks like what we saw in phase two, it's going to be a really exciting opportunity for patients globally.
Yeah, no, we're very excited. I guess, any last comments on the combination before we maybe move to just Libtayo as a monotherapy?
I would add that one of the things that we set out to develop when we got into immuno-oncology quite a while ago was to be able to have a toolbox of agents that we can combine. We have other agents in clinical development that we think could ultimately combine with a Libtayo fianlimab combination. To be honest, when we started with as a segue to Libtayo, we decided we needed a PD-1 to enable our entire strategy. We made sure that that PD-1 would stand tall and be second to no one. As you've seen, that's been true. That's the case. It's actually commercially doing reasonably well and probably surprising some of the people that originally said, you really want to get another PD-1? With fianlimab, it's the same story. We have another combination, but we're not done.
We have other things behind it. These things will come in waves. We're always building for the future.
I guess with that one follow-up, you also have a phase two in non-small cell lung cancer that's supposed to read out in the first half of 2026. I believe George has said lung is a tough nut to crack. How should we think about lung and other potential indications in the future?
Lung is a tough nut to crack. We took an early look, very early look last year and were not convinced that we had strong enough data to launch into phase three. What we are doing is letting a reasonably sized phase two study mature and read out to see what the PFS as well as response rate looks like. We will take a hard look at that. It is interesting that we are in this situation. I do not think we like to be convinced that we have a really potent agent to bring forward to help patients before we launch into phase three.
I think actually the first half of the coming year is going to be telling because we will find out about our melanoma studies and we'll be reading out the maturing of our lung studies as well as in addition to advanced lung cancer with and without chemotherapy on top of the combination. We also have some early looks at neoadjuvant perioperative studies in both melanoma and in lung cancer that will also be providing some information. It will be a very data-rich half.
Looking forward to it. I guess on commercial, obviously, Libtayo just got approval in adjuvant CSCC. I think the company has said that's around a 10,000 patient opportunity. How should we kind of think about that halo effect in CSCC and what a ramp might look like?
Yeah, it's a great question. We unveiled a pretty remarkable clinical trial result about a year ago. That was presented at ASCO this year, showing that patients who are resectable and undergo adjuvant treatment with Libtayo have about a 68% reduction of their risk for the disease coming back. This is, according to our customers, what we have been told is certainly practice changing. It's the first and the only treatment along these lines to be able to read out a successful study in this setting. What really helps us as we think about helping more patients globally is that we are already the leader in the metastatic space. What this now allows us to do is to talk to treaters in earlier settings.
What this is going to involve is involving many more specialties, such as your surgical oncologists, radiation oncologists, dermatologists, many of which have limited familiarity with immuno-oncology. The benefit here, obviously, is to be able to help patients who have that surgery to have a better outcome longer term. We also see, as you mentioned, the halo effect, the opportunity to have more of these metastatic patients come into the mix earlier on. What we see is that by the time a medical oncologist is ultimately involved in a treatment decision, these patients are very, very far progressed. We know that there's a lot of patients out there who still are being seen by these specialties who could be referred to a medical oncologist. I see this opportunity really working hand in glove with the metastatic business that we already have today.
From a commercial perspective, the amount of work that it takes to go into that, do you see that more as like a second half lift, or do you think that you could kind of see some of the benefits in the first half as well?
We're already seeing utilization within the adjuvant space. When you couple the study results from CSCC, NCCN guideline inclusion, category one preferred, and again, our customer familiarity with Libtayo in this setting, we're already hearing about guideline additions, patients being treated. It is more of a lift as we do have to get to a broader range of these treating specialties. My expectation is that we see this opportunity advance pretty quickly. It's the only one in the space. With the risk reduction that we've seen within that CSCC study, it makes for a very compelling opportunity to educate both physicians as well as patients how to get to a better outcome. Talk about nail biting. We were very worried about this study for a long time. We started it in 2018 or so, I think. Yeah, it was 1788 is the number.
Technically, the protocol was written in 2017. It struggled through COVID because bringing people back. We were nervous about competition, but we stuck through it. It delivered beautifully. People are thrilled with the results. We just get, I mean, we had a standing ovation at ASCO, which was like, wow, that was nice. People have really said, you guys nailed it. They are embracing it. We are not stopping there. We have also a cooperative group study looking at neoadjuvant settings as well to formalize the phase two results that we had a couple of years ago. We also have efforts underway in other approaches and even earlier stages of CSCC to try to bring in intralesional treatments. We are, and this is, of course, going to be earlier practitioners, not the advanced medical oncologists that are going to be seeing it.
We think this is from a time point from when we started in this field, there were a lot of skeptics that were not even convinced that CSCC was a real disease. I mean, we can go back to that. We have really staked out this area, defined it, performed beautifully in it, and have delivered great value to patients.
Not all monoclonal antibodies are made equally.
Right.
I guess, Justin, how should we think about the commercial opportunity here, particularly if we assume potential expansion beyond just adjuvant?
We're currently annualizing at about $1.2 billion in terms of global Libtayo sales. I would say 60% or so are coming from the non-melanoma skin cancer business with the balance being in lung cancer. We're certainly happy and excited to talk about our progress there as well. Adjuvant CSCC does represent a pretty material addition to the non-melanoma skin cancer business, 10,000 patients in the U.S., certainly a significant number of patients outside the U.S. as well. I think one of the things that we have to do is obviously first educate on the benefits of adjuvant treatment so that these specialties do not just radiate or resect and then the patient does not make it to the oncologist. There's also importance of educating on how it's important for patients to complete the full adjuvant treatment, which is about 48 weeks.
We oftentimes see in various market analogs that patients may only get out to six, seven, eight months. It could be for a variety of reasons. The study was run for patients to receive 48 weeks' worth of treatment. We want to make sure that all those patients have the best potential outcome of not having their disease come back. I would add, in the study, we provided patients with the option after their first four doses of Libtayo administered standard every three weeks to switch to a q6-week dosing regimen. The approval that we got is for either. They could either do 48 weeks at q3 weeks throughout, or they could do the total of 48 weeks with the first four doses being given every three weeks and subsequently every six weeks.
We've demonstrated in this study that q6-week dosing of Libtayo at 700 q6 as opposed to 350 q3 is effective. The comparison between those arms in the study who got straight q3 versus q3 switching to q6 showed maybe even a little better outcome, although it wasn't really powered for that, but certainly no degradation. I'm sure patients preferred coming in every six weeks. We think it's a patient-friendly regimen now after that. That should help also.
How do you make sure that patients go out to that 48 weeks of treatment? What strategies will you have in place to push that narrative?
Again, it just goes back to that's how our study was written. We don't know what a shorter course could mean ultimately to the outcome. So it's incumbent upon us to educate the various specialties within the surgical and prescribing community and then as patients as well as appropriate.
Perfect. Thank you. I guess non-small cell lung cancer, you touched on it a little bit. How is that progress? Is it just more so now grinding away? How should we think about it?
Great question. Yes, it's been a grind since the beginning. As my colleague Izzy says, I think there were a lot of skeptics wondering if we could even compete in that space. I think what we've shown is that we can. First of all, it helps to have great data. We are NCCN category one preferred, co-preferred in the indications where we are prescribed. We've been able to really show that this drug is also foundational to a lot of the other things that we're doing. I would point out that in the U.S. now, we have become the number two prescribed. We're at about 15% new patient share. Outside of the U.S., we have as much as 25%-40% new patient share in the high-expressing cohort where we see a lot of strength.
If you look at our clinical data, we do not have head-to-head studies versus some of the other market leaders, but you can see that our squamous data stands out very strongly. Our thought leaders do view squamous disease as one of the more high-end unmet medical needs. A lot of former smokers, challenges with longer-term outcomes. We are, as Izzy said earlier, beginning to show up as a more legitimate player within the cancer space. That also applies to lung cancer as our data continues to stand out. Obviously, we have significant investment with Libtayo as well as the pipeline in lung cancer going forward.
Very helpful. I guess, Izzy, I wanted to ask, what is your favorite child when it comes to the pipeline?
Oh, people ask me that all the time. I don't have a favorite child. I mean, I love all my children.
You love them all equally, though.
I have to say I do. Look, at the end of the day, we bring things into the clinic that we think have very compelling preclinical rationale and supporting data. At the end of the day, when you go into the clinic, you find out that things do not—we do not run a mouse clinic. What determines success in the clinic is sometimes a surprise. I would say we have a number of things that are cooking that are exciting. One thing that we have is we have a whole co-stimulatory bispecific panel of agents where we have been the pioneer. It is conceptually really elegant. We have seen different types of efficacy in different settings. In the prostate cancer field, we saw really promising efficacy, but some problematic immune-related adverse events.
We are continuing to move forward in that area, looking at combinations with PSMA by CD28 that can widen that therapeutic window and allow us to actually continue to deliver some of the striking responses we've had. We have a MUC16 by CD28. We have an EGFR by CD28. Those so far have been relatively modest in terms of delivering clear-cut benefit, which I think speaks more to the lack of understanding we have about how to optimally develop this area. We are pushing forward. As I said at the beginning, we do this with the idea of having conceptually appealing combinations.
In terms of new agents that we have in terms of CD3s, in addition to the hematologic space, which I do not manage, but we also have some promising data in ovarian cancer that people our MUC16 by CD3 has delivered very durable, well-tolerated responses in women with advanced platinum-resistant ovarian cancer. I am aware that there is a whole flood of ADCs entering the ovarian cancer space. This is a non-chemotherapy option that actually, when patients actually with very minimal CRS at the outset, that when they get through that is extremely well tolerated and provides durability of response beyond the time of their actual life expectancy from when they came in. We have some newer agents that are in the clinic.
We have a PD-1 directed IL-2 to actually deliver cytokines to the tumor microenvironment that is currently in dose escalation, showing that it's tolerated well and delivering some early signs of responses in a number of different tumor types. Hopefully, in the next year or so, we'll be able to discuss, present more. We also have developed, while we are focused on immunotherapy, we have excellent chemists who have come up with a novel approach. We think a novel approach developing topoisomerase payloads. We have a novel MET by MET antibody that is actually extremely well internalized. It is a great vector for delivering such an antibody-drug conjugate that actually will have, we think will have efficacy across a number of tumor types, lung, colorectal, others that do not necessarily have to have super high expression on MET, but it can work further. Those are just a smattering.
That's an amazing overview. Thank you. Clearly a lot cooking. I guess in the last minute, Justin, do you have any closing remarks on the commercial portfolio?
Just thrilled to be leading this great organization. We've recruited hundreds of colleagues from around the world who have worked on market-leading treatments. The portfolio continues to grow. As you say, we are currently launching Linvoseltamab in relapsed refractory multiple myeloma. That launch is going extremely well. That's a significant investment that we're making clinically. I think up to 10 phase III studies. We look forward to hopefully moving treatment into earlier line settings. We really do believe that like Libtayo, Linvoseltamab could be a powerful backbone opportunity for all lines of myeloma and perhaps even some precursor conditions. Hopefully more to come about that in the coming years, but couldn't be happier to be doing what we're doing here at Regeneron.
Thank you guys so much for joining us. We're very much looking forward to the first half of 2026. Very data-heavy. Thank you.
Thank you.