Morning, with a great first session of the conference. We've got Jazz with us, represented by Rob, who's their Head of R&D and Chief Commercial Officer, and Jack Spinks, who's the Director of IR. Thanks for being here. Just one correction. I'm the Chief Medical Officer. Yeah. Not chief commercial officer. Sorry. Chief Medical Officer and head of IR, yeah. I don't know why I would stay in my swim lane. Yeah, we wanted to spend most of today's session talking about zanidatamab, where you've got some exciting data, and it's a core part of your program. Maybe just by way of a brief introduction of the molecule, and can you talk to us about what makes it unique and sort of some of the data that's been emerging that suggests that this is a really unique and differentiated HER2 approach? I thank you for the question. I think that is a great place to start. You know, going back three or four years ago, we got very interested in this molecule based on what we understood about the mechanism of action, the preclinical data supporting that, as well as the early emerging clinical data to support the differentiated mechanism of action. Now that we have the benefit of additional data, we think the thesis is being supported. Let me just start with what's different about zanidatamab. We refer to it as a bispecific biparotopic antibody. That means that the two binding domains of the antibody, the so-called Fab fragments, are engineered to bind different epitopes of the HER2 receptor, and they were engineered to bind to validated epitopes. In other words, one binds to ectodomain IV, and the other binds to ectodomain II, ECD2 and ECD2. Those correspond to the binding domains for Herceptin and Perjeta. What makes this different? When you represent those binding domains on the same antibody, each antibody necessarily has to bind to a different receptor. The antibody binds to one receptor, the other Fab fragment can't reach that other binding domain on the same receptor, it has to go out and get a second receptor, that causes clustering, you can imagine as the antibodies stack up, you get this clustering. If you go back to the original Nature Communications paper, there's a really nice experiment demonstrating this, showing through immunofluorescence, you get this capping of receptors and then fixation of complement, that's one thing that's entirely unique to HER2 antibodies. It's the only antibody at therapeutic levels known to cause complement fixation and initiation of the complement cascade. Also has a highly active Fc fragment, such that you get recruitment of NK cells and recruitment of macrophages, so ADCC and ADCP as well. That's all highly unique. Also by representing or binding to those two domains, you see interference of signaling of not only HER3, but interference of phosphorylation, signaling through other human epidermal growth factor receptors. For example, HER3 is a receptor that is a heterodimer. An active HER3 receptor is actually a one domain of HER3 and one domain of HER2, and it interferes with that dimerization. HER3 is interfered with, and there's even evidence that there's interruption of signaling through EGFR. This is a really unique antibody that we felt differentiates from everything else that's out there. The clinical data that we saw when we in-licensed the product suggested that this would be true. We saw more activity than was demonstrated when in experiments where Herceptin and Perjeta were given. In fact, the preclinical experiment head-to-head showed that it was better than that combination. If you take biliary tract, for example, those response rates in if you take the IHC 3+ over 50%, certainly better than historical data with Herceptin and Perjeta. We also saw activity in patients who had progressed on prior HER2 therapy. For example, breast cancer patients who had just progressed on Herceptin and Perjeta were responding to zanidatamab. We were pretty confident going into the experiments that we had that this was differentiated, and it was in part differentiated by the immune activation. Fast-forward to when we turned over the card for the frontline GEA study, and people sort of said, "Hey, were you surprised that it was active in PD-L1 negative patients?" You know, after all, tislelizumab itself, when tested in frontline gastric cancer, was not active in PD-L1 negative patients, consistent with what was seen in all the other prior PD-1 or PD-L1 studies in gastric cancer, inclusive of KEYNOTE-811, which was being studied in HER2 positive patients. We said, "No, we weren't surprised because our thesis going in is that zanidatamab may trigger the immune system in a way that might synergize with PD-1 or PD-L1 inhibitors." We think that finding, in fact, is consistent with the mechanism of action and a very critical finding because now, once this is on the market, docs don't even need to test for PD-L1, which is certainly an advantage. You don't have to test and wait. We know that now we have access to that whole population. It's critical that we educate around that point because we certainly want patients to get the full benefit of zanidatamab with a PD-1 inhibitor. We know that patients in front line often don't make it to second line, you know, gastric patients. There's the synergy you wanna capitalize on, and you wanna make sure that patients really get all their effective therapies up front. We think that's a critical finding. You know, moving forward, we now have head-to-head data with Herceptin where we're clearly better in that study. We show that tislelizumab is adding, and we think there's a synergy happening in the PD-L1 negative. We certainly are now looking forward to other opportunities where either Herceptin could be replaced or Herceptin wasn't quite effective enough, and we think we have an opportunity, especially when we're combining now with immunotherapies that may create a synergy. Yeah. It's really helpful. Maybe just staying with the HERIZON-GEA-01 study for one second. You guys showed pretty meaningful benefits on PFS and OS, and there's a second planned OS analysis for the doublet. Can you talk about maybe weaving in a few things, sort of what the response has been from treating physicians to the data, so the level of excitement that you're seeing there, and then, maybe how you're thinking about that upcoming OS analysis? Sure Jack into the conversation, you know, how important OS might be for, you know, enabling, you know, full commercial scale up there? Okay. Yeah, I'm happy to start and then turn it over to Jack. The reception we've gotten has been, you know, very, very positive, you know, starting with the plenary presentation at ASCO GI. If you were in the room, you could see all of the top GI oncologists were there to see it. You could hear the questions and the responses. You know, they were seeing for the first time more than two years of survival in both arms. You know, arm B had over two years, and then arm C had more than 26 months. Unprecedented results in absolute terms and certainly compared to the control arm. I think very clear that Herceptin is a historical regimen in this setting. I would say as people got into the details of, you know, of adding tislelizumab and the value there and the benefit in PD-L1 negative patients, a lot of enthusiasm for using the triplet up front. We're very excited that the manuscript has been accepted in a major journal, and we're hopeful that those data will be coming very imminently. We'll further leverage those, that publication to ensure that we get NCCN guidelines, you know, as fast as possible. We also look forward to ASCO, where there'll be some additional analyses, especially around PD-L1 subgroups. You also asked about the next interim analysis. Remember, this first overall survival was planned as the first of three OS analyses. We have two more left. The way the study is set up is, you know, once it's sequential testing. Once you hit a hypothesis, you don't retest that. Formal testing of PFS, the analysis of overall survival in arm B, zani chemo versus the control arm, is what all the next allotment of alpha will go toward. We have a third shot on goal later with the full alpha allocation, if for some reason that doesn't hit. We still think this is coming about midyear. Before I turn it over to Jack, we certainly have been clear in all of our regulatory interactions around what's required for approval, and certainly OS was never required for approval. It very much helps that we have such strong data on OS, even at the interim, but a large enough PFS, which is certainly the case here, more than four months median, with a supporting trend in OS. In front line, where you have, you know, often significant confounding by subsequent therapies, it's generally enough. I mean, we're quite impressed that we saw as large an effect as we did. You know, even though arm B versus A isn't yet statistically significant, it's quite an impressive difference in overall survival. Keep in mind, different from the KEYNOTE-811 trial, where immunotherapies weren't available to these patients, we see evidence in our study that the control arm patients more frequently crossed over to subsequent immunotherapy. That's why we think when you compare PFS curves on our trial to KEYNOTE-811, they're practically identical. When you look at overall survival, our control does a bit better, most likely because of the more frequent subsequent therapies, subsequent immunotherapies. Despite that, we're still seeing, you know, very strong outcomes. Thanks, Rob. I think commercially, Leo, you know, we're really happy that we have the triplet OS, which was positive, you know, in the data readout earlier this year. I think importantly, you know, what these data show is a real differentiation here. I mean, as Rob was talking to, we have data that shows we have benefited PD-L1 positive and negative HER2 positive patients. I think commercially that sets us up really well. You know, our label, we do expect to have that triplet OS. We do have clinically meaningful results for the doublet. You know, we're already approved in second line HER2 positive BTC. That's really important when you think about this launch because the overlap of treating physicians is 90% plus here. I think from a launch standpoint, we're ready to go. I think Sam's team is ready to launch and, you know, certainly once, you know, we have that doublet data mid this year, you know, we'll be able to update the label with that for the doublet. As Rob said, right now we are approval based on PFS. We have statistical significance and clinically meaningful results for OS in the triplet, and certainly clinically meaningful results for the doublet with near clinical significance. I think our team's really ready to go. You know, and we don't expect that to be any issue at launch. I think Sam's team is really excited and ready to go to get this product on the market once approved. Again, our PDUFA date, which we received, is August 25th. We do have Real-Time Oncology Review and priority review that was granted by the FDA. The team's really looking forward to getting that on market once approved. Yeah. Really helpful. Yeah. Maybe just sort of add that of course we're not promoting ahead of an approval, but, as Jack mentioned, we have an MSL force who's educating around the data, and the continued publications are gonna be helpful there to have all the data out there. These are really the very same oncologists who are currently treating biliary tract with zanidatamab and would be treating gastric as well. Yeah. Makes sense. Obviously GEA is not the only potential indication that you guys are exploring zanidatamab in. I wanted to touch on breast cancer and the 303 trial. Sure. You know, it's maybe a challenging population, you know, post, you know, post an ADC. I guess, how are you thinking about why zanidatamab should work there? I mean, you've been pretty clear that it's, you know, a better binder, but, you know, as a later line population, maybe more challenging. Yeah More confounding factors. I guess can you share more about that? Yeah. I mean, no doubt going into a later line population, has challenges that a frontline population wouldn't. Nonetheless, in breast cancer, which may be different than other tumor types, the experience with a multitude of different HER2 agents is that when patients progress with breast cancer, they typically still have HER2-driven disease. Now, there are exceptions to that. I think even the best data now suggests that after an HER2, the main resistance mechanism is to the chemotherapy warhead, not necessarily to, you know, changes in the tumor biology. Even if you see, let's say, transient changes in receptor expression level, you know, you give a TKI, those levels may go up. You give, a depleting antibody, you may see those levels go down a bit. Over time, I think they sort of normalize. The hypothesis is that even later line breast cancer patients have HER2-driven disease, and they'll benefit from the most effective HER2 agent in combination with the most effective chemotherapy, and that is the premise for the trial. We're in a line where patients would get Herceptin, in this case, really for the third time because they've gotten it up front, and then they've gotten an HER2, which is essentially a Herceptin antibody with a warhead, and they have really nothing left. While you wouldn't expect, you know, to see the kind of results you get in a frontline trial, we do still think there's an opportunity to differentiate with a more effective antibody like zanidatamab. That was just the very obvious first place to go. I mean, every, you know, pretty much to a person, every KOL we spoke with said this is the big unmet need because after an HER2, there's just not going to be any data. You know, people will try various agents that maybe they hadn't gotten, but there's just not going to be any data, and that still remains to be the case. Now, I wouldn't say that that's the only place that we want to be in breast cancer, but it was an obvious first place to go, and as we accumulate data, as we have, showing, you know, let's say, increasing our confidence in zanidatamab, we're likely to initiate new trials. You're already aware that we've been working in the neoadjuvant space, and we think zanidatamab could have a real advantage there because there's flexibility around what to combine with. You might get improved efficacy, but you also may be able to combine in a way that there's reduced toxicity in that curative setting. The inherited data notwithstanding, it's important that we have good salvage regimens for those patients who don't achieve a full pathologic complete response after surgery. Really the goal is to increase the proportion of patients who do achieve that so that you don't need to go to a more intense therapy that carries with it risk, like pneumonitis or fatal pneumonitis. There's a real opportunity in breast cancer that's a little bit more of a complicated space, so we're being deliberate around getting good phase II data that we can learn from and then design the most effective and successful phase III trial. I think you're also aware that we're partnering with two companies on combining with novel HER2 TKIs. This is an exciting part of the field. You know, tucatinib has been effective in certain settings, there's an opportunity to improve upon that. We've partnered with Boehringer, we're evaluating the combination in breast cancer. We've also partnered with Iambic, again, evaluating that combination in breast cancer. There may be other places where that combination, you know, could make sense. Again, in a sort of phase I-B/II setting, you know, learning what we can learn about might there be synergies. We talked about TKIs potentially upregulating receptor density, which might play into the mechanism of action where having receptors to cluster, you know, will trigger a stronger immune response. We're very interested in that space. Again, going, you know, breast cancer is definitely a place where we think we can win. Now leveraging what we've learned about our ability to win head-to-head against Herceptin and the likelihood that we're gonna synergize with immunotherapy, we are leaning into other areas. Take, for example, the first-line BTC trial. There's no approved HER2 therapy in frontline BTC. We know that zanidatamab works very well in BTC, and that's a setting where immunotherapy is approved. We have an opportunity to go against no other HER2 therapy in combination with PD-L1. We think that's a high probability of success trial that will get us from second line into first line. Now that we know we've beaten Herceptin head-to-head in metastatic breast, GEA, a very difficult disease to treat, I mentioned that, you know, more than half the patients don't even make it to second line. We're now very interested in whether we could do something in the neoadjuvant adjuvant gastric setting. Here again, no approved HER2 therapies, after MATTERHORN now, Imfinzi is approved. We're exploring the concept of, you know, could we again go head-to-head against no other HER2 therapy, benefit from the synergy of immunotherapy in a population of patients who are in very good shape with good immune health, have a fairly low burden of disease. You know, is that a place where zani would really shine, you know, looking at that kind of opportunity? You know, I would also if you want me to go a little bit further. Go ahead. I would say we've got really interesting data in colorectal cancer that we've published, and we wanna, you know, chase that down. You know, we mentioned the partnership with BeiGene that initially is focused on breast cancer. zongertinib is gonna be front line in non-small cell lung cancer mutants. You know, that may be a place where adding a HER2 antibody like Zani could be effective. I'm also impressed, I don't know if impressed is the right word, but have taken notice that the population of non-small cell lung cancer patients who are overexpressing HER2, based on the literature that I read, could be as large or larger than the mutant population, yet there's not as much development activity there. We know we're working, you know, essentially anywhere we've tested zani where there's overexpression seems to be working. In our pan-tumor trial, we'll be enrolling colorectal cancer patients, we'll be enrolling non-small cell lung cancer patients who are overexpressing HER2, in addition to a number of other rare tumors where we might even get a broad indication depending on the results. Got it. zanidatamab is obviously critical to Jazz, but it is not the only part of the company. I wanted to touch on a few other, important parts and, you know, maybe starting with the sleep franchise. Sure. You know, there's gonna be a lot of developments this year in sleep. We've got a new class of agents launching, some more drugs coming on the market as well for the cataplexy side of things. I guess maybe for you, I guess, how do you think about how the market's evolving, how physicians might think about what's the appropriate way to treat some of these patients with hypersomnia? Obviously, there's also a commercial question embedded in there of, you know, how do you see the durability of the oxybate side of the business? Sure. Yeah, no, it's a very interesting field and, you know, as you know, we were really built around our hypersomnia franchise, so we have deep expertise here. I think the field's evolving pretty much the way we've been predicting, and I've been talking about it. Orexins represent a new class of alerting agents that seem to be, you know, as or more effective than other alerting agents that, you know, have come along. What we anticipate here is that the data in NT1 will lead to an approval. You know, so far we don't have meaningful data in NT2 or IH, and that may be somewhat different. What we're seeing from the emerging data are that it's clearly not addressing the root cause in any of the hypersomnias. You know, the root cause in hypersomnias, NT1, NT2, IH, is severely disrupted nighttime sleep. Until you address that root cause, I don't think you can completely treat the disease. I continue to think that Xywav as the only low sodium option with flexibility around dosing, you know, will continue to be the backbone for a substantial proportion of patients with hypersomnias. You know, those who are on therapy now and benefiting from it, I think will continue. We certainly are interested in orexins. We're bringing another one forward. We think that there'll be an opportunity for these to be complementary. I see that we have just about a minute and a half left. Could I extend that to our epilepsy franchise as well? Yeah. You know, we've become a leader in epilepsy, through our acquisition of GW, and I think you've probably followed the success of Epidiolex, which I think it's doing very well commercially because it's a terrific drug for multiple different types of seizures. It's being used broadly. It's very well-tolerated and easy to combine. You see polypharmacy where Epidiolex continues to be a backbone even when other therapies are laid onto that. We've leveraged that expertise to really wanna focus more broadly in epilepsies. I could have easily spent this whole time as an oncologist talking about the cancer franchise, but I'm really impressed with how genomics are now transforming the field of epilepsy in the way that genomics transformed oncology 20 years ago. We now understand, in many cases, the genetic causes of epilepsy and can not only target them, but sometimes reverse the underlying disease. We've brought forward several new, we said we have a new agent for absence epilepsy. I haven't said the mechanism of action yet. We've partnered to in-license a Kv7 inhibitor from Saniona. We have a Kv4 inhibitor in-house, as you know. We actually have a few other things in play. We see epilepsy as a really good opportunity to fit into our overall, let's say refined strategy around rare disease, rare epilepsy, rare oncology. We're out of time without my having an opportunity to talk about Modesto. Yeah which is a super exciting drug. Maybe if I could steal 20 minutes. Go for it, yeah. Go over. We've said the ACTION trial will have a opportunity for an interim OS by end of year, early part of next year. That's an interim. We would have a second bite at that apple. I'm excited about that because that launch has gone very well because there's such an incredible high unmet need. You know, as a pediatric oncologist, trained 25 years ago, the field didn't change much before Modesto. Now there's an opportunity to treat these patients with a novel targeted agent. The approval is in second line, but I think everyone knows that these patients have a very poor prognosis, and the best way to use any new agent is in front line immediately following their radiation therapy. ACTION will allow us to formally have a label in that front-line setting. I think the fact that we went over time just speaks to how much there is to the story and how exciting it is, and thanks again for being here. My pleasure. Thanks so much, Leo.