everyone I really appreciate it hope the morning's treating you well my name is Akash I'm a pharma and biotech analyst here at Jeffries is day one of at least the public portion of our New York City healthcare conference very pleased to have jazz pharmaceuticals one of our high conviction that's in in biotech and a company that I think is really at a point where they're seeing a transition to becoming really a full-fledged biotech story, scaling, and I think something that investors should be paying attention to. Rob, why don't I hand it off to you to give some introductory remarks, and then we'll get started with Q&A.

Thanks, Akash, for having us. And just a quick comment that Rob and I will be making some forward-looking statements today, so please do refer to our risk factors in our SEC documents and any guidance we refer to as our first quarter guidance that we provided.

Yeah, Akash, thank you for having us. I don't have any introductory comments. Happy to get right into your questions.

I love it. So, look, I think this is a question that I think I'll often hear from investors, which is, you know, I haven't looked at Jazz in 5, 10 years. I remember they had some sleep drug. You know, has the story changed? And it's kind of remarkable to me because, you know, you've done the GW transaction. You have a billion-dollar oncology franchise, even, you know, X, the Zahira acquisition. And yet I think intellectually, a lot of investors who haven't seen your story recently still think about sodium oxybate as kind of the primary focus. So this question is really like the jazz of the last 20 years doesn't need to be the jazz of the next, you know, 10 to 15. So when you think about your investment and your interest, whether it's in rare oncology, orphan, neuroscience, or just wholesale, you know, Zahira development, what's that mix in the next five, ten years for you as chief medical officer versus what we've seen historically? What are investors getting wrong?

Yeah, thanks for the question. So for me, I started seven years ago. This was my eighth ASCO as Jazz CMO and head of R&D. You know, when I started, as you said, we had some important products in oncology, niche products like Defetelio at the time, Irwin Ace and Vixios and we had Xyrem not yet Xywave and I came to jazz really to build an innovative biopharma company and really expand R&D out so that we could be doing development and innovative areas from the very beginning of research you know through through medical affairs and to your point Akash You know, I think we've been even more successful than I thought we might have. We've done some very important things internally, so developed Zywave in-house as a safer oxabate for patients with narcolepsy, and then extended its label in idiopathic hypersomnia, addressed a critical need for Urban Ace where there were drug shortages by developing in-house a novel manufacturing process that gave us Rylase and then began to build the pipeline around core competencies in new areas to diversify our business ultimately. And some notable things there, one of the earliest oncology deals we did was for Zipselka. That was intended to be a second-line product for small-cell lung cancer. We had the vision of saying, you know, this really could be used in frontline maintenance. And that was something that had never been done in small-cell lung cancer before, because those patients have a pretty rough induction with chemotherapy and typically need a break. Because Zipselk is well-tolerated, we were able to weave that into a maintenance study, We did that in partnership with Genentech, and of course now have a front line label Interesting data at ASCO this year showing that it's having a benefit even in patients with an immunosuppressed phenotype, so-called tumor-associated macrophage high, and really positioned well in that front line. We, of course, brought Xanadatamab in on the basis of biliary tract data, saw that through an approval executed on the frontline GA study, which we're pleased as the first ever Jazz New England Journal of Medicine paper published last Thursday, I think definitively showing that this should be the HER2 agent of choice in frontline chemo and should be combined with PD-1 antagonists. And so I think we've been able to diversify and get into new areas in oncology. Of course, there was the chimerics acquisition last summer, and Modeso is off to a terrific start as a pediatric oncologist to see that we now have a treatment option for these patients. It's amazing and very excited to see that action could bring that into the front line. Of course, a major transformative deal for us was the GW Pharma deal, where we brought in what's now the largest grossing epilepsy drug in Epidiolex, and importantly, created for us an in-house expertise from research, literally discovery chemistry, through commercial in epilepsy that we're now leveraging. We announced we have JZB047, which is an in-house invented, discovered molecule for absence epilepsy. And we've positioned ourselves as a real partner for choice in a rapidly expanding epilepsy field with new opportunities coming from our improved understanding of genetics and epilepsy. And so deals like Saniona and others that I think we will be well positioned to be a partner of choice for. So in those, as you say, five to ten years, you know, I think we've shown that we know where to focus. We can select good deals for partnerships.

We're discovering and developing molecules in-house, and we're executing well, not only on the commercial side, but when we have an opportunity like ZANI, GEA, we can go from data to a final submission in essentially three months understood one one thing i do want to kind of close the loop on it's it's interesting you know we i cover lillian certainly i think their perspective on orexins and the importance of really modulating cognition and sleep is far more broad than just let's say an orphan market um you know we think about ADHD or, you know, 25% of patients with Alzheimer's suffer from solminants, right? And I do think there's probably going to be that wider perspective. I know your team's been working on your own internal erection programs that have had some safety issues in the past, but it does seem like you may need different PK and you may need a different product profile. You're not thinking about just MWT measured four times to have coverage in these other indications. So can you talk about your long-term approach in sleep? with what we're seeing with orexin biology.

Thanks for the question, and I think great insights about where the field's going and what the optimal molecule might be. So, you know, it's interesting. We certainly started by saying we're very interested in this because the early data showed it's a very potent wake-promoting agent, but also that it's likely to be complementary to Zyway. It's not likely to improve disrupted nighttime sleep, and in patients with narcolepsy type 1 or type 2, 2, idiopathic hypersomnia, the root causes disrupted nighttime sleep, and there's no wake-promoting agent that can address that, and it's certainly not the case for orexins. So we started to talk about that, and I think now that's taken more as a given. Your point also that whether you're talking about hypersomnias or other potential applications, it does matter the clinical pharmacology and the PK profile. And so for us, we think there's an opportunity still to have a best in class. What we've seen so far is drugs that have a long enough half-life for even on that first day, you're seeing reports of insomnia. And to your point, NT1 is very, very sensitive to these agents because of the loss of orexin neurons and the massive upregulation that happens with orexin-2 receptors. Very, very sensitive. But when you get into other hypersomnias or diseases like ADHD or cognition and Alzheimer's disease, you're going to need to push that dose. And you're going to need to be able to do that and still have the exposure come down at night so that you don't disrupt sleep in any of those conditions, which would be counterproductive. And I saw this when I was working at Merck on the H3 inverse agonist programs, where we had five, none of which progressed, all for the same reason. The half-life was just too long. And so we did, with the Sumantomo collaboration, we did have a molecule that was in the clinic that failed due to safety reasons. We do have a backup compound that's preclinical that we hope to comment further on in the near future. And it's our aspiration to have a compound that's differentiated in many ways, inclusive of a more suitable half-life across indications. So I do think there's time. I remember the first approval is NT1 only. We still haven't seen any data, even in other hypersomnia. Plenty of opportunity for the field.

Now, maybe getting into Zahira development, and I'll give you kind of a near-term question first, which is really the label that you expect with Zahira. And the question we'll often get is, like, could there be a narrow label in, you know, ICH 2-plus versus 3-plus? I mean, I have my own view, given your clinical data, but I'd love to get your take. How should investors think about the label you'll be getting with your PDUFA data?

So, you know, we wouldn't comment on specific label negotiations, and it's still early enough in the process that that will play out. I'll tell you my view of what I think the label should be. And I think that starts with what do we think we've proven with this clinical trial? So the clinical trial, first and foremost, was a test of ZANI versus Herceptive. And definitively, no matter how you measure that, we believe ZANI replaces Herceptive. I think there's a role in most of the, really every GI oncologist I speak to says that trastuzumab is historical regimen here. The second question, even though it wasn't powered, was does tizolizumab as a PD-1 inhibitor have benefit? I think those results are also clear. And not surprisingly to me, even though it might have been a surprise to others, we see benefit in the PD-L1 negative patients, which is notable because the prior studies with Keytruda and HER2 positive, N-negative, and the Volumab, Tizolizumab in the HER2 negative populations, none of them showed benefit in PD-L1 negative. And we think this is because of the differentiated mechanism of action for Xenodatumab, which is highly immune active. It's the only antibody that fixes complement and activates the complement cascade and also triggers ADCC and ADCP. So you have this massive recruitment of NK cells and macrophages causing inflammation at the tumor site and synergizing with immunotherapy. So we think that is the new standard of care, the triplet. Your question about what to expect from the label, I expect both drugs to be approved. And I also expect it to be, well, let me say this, I think the data support, because I can't speak for the FDA, the data support that both drugs will be approved, the data support its use irrespective of PD-L1 status, and you asked specifically about IHC 3 plus and 2 plus, you know, here we have a trial where the great majority of patients, more than 80% were 3+, so a very small subset. And when we look at that subset of IHC 2+, the surprising results of the IHC 2-plus overperforming, I think, can be easily explained by small sample size variation and some confounding factors there. And we certainly are positioning it that way with the FDA.

Understood.

Now, ultimately, if it's somehow the label is not inclusive of 2+, I think the data and information are out there in a meaningful way that docs understand that XANI is superior to Herceptin, regardless of, you know, 3-plus or 2-plus.

And that's something I think we hear with our KOL work, is that biological question has been seemingly answered. This is better than Herceptin. Now when we think about really uptake, and I know you're not on the commercial side, But I can't help but think, you know, this is something where you've shown a clear benefit over standard of care. This is a well-defined patient population, and, you know, you have kind of pretty robust clinical data. When you think about, you know, your time at Merck and how fast Keytruda uptake was in some of these indications, how should we be thinking about that for JAZ here in first-line GA?

Yeah. I mean, this is the first study to show median survivals over two years. you know, over 24 months for RMB and over 26 months for RMC, we think it's definitively better and we're acting with a great deal of urgency and so is the FDA. So, you know, we had data end of November and our submission was complete, you know, even with the intervening holiday by the end of February. And so we're moving with great speed. The FDA gave us RTOR, which meant we were able to give them data ahead of the final uh ahead of finalizing the submission they gave us breakthrough designation and priority review so i also see them moving with speed we had submitted to nccn based on the abstract even knowing that nccn typically likes to have the full publication but we wanted to get get them thinking about it at least and as soon as we had the publication in New England Journal last week. We've updated it. And so, you know, the situation, I won't speak to the commercial because that's not my expertise, but we're approved in BTC. These are the same doctors who are treating GEA. So we're on formularies. They have the drug in their hands. They know how to use it. You know, this is a tight community. They're super excited about the results. He certainly appreciated that at the recent ASCO meeting. We hope NCCN acts quickly, and we feel the FDA should act on or before the PDUFA date. Okay. Based on where we are.

Very interesting. Now, and then maybe just lastly, two other points on this.

Number one, I know for the doublet, there's a potential another OS interim that's occurring. yeah can you kind of frame expectations you've already hit on OS on the triplet what are your expectations for that second interim roughly when would that occur and is that something we should expect a positive interim OS yeah so you know first of all the survival data are not needed for approval in the US give especially given the magnitude of the PFS benefit but we also you know have an interim look at survival, even though arm C and A was, quote, stat-sig, and arm B versus A was not stat-sig, you know, statistical significance has also to do with how much alpha you put against that, and this was the first of three survival analyses, so we clearly didn't put much alpha against it, but still, we have the opportunity to see the data, to see the magnitude of benefit, which was, you know, the median, more than 24 months versus less than 20 months. And the precision around that, given the large size of the study and the number of the events, I think this is convincingly having a survival benefit, even if it wasn't, quote, STAT-SIG at this first interim. And I believe the FDA appreciates that as well. We do have a second interim that is still expected mid-year this year. Will that come before the approval? In a sense, I hope not because, you know, I want the approval to come as quickly as possible. If it does come before the approval, we'll try to work it in. If it doesn't, there is a mechanism for a rapid update to the label through what's called a post-approval supplement, label supplement. So we'll get the data out there as soon as we can and update the FDA as well.

And just to be clear, I know, obviously, we have to see what the data plays out. So let's put two points on that. A, it seems like you're extremely confident that this will show an OS benefit, whether it's in the second or third interim. But B, it does not seem like you're also reasonably confident, and I am putting words in your mouth, literally, so agree or disagree, that you could potentially show that benefit in that second interim.

I think we do our own probability calculations, which I don't necessarily share, but I would say it's still an interim. You know, the biggest amount of alpha is at the final, and that also is contributed to by the fact that you have more events, and so overall you have more power. But I think there's a meaningful opportunity here where we wouldn't be doing it. But I think the more important point is I'm not sure stat sig is the important issue because, you know, from a statistics perspective, I look at the point estimate and the confidence bounds around that, and that tells me the precision of that estimate. and it's clear there's a survival benefit even after the first interim.

Understood. Now, you know, Rob, you previously worked at Merck, which you alluded to, and I think it's funny. We talk so much about the PD-1 VEGFs and this idea that, hey, wherever Keytrude has worked, we're going to replace that with a VEGF by specific, but no one really says, hey, let's look at wherever Herceptin's worked and why isn't Zannie there? Or at least that discussion doesn't happen enough. And I think part of it Bridging into that, when you really look at how Keytruda generates revenue, I think there's a shockingly high amount, which is in a maintenance setting, which is neoadjuvant, post-resection. And I don't think that's well appreciated by the street. And you're actually developing that kind of adjuvant strategy with Zannie. Can you talk a bit about that? What are those big readouts you have? And what are the sizes of those adjuvant opportunities relative to, let's say, first-line GA, where I think investors think about this as, let's say, a billion, a billion-five opportunity?

Yeah, that's a great question, and we are thinking about it that way. Now that we have head-to-head data with Herceptin, wherever Herceptin is the backbone, we think Zannie could do better. So definitely think, and by the way, there are places where Herceptin wasn't quite good enough to ultimately get a foothold, where we also think, so the example there is frontline BTC, no approved HER2 therapy. You know, the strength of the data we have in second-line BTC suggests that our ongoing front-line trial has a high probability of success, especially since it's combined with an immunotherapy. So the lessons from 301, as you say, are anywhere where Herceptin goes, we should be able to But also, we think we're triggering a synergy, as I explained before. So the opportunity to combine with a PD-L1 may create synergy. So again, that front-line BTC trial bodes well. To your point, though, on neoadjuvant, adjuvant setting, XANI is especially well-suited for that because, remember, this is often a curative setting, so you want well-tolerated drugs that can contribute not only to the cure but also to the overall tolerability of the regimen. So in the breast cancer space, we think we have an opportunity there. It's a little bit crowded, and it certainly is a little bit complicated when you look at various subtypes, ER positive or negative, or the various molecular subtypes. which is why we're starting with a phase two. So we have our own phase two in that setting, as well as partnering with iSpy and MD Anderson to generate additional data. And we do hope that on the back end of that, we will have an opportunity to do a pivotal trial in that setting, and that would be very valuable. I want to come back to maybe other opportunities in breast cancer as well, but you asked specifically about neoadjuvant. So while we haven't committed to a neoadjuvant adjuvant trial in the gastric space if you're using the same principle you raised, which is wherever Herceptin is alone or hasn't yet had a foothold, and wherever you can combine with immunotherapy, now we see how active it is in gastric. That's a logical place for us to explore as well.

I want to make sure you get to all your questions, but I'm also happy to talk about at some point the rest of the development program, where we might go in breast cancer from here, other indications yeah i mean i mean actually i i i do want to hit on kind of posting her too and um talk to us about why you're so confident that study will be successful because again i think a lot of people haven't done work on that study that's reading out next year that's you know 2027 akash problem but um uh you know this seems like the next big you know revenue driver for zahira What's the biology showing that makes you confident that that trial is going to work? And how is kind of Herceptin-Projeta done in a similar setting so far? Because I know a lot of people looked at the Jacob study and some of these PYR trials with GEA and applied it. But Zaney obviously outperformed. What's the precedent here in a post-NHER2 trial?

Yeah, so it, again, is the principle you raise, which I think is very insightful. If Herceptin is the standard, you should be able to beat it. And so that is the premise of 303, is this is against Herceptin. Patients come in, they're assigned their chemotherapy, they get randomized to ZANI versus Herceptin. A couple of important things around why that might work. We do have data with Zanidatumab in a couple of different places, a late-line monotherapy study, combination with anti-CD47 and in the ER-positive group combo with fulvestrin and palbociclib, showing that we have activity after multiple prior HER2 agents, inclusive of growing data showing activity after N-HER2. And that makes sense because, you know, while there can be some mutations that occur that make cancers resistant to HER2 agents broadly, typically the resistance mechanism for an HER2 is resistance to the chemotherapy, so that's why we think there's a rationale to use it there. The other rationale to study it, for this to be the first major study we've done in breast cancer, is how the treatment landscape is evolving. You mentioned what happens to Cleopatra. Cleopatra is the front-line regimen now, Herceptin, Progetta, Taxate. Well, if Nhertu becomes entrenched in the front line, Nhertu is essentially Herceptin with a topo payload. The study actually included Progetta. So patients might be getting Herceptin, Progetta up front. So what haven't they gotten by the time they get to the second line? Well, they haven't gotten a Taxate. and they haven't gotten other agents that they haven't gotten zani obviously but other agents that might synergize with zani so we've become very interested in best-in-class her2 tkis which is why we have the partnership with behringer and the partnership with iambic to look at what should be best in class so if you're in that setting zani plus a tki that may actually increase receptor expression, play right into the MOA for ZANI, that's a promising combination. So clearly we went to 303, which is, you know, at the moment a three-third line, fourth line study because it's the highest unmet need, and docs were saying we don't know what to give in this setting. We're also interested in studying breast in other areas, as I mentioned in the neoadjuvant adjuvant, but I think there's, depending on the data that we're generating in our phase 1Bs, I think there's an opportunity to be in an earlier line even, which could be helpful because, you know, front-line GA, you saw the amazing effects in a naive population. You want to give your best therapies up front. You know, as you get to third and fourth line, that's a more challenging population to study. And just like for Zipselka, where it's effective in second line, but much more effective in that line, you want to progress the drug earlier.

So a couple of points on that. But what is your general confidence for the phase three trial you have in that kind of more refractory post-in-HER2 setting? Are you confident that trial is going to be successful? And then number two, you mentioned you have data sets that are emerging with HER2-CKIs. What patient populations are you running those combination approaches in that might inform a front-line strategy there?

So, I mean, I wouldn't have started a pivotal trial, Jess, if I wasn't confident. We started it before the GEA data, and given how well Danny did against her septum in GEA, it does give me even more confidence for the ongoing trial. The initial evaluation of the two TKI programs, the zongartinib and the iambic compound, is in breast cancer. And I think that could, you know, these are both brain penetrant molecules that could address the specific problem of brain mets. So if you think about HER2-CLIM, which is tucatinib, Herceptin, PEN, chemotherapy, you have the opportunity to replace Herceptin with best-in-class and replace the tucatinib with the best-in-class, not only for efficacy but better tolerability because the greater selectivity of the new PKIs. You could then be better positioned in a true second-line inclusive of patients with brain pain.

Understood. Now, you know, this is a, like, you talked to Exilexis, and they had to develop Cabo, and now they're having to develop Zanza, not as large-cap pharmaceutical companies, and it becomes this idea that, look, partnerships are not a nice-to-have, like, they're necessary because we need to get entrenched with standard of care and also how the field evolves. When you think about, you know, potential partnerships with pharma, where you're, you know, split economics and certain indications, let's say similar to Checkmate 9 ER with Bristol and X-Alexis, is that possible when we think about the broader opportunity for Zahira? And you know, what's your take about potentially combining Zahira with APD1 budget?

Yeah. Great questions. Just looking at the clock. So I'm very open to these partnerships. In fact, I think the Genentech partnership on Enforte was fabulous for both companies. We both had expertise we brought to the table. We both had molecules that made sense to put together. We collaborated on the execution. We shared the cost, and it was sort of flawless. You know, what happens then in the commercial setting may depend a little bit. In the case of Zipselka and Atizo, you know, we are collaborative, but it's not a formal arrangement. And I think, you know, we're both promoting, and that's working out just fine. But there absolutely is more opportunity to do that, especially when you get into novel combinations, right? And so if you think about, so we published in our phase one, only five patients at non-small cell lung cancer, but we had activity there. Now, those are the overexpressing patients. There is a separate population of non-small cell lung cancer where there's activating mutations. That's of interest, too. But in patients who overexpress HER2, we think we're going to be active. And so in the basket trial that we have on Gung, we are enrolling lung cancer patients. We'll get some additional data there. But the path there, which is much more open than the patients with activating mutations, would be in combination with immunotherapy. And, you know, currently that would be with a PD-1 inhibitor. But if you're thinking about skating to where the puck's going, so to speak, you would consider a novel immunotherapy that might be even more effective. And so very open to partnership development in that kind of sense.

Are those potential announcements we could get this year about broader partnerships with Zahira?

You know, we're having lots of conversations about this, so possibly. Commitments there, but, you know, we have a fair amount of inbound interest, and we have a clear idea of how we think this should be optimally developed, so we're having conversations where it makes sense.

Last question. I'm going to sneak it in because I'm staying in the same room. um in terms of the the basket trial and that pan tumor trial i think a lot of people look at it they're like okay well cool they're running you know a dose finding signal finding study and your team has been very insistent no no this there's a registrational path forward yes with this trial yes talk to me about what that disconnect is what is and how are you going to be able to take that data set and actually go into the market in certain yeah and just so you know we've had interactions with FDA, so we're clear what their expectations are, so we know what we have to do to get there, and it includes having a broad enough range of patients and having strong enough data, and so time will tell.

We do have interim analyses where we can go back to them and check how we're doing here, how many more patients, et cetera. Remember also, it is a, you described it correctly, it's a basket trial, the goal of which is to get a tumor agnostic indication, But the other goal is also signal finding. So we have colorectal cancer patients being enrolled there. We have non-small cell lung cancer patients being enrolled there who would contribute to the agnostic indication but might, in and of themselves, ultimately get an accelerated clue. So it can be used for multi-purposes.

We're out of time, but I really did enjoy the conversation. Thanks so much.