Good morning, everyone. Day two of our Jefferies Healthcare Conference. I really appreciate it. We're getting technically day three. My name's Akash Tewari. I'm an analyst here at Jefferies. I have the pleasure of hosting the Jazz Management Team. Renee and Rob, thank you so much for taking the time. I will personally say Jazz to us is actually shaping up to be one of the highest-performing events we have. I think the management team's in the midst of transforming into kind of one of the more interesting oncology portfolios we're seeing internally. HERIZON- GEA, when we get asked by investors, "What are oncology readouts we're focused on and we've done a lot of work on?" this one's actually top of the list. So I'm really excited to talk to the team today.
Maybe I'll hand it off to Renee and Rob to give some intro remarks.
Great. Thank you. We're delighted. Thank you for inviting us. Just to be aware, keep an eye out. We will be making forward-looking statements today. Please see our website or SEC filings for the full list of risk factors. Any references to guidance are as of early May when we had our first quarter earnings call. We're not updating or reiterating today. Turning to the business, we've made significant progress. We're sitting here near the midpoint of the year across all three of the value tracks in our business: commercial, R&D, as well as corporate development, which has closed. They're integrating the Zymeworks transaction, bringing zanidatamab into our portfolio, which Rob will speak to shortly.
Also, in general, on the commercial front, we feel confident looking at our full-year revenue guide to the $4.15 billion-$4.4 billion, which is 5% growth as of this point, driven by not just on our sleep portfolio, which continues to show growth and demonstrate differentiation as Xywav, which we still expect to be a billion-dollar product this year. And I'll remind you that we have settled with all 10 of the current ANDA filers, putting us in a position under those settlements where we've granted those ANDA filers a right to launch at the end of the next decade. So very neutral kind of scenario for earlier in certain circumstances. So feeling very confident in the durability of that franchise. And then also in oncology, we have the potential for three separate launches over the coming quarters.
Rob can talk about that further with the Zepzelca, first line, and just second-line maintenance, as well as BTC. in Europe. An exciting time for that part of our business. I'll just close by saying we're also in strong financial position. There's a lot of uncertainty, a lot of volatility coming out of the current administration. We're watching these areas closely. I think we're well-positioned based on what we know today. Importantly, our financial position puts us in a position to be able to continue to invest in our commercial products to drive growth in our pipeline, as well as in continued corporate development. Rob?
Hi, everybody. Just back from a very exciting ASCO for Jazz. We had multiple publications there, three oral presentations on Monday. Headlining that is our IMforte data, which is the study in frontline extensive stage small cell lung cancer for patients who have not progressed after induction chemotherapy. We're randomized to get either Zepzelca or placebo, and we saw, as we said previously, statistically and clinically meaningful survival and progression-free survival results, so from the point of randomization, the Zepzelca arm was a median of 14.2 months versus 10.6 months, and therein lies, for these patients, they had completed induction chemotherapy, which took between three and four months, and so altogether, for this subpopulation of patients, their median survival was between 16 and 17 months, which was highly encouraging. This was accompanied by a progression-free survival difference of 5.4 versus 2.1 months in the control arm.
I think importantly, very well tolerated. Just sort through those safety data. Important to note that this Grade 3/4 AEs was only 6% in the experimental arm compared to 3% in the control arm. Numerically, there were higher AEs, but these were largely driven by uncomplicated neutropenia, so not problematic for patients, but serious infections or overall neutropenia was uncommon. We were also excited to present an update to our frontline phase two GEA data, zanidatamab plus chemotherapy, where for the first time we had mature enough information on overall survival with the median now 36.5 months, which certainly compares well cross-study to other more recent publications, and the PFS was maintained at 15.2 months, and this is part of the reason in conjunction with other data, including a separate phase two zanidatamab chemo plus tislelizumab, showing favorable PFS in that population.
It gives us confidence around the expected readout of the frontline GEA study, which Akash mentioned is expected for later this year. We're also really pleased with our Zymeworks acquisition and integration. We had data as well at an oral presentation on Zepzelca. Of course, we have a brief update of August 18th of this year for that product. Other important upcoming events for the IMforte data. We said that we've submitted the supplemental for that and expect to have an update on the brief state in the near future. Lastly, we had a positive CHMP opinion for zanidatamab in Europe for BTC and expecting approval there soon. A lot going on for us. I'm excited to take any questions.
Yeah. Thank you. I really appreciate it. And it was a year ago when we were also asking about that HERIZON-GEA-01 study. And Rob, you're always very conservative and scientific in nature, but I could always sense that your team has a lot of confidence. And even talking with Ken yesterday from Zymeworks, sometimes in oncology, it's like, "Okay, it's going to be marginally better than standard of care." And I think when you guys talk about being the best potential, it seems to be standard of care changing PD-1 high, PD-1 low. That seems like the bar that your team's going for. When you think about what would be a paradigm shift, what's the profile when it comes to PFS, OS, and safety that you'd ideally want to deliver to kind of really change how GA's treated?
Yeah. So thanks for that. For me, for starters, it's reason to believe. So a lot of data published, Nature Communications, elsewhere, showing that zanidatamab is really highly differentiated. It clusters and internalizes receptors more effectively. It's much more active from an immune perspective with highly active Fc fragment and the only antibody that fixes complement. And the clinical data support this when you look at cross-study comparisons of BTC or activity in breast cancer or other cancers after other HER2 agents. It clearly is differentiated. You see that in the BTC data. You see that in the frontline studies that we've alluded to. We certainly think the frontline phase two study suggests that this is going to be a really meaningful difference. Certainly, recent precedent in Keynote-811 kind of sets the bar for us, maybe.
But we certainly have aspirations that it's going to be clearly differentiated both on PFS and whatever OS trends we're willing to observe. It's not an ADC, which has its advantages. It's highly active from the perspective of interfering with signaling for the reasons HER2 growth factor signaling for the reasons I mentioned, but also highly immune active. But it also makes it very well tolerated. As a monotherapy, very, very well tolerated. In combination, you see some toxicities that need to be managed, but certainly we're showing are manageable. So mainly diarrhea, but when combined with chemotherapy, well tolerated. If it's combined with things like capecitabine, which in and of themselves can cause diarrhea, you certainly have to have some experience in doing that prophylaxis and managing the capecitabine component, which certainly our investigators are doing well. And we're sort of educating practitioners on also.
And Rob, let's put it this way. Keynote-811, kind of like a month and a half, two months. The way I feel like your team's thought about it is kind of in that three- to five-month PFS range would be clinically meaningful. Is that a fair way of thinking about it?
And ultimately, depending on the OS trend as well, you might see some differences between the arm that has Tislelizumab. Immune therapies tend to show more effect on the OS. But the beauty of combining them because I think you can get sort of the PFS impact and the longer-term OS impact. And just to remind the audience, we have three OS analyses planned. We'll see the first of this when we look at PFS, but we have two more shots at that apple, depending on how that ultimately goes. But again, for reference, I know you're very familiar with the data, but if you look at the past pivotal trials, and there were three well-conducted pivotal trials: ToGA, JACOB, and Keynote-811, the range of PFS in the control arm is between 6.7 and 8.1 months for median PFS, with 8.1 being the most modern example in Keynote-811.
As mentioned, of course, it's a single arm. We had in the centrally confirmed HER2 positive group, we had 15.2 months as a median in the data we just updated, incrementally better than that 16.7 months in the separate study that was conducted by BeiGene. Tislelizumab as added to that combination.
It's interesting. I had Manoj did a lot of the work for us internally when we were looking at HERIZON-GEA-01. And the first time he looked at the data, he said something kind of interesting to me. He says, "Akash, I'm finding a stronger correlation with median duration of response on OS than PFS." And when he's fielding one of the Jefferies, the whole question is, "Oh, can you go to PFS? And then what's the OS translation?" Is it fair to say you're very confident that whatever signal results that you show on PFS, you're going to have something equally as strong on OS? There will be a solid kind of translation when we go from PFS to OS, given you're seeing these kind of hyper-responders with some of these HER2 connotations?
Yeah. I would say for this disease entity, we know the PFS correlates fairly well with OS. And we know that Zanidatamab being well tolerated can be given for long periods of time. So we think we're going to get that durability. And in a global trial, we think that ultimately translates into good OS as well. There certainly is going to be some level of confounding of OS as patients transition over to active therapies because they do exist in the second line. But we do think in this disease setting, pushing that PFS out ultimately translates into better OS as well.
I was talking to Ken yesterday, and he said something that was quite interesting. He said if you look at the Keynote-811 study, half of the patients didn't actually get anything else after they progressed, so I think there's some tumor indications where there are more confounders. It seems like GA is uniquely underserved in terms of agents that you can give after, but I guess the question for you is, there has been some change in the field. I mean, people just use it in HER2. I would kind of use it in HER2 anyway. How confident are you that the PFS and the standard of care in GA that we saw in the Keynote-811 study is going to be similar to what you're seeing here?
Because it's also notable there are geographical differences, I think, between both studies too that I think I'm not sure investors totally understand.
So, certainly when you get to because you'll have to do a cross-study comparison with Keynote-811. You'll have to take into account some of these differences. I'll just remind the group: when we see the first OS we see at the time of PFS, that is the first of three. We're not expecting that to be fully mature. We get two more bites of that apple. We may have to wait for some more maturity on that. That's one important point. The other point is that this is a global trial. For the zanidatamab trial, because Keytruda was available in the U.S., we did not enroll in the U.S. We emphasize more Europe and globally, where the availability of Enhertu isn't quite as significant, especially off-label in the U.S.
And so there may be less of an issue with crossover to Enhertu in the second line. We'll have to see. I'm not speaking to any data that I've seen, but.
You apparently can't reimburse Enhertu, so.
Yeah, for example. So again, I think that we're optimistic about what we'll ultimately see on OS when we have enough maturity there.
Understood. Now, just maybe just lastly on OS, I think the question we're getting is, and I totally agree with you. Unrealistic to expect the same thing from OS will occur when PFS begins to hit. That's pretty standard in oncology trials. I don't expect that to be OS that big at that point. There's a sense that probably end of 2026 is probably final OS. So two questions. A, when the PFS data hits, will there be commentary from Jazz on a trend on OS, or will there be no comments? I think that's more of a blocking tackling question I get from investors. And then number two, I think if you agree PFS and OS can translate some repeat vector delta, I would say it's also not unreasonable to think that another interim OS hits before the end of 2026. Would you generally agree with that?
So I'm taking the second first. I do think, remember, we increased the sample size to have better OS that allowed us to sort of take what had been the final OS and create another interim without really losing anything. So whatever probability you're assigning to the OS hitting at that point, that gives us a second early shot at OS. We haven't commented yet on whether we would show the data from an OS interim. I want to be thoughtful about that. And there may be some consideration as to, given where we are in the trial conduct and the maturity from a regulatory perspective as to whether we should be sharing that or not. So we haven't said yet, but as we get closer, we may be able to provide some more details on that.
Thank you.
Maybe just to add to that, just to clarify, we also do still expect to have a submission that would contain PFS and that that would be sufficient as long as there's a positive trend in OS. And we've had some questions about that recently. Our view hasn't changed there.
Perfect. That's super helpful. Okay. Now, coming back, going to ASCO, I feel like one of the biggest unanswered questions is, what are you using that for in topoisomerase? Right? Like a small cell, breast. All these indications are going to have pharma companies taking abominable combos with topoisomerase ADCs. And I feel like the field is completely. We have no idea what to do after. And you go to Destiny-Breast06, and we're all stumped as well. This is a huge issue. And I look at Jazz as kind of uniquely positioned with Zanni in terms of what is the optimal agent to give after Enhertu in HER2. Right now, it's like DV from Pfizer and maybe the Ambrx's molecule. What I get questions on is, well, Akash, I agree with you, but Jazz is really going through that. What is their plan?
You guys have been quiet in terms of your enrollment and your strategy with expanding Zanni after the HERIZON- GEA study. Can you also understand what is the development plan? What are the indications we should be paying attention to?
Yeah. Thank you for that question. So I've been working in breast cancer for quite a while. I was actually at Merck when we set up the I-SPY, Keytruda collaboration with I-SPY, but more recently worked with a lot of the top KOLs on Trodelvy. And so literally the day we closed this deal, I was getting a lot of phone calls to say, "Rob, there's a real issue here with what to do after Enhertu and breast cancer." And given what KOLs have seen in terms of its activity, not only just frontline activity, but activity in patients who had progressed on prior HER2 agents, including Enhertu, there was a lot of enthusiasm for working Zanidatamab into a metastatic breast cancer setting. And I think the data since then have supported that even further.
I mean, the premise the KOLs were bringing to us was we just don't have much data in these other HER2 agents, and in a scenario where Enhertu plus Perjeta, which is based on ASCO data, suggests that that may be the frontline standard. Now patients are getting a Herceptin-based ADC and Perjeta, so you wouldn't move that frontline therapy to second line, and so what else do you have? Things like PD-1, Keytruda/Mib. There's some good real-world evidence data from Flatiron suggesting that there is diminished activity in patients who've already progressed on Enhertu. Not the case for Zanidatamab in the data that we have so far, and so that has increased even further the interest. We've already launched, as of, I think, almost a year ago, our pivotal program of Zanidatamab in breast cancer patients who've progressed on Enhertu.
And we had several great meetings with steering committee members over at ASCO. The excitement to do this continues. And while we haven't provided a timeline yet, we think the trial is going very well.
Enrollment's going fast.
Yeah. Well, I didn't necessarily use the word fast because, what's that relative to, but there's clearly global interest in this trial. And I would say we're still activating sites because it's a large global trial. When we get to a point where we're fully activated and we see that enrollment rate, we're going to update our timeline so we have more clarity on that. But clearly, as I go around the world and talk to docs, they want to participate in this trial.
Just two points on that. If you're going to give me two other indications where no-brainers saying these things, you can do CRC, you could do bladder, and just weird indications where even ovarian HER2 ADCs are somehow showing really good responses there. But the one no-brainer one to me is just neoadjuvant GA. I mean, just adjuvant GA, and you can have a really, really durable response. Can you talk about where you are with that study and how quickly are we going to get these trials announced? Because that's what I'm hearing from investors. Yeah.
So I could certainly, if anyone has another hour, I'll stay after and talk about my aspirations there. But to answer your question specifically, in neoadjuvant space, there's a lot of interest in zanidatamab because it's so well tolerated. And so we're in I-SPY, breast neoadjuvant. If we are frontline therapy in GEA, it's logical to think about neoadjuvant there. We saw the Matterhorn results, so now we know what the standard of care is there and will be for a long time. So we have a premise at least on which to build. But as you said, we've seen activity anywhere that HER2 is a driver, regardless of prior HER2 therapies. So there are places like colorectal cancer where we have very strong data. Is there a way to intercalate into a somewhat changing landscape there? Lung cancer can be.
Tumor as well.
Yeah. Lung cancer can be a place where we would potentially see activity. And Renee's just reminding me that, of course, we have an ongoing pan-tumor program that allows, at least in the very late line setting, would allow us to address any tumor that's overexpressing.
And maybe just on that point before we get into some strategic questions on this, after they did the pan-tumor trials and they were able to kind of get accelerated pathway approval, I think the question I get because zanidatamab did a lot of these ASCO studies. Jazz knows this. He was there. So the question I get from people is, well, why is Jazz also running these trials? Don't they have evidence on where this has activity? Is there a registrational path with pan-tumor that you think investors are?
That's the interest.
Okay, so what does that look like and what indications?
Yeah. So certainly, because we do have data that gives us confidence, more data, I think, is even helpful just from a publication and dissemination perspective. There is a path based on this study, we believe, to a pan-tumor indication. There is a bar out there because Enhertu is already approved in that space. But our understanding is that there would also be a path for Zanidatamab provided that we demonstrate adequate and risk.
What's the bar in your mind?
This is a little different than other approvals. When you have an accelerated approval, it's not considered available therapy. Your historical comparator is really something after that. Once there's full approval, then that becomes a comparator. Right now in HER2, that's accelerated approval. They will ultimately get full approval. Here's what's different in this study because it's a rare tumor. That population is quite diverse. The full approval will be on the basis of only a single arm. I think regulators view that a little different than having to compare to, say, randomized data, tumor by tumor. I do think there's a path. If we're able to show that the benefit-risk is comparable, there should be a path.
For me, given how well tolerated Zanidatamab is as monotherapy and the ability to give that for a continued period of time without people coming off the toxicity and the durability that you therefore see, it becomes a really competitive choice across any tumor type.
Got it. So I kind of covered both Zymeworks and Jazz, which I feel like the only ones. But it was interesting when Ali, the former CEO of Zymeworks, he was talking about Zymeworks in a weird way. The way he talked about Zymeworks was like, "Every single line of Herceptin, we want to replace." Kind of like the PD-1 by Jazz. They want to go everywhere with Keytruda. Why not try this? This is what we're going to go for. It's a really broad development problem. You talked to Exelixis. One of the things of Cabo is they had four companies pitch in to help with the investment needed to run these types of studies. You guys have ambitions with Zymeworks, but this is a large-cap development program. That's what Ali always used to say.
When you think strategically, right, because you're going to head out, you're going to step back, you're like, "GEA, this is showing something different." Now GEA, we have a different data set than Herceptin. There seems to be. Now we have to step back and say, "Do we want to go big or not?" And what do you think about either strategically giving this as a larger transaction or partnering, which has become pretty common these days with Zanni once you get that HERIZON-GEA-01 approval?
I mean, without getting the science answer, without getting very tactical about it, whether it be Merck or AstraZeneca or more recently at Jazz, I've always had the mindset that if we can create value for patients and for the company through a partnership, we should be considering to do that. And if ultimately it sets us there faster, gives us more capacity, then it makes a lot of sense. So for example, the IMforte trial was our brainchild. We brought this to potential partners. We ultimately did the deal with Genentech, who ran the trial because they had done two prior small cell. It only made sense for them to do it. That was a very fruitful partnership. And we certainly recognize that in some cases, you'd want to be combining with either novel agents or agents that are still substantially in development, even if approved.
It may well make sense to partner from a development perspective. And I don't know if Renee has anything to add from a more commercial perspective.
Yeah. I would just say good data can open a lot of doors and provide a lot of options. So we're excited to be able to see the GEA results. We look at all options to be able to both maximize the full potential of zanidatamab, but also the potential for our shareholders. Being on the market in BTC already gives physicians the chance to get experience. We have our field teams already on the ground doing a lot of medical education. Institutions, large community-based centers are able to start getting experience and having the drug go through their systems. So by the time we turn over the GEA card, we will be going very quickly to get on NCCN guidelines. Of course, we won't promote before approval, but we expect that there would be use as soon as GEA can be reimbursed.
And then, of course, Rob outlined the breast cancer study already underway. We do believe there are multiple opportunities here. We've said we think it's a $2-plus billion opportunity. And if we optimize, maximize that through additional business development, so be it, but we are highly focused on ensuring that we invest to get the biggest potential out of this asset.
Understood. Maybe just stepping back into narcolepsy. I mean, Jazz has been the name in narcolepsy for two-plus decades. I mean, I don't think there's a company that has had a longer relationship with double the diagnosed patients, right? For orexin, obviously, we've been very bullish on them. We think they're going to be a transformative agent. And I think psychologically, for a lot of the sectors, it's really hard for us 25, 20, 30, what's going to happen? There's so many key players. It just becomes impossible to do a single risk, right? You have your own orexin program. There's been some safety issues that have shown up. And I just can't help but think in the back of my mind, there's no way a company with the history of Jazz and narcolepsy is not going to have a bona fide agent in a transformative treatment, right?
So where are we with the internal one? Because I know the studies have restarted. But if it's not delivering the profile that you really want from patients, I mean, how aggressive are you guys going to be in terms of looking externally? Because there are several assets out there that are getting to that kind of proof of concept.
I'll answer the first part. We are dosing in patients with the compound that's already in the clinic, and we do have a backup program that's preclinically that we hope has a better profile. We certainly would look to leverage what we've learned from the field to shortcut some things and to move either of those programs quickly where appropriate. I'm certainly continuing to watch the data as they evolve to understand what ultimately would be the most optimal use of orexin, which is given during the day as a weight-promoting agent, for which there are no data to suggest that it would improve nighttime sleep. In fact, whatever data we have actually suggests that it might be counterproductive for nighttime sleep, with reports of insomnia and PSG data suggesting that there's not an improvement or even sometimes a worsening with persistent exposure.
In our own development program, I'd be very excited to kind of put to the test our hypothesis that Xywav is really the best treatment for the root cause of narcolepsy and that the Orexin class may be the best daytime alerting agent to implement that.
So a couple of things on that. Because when I look at the data, I would agree. There is insomnia. It does seem to tolerate over time. What I think was also interesting was that on sleep latency, there was a worsening on sleep latency. That also started to improve, but it took some time, right? But on the same side, when I look at sodium oxybate, you don't get your immediate benefit. It takes about three to six months to get your max benefit on MWC for sodium oxybate. In terms of REMS normalization, which I think you're seeing signs of with the phase 3 data from World Sleep, it may take some time to get there too. But the question I get from KOLs is, why wouldn't Jazz run a combination study? So where's the appetite in terms of exploring whether that's the optimal approach?
Are we going to get an announcement soon?
We're not saying we wouldn't. And I do think that it's logical to use them in combination, obviously, Xywav at night and orexin during the day. But I do want to just take a moment to be sure we understand that REM onset is not the only important measure of quality of sleep. In fact, it's probably the least important. If you've ever had chunks of sleep debt like I experienced during successive shifts and while I was in residency, you accumulate sleep debt. And when you do that, it's very easy to fall asleep, but you don't necessarily get adequate restorative sleep. So in the PSG, you really want to look at total sleep time, deep sleep, which is restorative, and REM sleep, and how much you're waking up during the night.
To be fair, you're definitely not showing that. Maybe last question. I know we're out of time. But Renee, for you, we've been very conservative on sodium oxybate from 25 to 30. To me, the oncology story should be good enough that I don't have to make that complaint for investors. But there's this interesting question. Are there going to be this deluge of Xyrem generics that are going to enter in the back half of the year? It seems like if that was going to be the case, you would see companies making a new REMS program. Are you seeing generics making REMS programs? I'm sure you would know because they have to have some communication. So have you heard of a new REMS program sprouting up that we don't know of?
I would say we are very familiar with what's happening in the space. In order for generics to come to the market, they have to have an approved product, and they have to have a REMS that can distribute the product and can talk to all of the other REMS. That can happen in the beginning of 2026. In terms of the impact of Xywav, we continue to see its durability and growth remain. I would say what specifically happens to the market will depend on how many generics come in, what those price points are, and then for our franchise, how strongly we continue to support the differentiation of Xywav from patients, physicians, as well as from payers. Just stay tuned. Additional data coming at APSS next week.
I'm excited for that, and I will take that as a maybe not on a REMS. We'll see. Hey, thank you so much. I know we're over, but I really love you guys.
Thank you.