Everyone, good afternoon again, and thank you for joining us at the 2026 TD Cowen Biotech Oncology Innovation Summit. I'm Joseph Thome, one of the biotech analysts here on the team at TD Cowen. It's my pleasure to have with me today two members of the Jazz Pharmaceuticals team. We have EVP, Global Head of R&D and CMO, Robert Iannone, and we have the Head of Investor Relations, John Bluth. Thanks, guys, for joining us today. Maybe to kick things off-
My pleasure to be here, Joe.
Yeah.
Good to have you here as well.
Joe, just very quickly, a little housekeeping. Rob and I may make some forward-looking statements today, so please do refer to our SEC filings to reference those. We also may refer to earnings and guidance. If we do, we're referring to our most recent guidance as of our first quarter update. The same is true of any non-GAAP financial measures we discuss. You'll find a reconciliation in our first quarter earnings report. Thanks, Joe, and thanks. Happy to be here with you.
Yeah. Maybe just to start things off, obviously, a lot of progress at Jazz over the past year. Maybe, Ken, if you want to give us a brief update on what we've seen with the business, where we're headed, and maybe specifically over the next three to five years, where do you see the oncology business headed for Jazz?
Right. John, would you like me to start.
Yeah, Rob, why don't you dive in there, as the oncologist?
Sounds great. Thanks for the question. Incredibly exciting times for us at Jazz. This is now my seventh year at Jazz, and it's been quite a journey building a pipeline, building R&D, and increasingly having an important stake in oncology across a number of different programs. For zanidatamab, starting with the approval in second-line BTC, this was a major accomplishment. We also saw an approval for MODEYSO in high-grade glioma, an area extremely high on that need, and also expansion of ZEPZELCA into the front-line for extensive stage small cell lung cancer, where we think ZEPZELCA will be the most impactful. In terms of our pipeline beyond the most recent approvals, I would emphasize zanidatamab and the incredible opportunity that that provides. You've seen the top-line data for the GEA trial, front-line GEA trial. We're expecting publication in a top-tier journal, hopefully in the very near future.
Our process for submissions globally are underway. We have breakthrough designation in the U.S. as well as real-time oncology review and priority review, giving us a PDUFA date of August 25th, and we are expecting approval on or before that date. We are also expanding out in other areas for zanidatamab. We have a trial in later-line breast cancer, post ENHERTU, which is accruing very well, and we said expected to complete its accrual mid-year next year, with results as early as late 2027. We also have an opportunity from a basket trial that we're conducting with zanidatamab, where we potentially could get a pan-tumor or tumor-agnostic indication, and that continues to progress as well. An early pipeline also that continues to grow and progress. For oncology, really exciting times for us.
Great. Excellent. Maybe just because it's been such a large investor focus, we can start off with first-line GEA. I guess first we have to ask, are there any sort of updates on the progress of the regulatory review for frontline GEA, and maybe what's the team doing now to make sure that you're ready for a potential launch, given that it is under RTOR, and could essentially come any day?
Sure. Yeah, without commenting on details of regulatory interactions, which we don't do, there has been a steady flow of information that we have put into the public. We said we had RTOR, and if you back-calculate from an August 25th PDUFA date for priority review, we would have completed that submission at the end of February. With real-time oncology review, we would have had the opportunity to provide data sets ahead of that to enable the FDA's review. Now, we only had data through the end of November, so it was a pretty rapid, very proud of our team for so quickly mobilizing to get these critical data and information to the FDA.
We didn't have a lot of time in there, nonetheless, we were able to leverage RTOR to facilitate even the FDA's review, even ahead of our completing the submission at the end of February, which is what's set for the PDUFA date. We were pleased to get breakthrough designation and of course, pleased to get priority review. We think we're on track for an approval by or even ahead of that PDUFA date.
When you think about-
We're expecting a publication in a top-tier journal, and as soon as we have that publication, we will update NCCN. There is a possibility of a NCCN adoption even ahead of an approval.
Great. When we think about a potential label, maybe can you go into some of the data specifics that give you confidence that you can get a broad PD-L1 positive and PD-L1 negative label? Is that your expectation? Maybe when you think about, in a triplet regimen potential combination partner, do you think you'll be agnostic to combination partner in real world practice? How will that kind of.
Yeah
Factor in when you think about the PD-1?
Let me start by just telling you what I think the data showed. The experiment was designed to test head-to-head zanidatamab versus Herceptin. Those results are clear. Zanidatamab definitively beat Herceptin, no matter how you looked at the data, which endpoint you looked at, and Herceptin really should be a historical regimen. I think that's the most important thing. For these patients, the first decision a doc faces is, how do I address the HER2-driven disease? Now there's a new standard of care, I believe, with zanidatamab as frontline GEA. The next question is, would patients benefit from a PD-1 inhibitor? Lots of prior data with PD-1 inhibitors in gastric cancer broadly clearly established, although only in the PD-L1 positive subgroup. All of the labels have that limitation of use in our PD-L1 negative patients.
Certainly in HER2 positive gastric cancer, KEYTRUDA demonstrated a benefit, again, in PD-L1 positive patients. Lots of prior data that a PD-1 inhibitor is effective in gastric cancer, HER2 positive or HER2 negative. This trial was designed to look at that as well, as you know, with the third experimental arm where we added tislelizumab. I think the data are also definitive across PFS landmarks as well as overall survival, that adding a PD-1 inhibitor, and tislelizumab in this case, is adding benefit. The study wasn't powered to show a difference between the two experimental arms, it certainly is definitive when you look at Arm C with tislelizumab compared to Herceptin chemo, with a 26-plus month median overall survival versus less than 20 months.
Clear that tislelizumab is adding benefit, and importantly, in both populations of PD-L1 positive or negative, I think the data are clear there. They contrast all prior data, you might say, well, why would that be the case? How do you explain this? We think the differentiated mechanism of action that zanidatamab has is explaining this. We know, as has been published in Nature Communications, that the mechanism for zani is different than even giving the combination of two antibodies like Herceptin and PERJETA, and the reason is that zanidatamab binds to two different receptors. Once the antibody binds to one receptor, the other open binding site can't reach around on the same receptor. It has to grab another receptor, and that causes receptor clustering, internalization. It also creates an opportunity, importantly, for a complement to be fixed and the complement cascade to be triggered.
That in addition to a highly active Fc fragment, which recruits NK cells, so-called ADCC, and recruits macrophages, so-called ADCP, we think we're creating inflammation at the tumor site that then synergizes with this one. We think the data support a broad label around PD-1 or PD-L1. Ultimately, the study was done with tislelizumab. That's where we generated the data. I think there's a lot of information that PD-1s broadly work in gastric cancer. We are generating data as well, through an investigator-initiated trial with KEYTRUDA as well. However, really no obstacle to using tislelizumab within the set.
Great. How large of an opportunity do you think the frontline GEA opportunity is in the U.S. and ex-U.S.? Maybe has that changed at all after you've seen the full data from the trial in your mind?
Well, our estimates are there are about 8,000 HER2-positive patients with GEA in the U.S. Sometimes those data could be refined, but I think importantly, because the results of the zanidatamab trial are so definitive, there's a real impetus for docs to ensure that they know the HER2 status of their patients, and they have the opportunity to give zanidatamab or tislelizumab or another PD-1 inhibitor. You mentioned about are you ready to launch? Sorry, I didn't answer that question when you mentioned it earlier, but we certainly are ready to launch by the time we get approval. There are a number of things that have facilitated that. As you know, we're approved in second-line biliary tract cancers.
Yeah
Is approved in second-line biliary tract cancer. These are the same community and academic treaters as gastric cancer. We're already out there on the market. We have the opportunity for an early NCCN adoption. We are already able with our MSL force, obviously we're not promoting, but we're able to do critical education that's necessary to sort of prepare for the launch. We do feel confident that it'll be a strong launch.
Maybe on that, how rapid, I guess, do you expect the launch to be? Is it going to kind of roll out at physicians at targeted centers first before expanding? How do you think this will be incorporated in terms of that? Second, the company does a really good job at kind of breaking out the narcolepsy and IH population with Xywav, and you can kind of see the contributions from each indication in that therapy. Is that possible with Ziihera where you'll be able to see this portion is BTC, this portion is GEA, or how will we know how the launch is going?
Yeah, I'll be careful to stay in my swim lane, so to speak. As the R&D guy, I won't comment on things that I'm not familiar with. John may be able to help me out there.
Okay.
Again, I'm not in a position to comment on the projected speed of adoption. I'll just reiterate that the data, this is the first time we've seen survival data over two years, with a median of over two years. This is a very poor prognosis disease. Half the patients don't make it to second line.
We certainly will be out there, the medical affairs group, educating on the importance of doing the testing and adopting this therapy in front line, zanidatamab with a PD-1 inhibitor, in order to ensure the best outcomes for patients. I think one thing that facilitates that, as I mentioned, is the data are consistent across PD-L1 subgroups, so there's no need to wait for that test result to come back to make a treatment.
Joseph Thome, in terms of differentiating BTC sales from GEA sales, they are different dosing regimens, but the GEA population's much larger. We expect the growth that we see in Ziihera to be really driven by GEA uptake. It's very hard for us, Robert Iannone mentioned the overlap between the physicians, so it's hard for us to see sort of differences in prescriptions, BTC versus GEA. We'd expect it to be driven by GEA, and really, revenue's the biggest metric to look at, as we start to see the launch unfold.
Perfect. Maybe we'll turn over to the breast cancer indication. I guess, can you just highlight a little bit what gave you the excitement to go into the breast cancer study? Relatedly, with GEA, it was pretty, quote unquote, "easy" to kind of guess what the comparator arm was going to do because we had a couple trials to go off of. Post ENHERTU in the breast cancer setting, I think data's still kind of developing there. What do you think the comparator arm is going to show? What did you power the trial for that comparator arm in breast cancer?
Yeah. Just to start with why I go into breast cancer. Especially as we turned over more and more cards, and that started with the second line BTC trial that led to the approval. Additional data in breast cancer front line, later line with chemo, combination with novel agents like CD47, combination with non-chemotherapy agents in the ER positive group. All of this has been published with palbociclib and fulvestrant, for example, demonstrating that there's activity despite the fact that patients would've received multiple prior HER2 therapies.
Sometimes including not only Herceptin, PERJETA, T-DM1, possibly tucatinib, and in many cases ENHERTU. The differentiated mechanism of action giving us confidence that it would be active even in later line breast cancer. We also saw an emerging gap in the data as ENHERTU moved to front line. Many breast cancer oncologists approached us about this to say, As ENHERTU gets to the front line, there'll be a gap in the data as to what to use. You alluded to the fact that, how do you know how trastuzumab will perform in this setting? The treatment landscape has evolved. The fact is that we had to make some assumptions, but it probably is evolving over time. We'll have more data to substantiate that.
This was an opportunity for us to get into that later line post HER2 space as an initial foray into breast cancer, not necessarily the only thing that we'll do in breast cancer, especially as we gain conviction around molecule. Specifically to your point, I won't say what our protocol assumptions were. We cannot share that level of detail. However, we use the data that are out there, and we do recognize that that's probably evolving as we see real-world databases coming out post ENHERTU.
Maybe to wrap up the zanidatamab part of the discussion, the company historically had put out this sort of $2 billion potential for the asset. I guess now that we have more clinical trial data, when do you think the company might be in a place to revisit that number? Or, do you think that's still the right number when you include BTC, GEA, and breast cancer? I guess, how do you see that kind of peak potential evolving?
I'll stay with my pattern of giving all the hard questions to John. Maybe I'll start and just describe how I see the zanidatamab development program evolving, say from the time we first made that statement, which was actually a $2 billion-plus statement. A lot has happened in terms of data that we've generated.
We've now been in the marketplace with BTC, and we're confident that it's performing the way you expect based on the data. Our frontline BTC trial is progressing as planned. As John pointed out, that's a smaller population, but very important. For frontline BTC patients, again, many of them don't make it to second line. There's no approved HER2 therapy, so our experiment is versus nothing. It's in combination with a PD-1 or a PD-L1 inhibitor, and we now know, as we discussed earlier, from the GEA trial, that we're clearly seeing synergy.
In an opportunity where you're against no other HER2 agent, and you have the opportunity to synergize with immune therapy, we think that's a high probability of success trial, and that will expand our markets in BTC frontline, and hopefully change practice around identifying those patients early. We then saw the GEA data, which we've talked about.
I'll speak for myself. I was optimistic about a positive trial outcome. I think this even exceeded what I might have predicted at this first interim for an overall survival.
The PFS benefit was substantial across both arms. The overall survival benefit was substantial. Of course, it was only the triple that was stat sig. Remember, stat sig is a function of how much alpha you put against it, and we only put a small amount of alpha as the first interim. Arm B still showed over 24 months median survival, compared to less than 20 months. I think the results are definitive, and I think that probably drives the level of enthusiasm. Plus, the idea that now this is the whole population, in combination with a PD-1 inhibitor, where you would expect the duration of therapy to be longer. We've seen that in the trial. I think we could be sanguine about the opportunity in frontline GEA.
Rising tide lifts all boats, as they say. Certainly as you accumulate data and you gain confidence and conviction about the drug, I think you increase your confidence in other areas. Breast cancer is the next area that's very important to us. We talked about the trial that's ongoing. You and other listeners may be aware that we're very interested in early breast cancer. We have a collaboration with I-SPY, a collaboration with MD Anderson, we have our own ongoing trial, which is a phase II. We hope that that will ultimately lead to a phase III in the neoadjuvant space. Speaking of neoadjuvant, while we haven't made any definitive plans here, we certainly are interested in, are there other areas of gastric cancer where HER2 might be used? Again, early gastric cancer, no approved HER2 therapy.
We now see that Imfinzi is approved there, very similar to frontline BTC, where we'd be against nothing, in combination, possibly synergizing PD-1. Back to breast cancer. I think there's other areas we could explore. We have a partnership with Boehringer. We have a partnership with Iambic. As we see these novel TKIs come up and seem to be differentiated, good evidence that the combination of an antibody like zanidatamab with TKI could be also synergistic. TKIs tend to raise the expression level. Plays right into zani's mechanism of action around clustering and immune activation. We see that combination potentially being studied in other breast cancer settings as well, and we'll see as the phase II data emerge, what we'll be able to do there. I think that combination could be relevant in other settings as well. We touched on the Basket trial.
That's important for a couple of reasons. It is an opportunity to get a tumor-agnostic indication, which we know is possible in this area of HER2-positive disease. It's also giving us a chance to further explore tumor types like colorectal cancer and non-small cell lung cancer, for which we had some prior data, but we're looking to extend our observation to understand whether we could get into those areas as well. We published frontline data at ESMO for colorectal cancer. We had previously published later line monotherapy data for colorectal cancer. It's an interesting space that we're following careful. When we had said $2+ billion, I think it was really around BTC, GEA, and the one breast cancer trial that we had started.
I think we clearly are beginning to put into place plans that could extend the value of zanidatamab, but we haven't put a number to that.
Great.
John, what would you add from that?
No, I think you said it well, Rob. It's a $2 billion-plus peak sales estimate, and now that we have the data from GEA and we're in these new areas, it's an area we'll look at and see if it's appropriate to refine going forward.
I think one of the nice surprises to the Q1 financials was ZEPZELCA's strong performance after moving into the frontline. I guess, how should we think about continued performance of that asset?
Thanks for asking about ZEPZELCA.
Yeah.
We're really proud of that. When we brought that asset in, which was positioned as a second line, we pretty quickly recognized the opportunity in frontline. We saw that patients progress rapidly after finishing their induction chemotherapy, and an opportunity to use a drug like ZEPZELCA, which we felt was very well-tolerated. There was some resistance to that because many docs said, coming off of platinum therapy, patients don't want to get another therapy.
We proved that you could do it, and you could do it safely and with significant benefit. Also that that is the time to intervene. The progressions are so rapid, many patients don't make it to second line. Also to sort of preempt that progression, or stall the progression, that's important from a quality of life perspective as well. Of course, we also saw an overall survival benefit.
Part of our rationale, in addition to preempting that progression as a maintenance therapy, was that we had phase II data in second line. We had some preclinical data suggesting that there could be a synergy with immunotherapies. The ASCO abstracts are out now. I don't know if you've had a chance to start to sort through them. I'll call your attention to one on ZEPZELCA that looks at the impact of tumor-associated macrophages. These are immune cell that cause immune suppression and can interfere with the benefit that you might see from a PD-L1 antagonist like atezolizumab. We looked in the IMforte study, and in fact, it proves what has been known before. Tumors with high tumor-associated macrophages don't do as well when they get atezolizumab.
On the other hand, the combination arm did quite well, and so clearly, giving the combination for those patients who might otherwise be somewhat resistant to the immunotherapy is rational based on these data. Again, evidence of synergy, and I think the key message there is ZEPZELCA is going to have its best effect in front line. It's going to have an effect across the populations that were studied. It's not dependent on a biomarker the way DLL3 might be. I t seems to be synergizing with immunotherapy. Give it up front with immunotherapy, don't save it. And that really has been our focus at the promotions front.
Great. With that, unfortunately, we are out of time for the session, but thank you both for joining us. I know we'd also didn't get through MODEYSO and the BD activity in oncology potentially this year. Give investors something to wait for next time. Thank you both again, and thanks to everyone for tuning in.
My pleasure.
Thank you.