Jazz Pharmaceuticals, Inc. Deutsche Bank 2026 Healthcare Summit

Potential synergy that you can get when using zanidatamab, a highly immune-active antibody, in conjunction with immune checkpoint inhibitor like tislelizumab. Really pleased with that, and on the heels of it, remember we had stat sig overall survival benefit for the triplet arm at the time of the first interim analysis with two additional scheduled OS analyses. At that time, the arm B or the doublet arm was trending very favorably but not quite stat sig. On the second interim analysis, we now have a stat sig result for the zani-chemo versus the control arm. Encouragingly, as we said in our press release, the hazard ratios for both of the experimental arms continue to improve even from the first interim analysis when you look at the overall survival, which is consistent with highly immune-active drugs, where you tend to see that benefit beyond the medians.

Later on that curve, you see more durable benefit, and you would expect to see the curve separate. We are excited to publish those data as soon as we can at an upcoming medical conference. Just quickly mention some other areas that we are leaning into on Ziihera. We have our frontline BTC trial, which is well underway. We have our late line. That is pivotal trial. We have our late line breast cancer pivotal trial that is well underway. We also have a pan-tumor trial that could get us a tumor-agnostic indication, meaning any patient whose tumor overexpresses HER2 and is refractory to standard therapies could potentially get it. Within that trial, we have had some interesting colorectal cancer results.

That combined with other data we had earned us breakthrough designation with the FDA, and we are working with them to plan on an approval path in colorectal cancer while we pursue broader indications, potentially even including non-small cell lung cancer. Clearly, Ziihera has made a lot of progress. We think its unique mechanism of action is highly differentiated and is really best in class, going to be a new standard of care in biliary tract and gastric cancer. We are investing heavily behind that, as I mentioned, in our pivotal trials. Super excited about our epilepsy portfolio as well. We announced recently that EPIDIOLEX, which has a very long period of exclusivity into the late 2030s. We are initiating four new clinical trials, as well as having submitted an application for a solid oral dose or capsule formulation.

Those new trials include a phase II in focal onset seizure as a kind of evidence generation trial. It includes a phase II/III potentially pivotal trial in juvenile myoclonic epilepsy. It includes a phase III in a broad array of DEEs. Of course, we have an indication for seizures associated with three orphan DEEs, so this potentially will broaden that label even further. We have an evidence generation study in LGS in adults to further support the use in that setting. Super excited about EPIDIOLEX and its impact it is having and the longevity there. We certainly think of ourselves as an epilepsy company. We have mentioned in the past, we have two pipeline products, one for absence epilepsy in phase I, and we have now recently plan to bring our Kv7 into phase I, which we think is potentially a best-in-class Kv7 opener.

In addition to that, very pleased to say that yesterday we closed on the Actio deal. You haven't seen the data on that yet. I mean, we certainly have as part of the due diligence, and we hope those data will be published soon. We were very excited to be in another rare epilepsy where, in this case, we think this inhibitor addresses specifically a single gene mutation, which is responsible not only for the epilepsy in these patients but the developmental challenges that they experience. A targeted, personalized medicine here could make a tremendous difference based on the pre-clinical and clinical data that we've seen. Also excited that the ACTION trial for Modeyso continues to progress as planned, and we've reiterated the timing next year on the interim analysis for overall survival that would give us an early opportunity for approval in frontline high-grade glioma.

Currently, our approval is in refractory high-grade glioma. That's an interim analysis, so if it doesn't hit, the trial continues until completion. Lastly, just recently announced that our next generation orexin 2 agonist has cleared the IND and is expected to go into healthy volunteer studies this year. That's kind of the key highlights from my perspective. Maybe I'll pause there and leave it open to any questions you might have.

Yeah, thanks. Great question. We were interested in zanidatamab, I would say in the earliest stages because of the novel mechanism of action. This is the first HER2 antibody that had a biparatopic engineering structure. What that means is that each antibody actually has specificity for two different binding epitopes on the receptor. Now, those binding epitopes were selected because they were clinically validated. It is ectodomain 4 and 2. Those correspond to where Herceptin and PERJETA would bind. What differentiates it is when you put it on the same antibody, each Fab fragment of the antibody has to bind different receptors, unlike giving Herceptin and PERJETA together. When that happens, the antibody binds to one receptor.

The other Fab fragment can't reach that binding epitope on the same receptor, so it grabs a different receptor and pulls it in, and then sequentially happens with the additional antibodies. What that does is cause, and this was demonstrated in the Nature Communications paper, it causes receptor capping and clustering, internalization, but also importantly, fixation of complement. What really differentiates this molecule is it triggers the complement cascade, and that does not happen with any other antibody. It was also engineered to have a highly active Fc fragment. If you think of the antibody as a Y, the Fc fragment is what typically induces immune responses, recruiting macrophages and NK cells. You have complement cascade activation, you have recruitment of NK cells and macrophages.

You have an antibody that not only blocks HER2 and HER3 signaling internalization of the receptor, but triggers the immune system in a way that other antibodies don't. It is for that reason that we had the hypothesis that this could synergize with PD-1 inhibitors. When people were surprised that we had activity in the frontline gastric trial in the PD-L1 negatives, and I could see why that would be a surprising result, because four prior studies with three different PD-1 antibodies all showed no activity in PD-L1 low patients, including the KEYTRUDA trial in HER2 positive disease and including tislelizumab in the all-comers population. Yet our phase II showed we had activity in PD-L1 negative patients, and we think it is because of the immune activation that happens with zanidatamab. That mechanism of action is what really first got us interested.

It was early days, though, and we hadn't seen much clinical data, so our business development group made a $50 million bet to say, "We get an option once the biliary tract data come out, and if we don't like it, we walk away, and we give up the $50 million." We were very pleased with the biliary tract cancer data. As you know, over 40% response rate, very durable. If you look at the IHC 3+ population, which is what is in the label, response rate. That really is very differentiated from any historical data with Herceptin and PERJETA, which never achieved approval in that setting. We also thought they had very logical development paths, so fast to market in biliary tract, going after some clear white space where it could win in frontline gastric cancer, where only Herceptin was approved.

Then we felt the deal paid for itself on the basis of those two indications. But we also saw in the phase I data and based on the mechanism, the opportunity to go much further beyond that, as I described earlier.