David Amsellem: Hey, thanks. Can you talk a little more about Epidiolex and what drove the performance? Are you seeing double digit volume growth, both US and x-US? And was there any stocking benefit that we should be aware of? Thank you.
Bruce Cozadd: Thanks for the question, David. Renee, maybe I’ll turn that one over to you.
Renee Gala : Sure. Yes, happy to comment. So as we look at Epidiolex, as we’ve said in the past, we tend to see a more gradual buildup over the second half of the year. And then that works off over the first half of the year. We saw a very small amount of that in the fourth quarter in terms of buildup. But we are seeing continuing demand growth. And we’re seeing that across both the US as well as in Europe. We’ve said in the past what continues to resonate with physicians, providers, patient is really the understanding of some of the beyond seizure benefits as well as the synergistic effect we’re seeing with clobazam. We see continued opportunity in the adult segment. That’s an area we’re starting to focus a bit more on. And that we expect to be a driver of growth in 2024.
And then more broadly, as we look at how Epidiolex is viewed in the market as the number one branded treatment, it continues to be seen as a very well characterized and tolerated drug, which means that lends itself well to polypharmacy. That’s the norm in this area. And the data that we continue to generate both as I just described in terms of with clobazam and the data beyond seizures and just further understanding of these effects that you’re seeing is creating greater demand from our physicians stating they intend to use it earlier in their process of this polypharmacy with patients. We are seeing growth outside the U.S. as well as I mentioned, so we’re continuing to both launch in new geographies and then add indications within existing geographies, and so that growth is proceeding nicely as well.
Operator: And we will take our next question from June Lee with Truist Securities.
June Lee: Thanks for the update and for taking our questions. When you do report top line data from Suvecaltamide essential tremor, well, you have a Go-No-Go decision when you report a top line, or is that something that you still have to consult with the FDA in an end of Phase II meeting before being able to comment on a Go-No-Go decision? And is the advancement into Parkinson’s disease dependent on the outcome of ET, or are they independent events? And just quickly, anything you can share on the latest on orexin program. Thank you.
Bruce Cozadd: Okay, so the first part of the question was around essential tremor, and I would say in general our practice has been to share top line data on a timely basis. Whether we comment precisely at that time on next steps, remains to be seen and remains to be, it remains dependent on the data. But in general, our view is we know what we need to move this program forward, so I’m not sure that barring a surprise in the data, that would involve a different regulatory interaction. Rob, anything else you want to add on ET or on orexin?
Rob Iannone : I would just say that with regard to ET, I agree with you that, we’ll see the data and we’re not expecting to have to talk to FDA before providing some guidance on that. It certainly is positioned as a pivotal trial. We’re very excited about it given the high unmet need. There hasn’t been an approved drug in 50 years and what’s available there is pretty poor. We think we have a differentiated mechanism action and a best in class calcium channel modulator. Certainly this trial was built to be part of a pivotal program, so I think it’ll be quite informative when we do see the data. I don’t think Parkinson’s disease tremor is a direct read through, but certainly strong data and essential tremor would give us more confidence in this target overall. And then finally on the question of orexin, there are no updates there. We’re on pause while we’re examining the safety findings that we previously characterized.
Operator: And we will take our next question from Gary Nachman with Raymond James
Gary Nachman: Hi, good afternoon. So on zani, just what’s the timeline for expanding further into breast cancer? Will you be doing that in parallel with BTC and GEA? And then, regarding increasing the size of the GEA trial, just describe what you hope to see from that interim OS data. And next year, is it possible that GEA could contribute to the sales of zani and not just BTC? Thank you.
Bruce Cozadd: Rob, I’m going to turn this one over to you.
Rob Iannone : Yes, so similar to the answer I gave previously, we have been working in breast cancer already, both in the metastatic setting for HER2 positive cancer, and then we published recently on HER2 Positive, ER Positive Breast Cancer at San Antonio last year. We published on early stage disease. So we have been working in breast cancer and publishing on those data, and we are progressing further development plans in those areas. It’s not dependent on any other readout. With regard to the changes to the GEA study, again, we made those changes to ensure better power for the overall, final overall survival endpoint. We plan to read out the progression-free survival based on the original sample size, so that it has no impact on the overall timeline.
And we know from health authority interactions that in this setting, PFS is adequate to support approval. It’s usual and typical to do an interim analysis, albeit early on OS at the time that you’re looking at PFS. And generally health authorities just want to be sure that something funky is not happening, that you’re not seeing somehow a detriment in the OS. But there’s not an expectation that OS on that first interim would be well-powered. Then of course we have the second interim analysis, which is occurring around the time that it would have on the original trial, which is why we believe we sort of have our cake and eat it too, if this change. And then on the mature OS data, we’d have more power.
Renee Gala : And then with respect to –
Rob Iannone : I mean, in terms of, sorry, I didn’t get to the — didn’t address the question on revenue in 2025. There’s a scenario where we are, given what we’ve shared around BTC, that we are on the market for BTC. And as we read out the data for GEA, we certainly have a faster path as a supplemental in the US to get an update to the label. But we certainly will also publish and seek compendia listing even while we are progressing the supplemental BLA.
Operator: And we will take our next question from Akash Tiwari with Jefferies.
Unidentified Analyst : Hi, this is Avee on for Akash. Thanks for taking our question. Just a quick one on zani in GEA. So given the mechanism similarity between Herceptin Pergola combo and zani, why do you think their Phase III GEA trial, JACOB, failed? It doesn’t seem to be like HER2 expression related, given the treatment arm enrolled roughly similar HER3 population compared to the comparator arm, which is Herceptin plus chemo. So is there anything you are doing differently in your trial? Thanks.
Bruce Cozadd: Rob, you want to take that?
Rob Iannone : Yes, happy to, Bruce. So first of all, while the epitopes on zanidatamab do correspond to the same epitopes that Herceptin and pergola independently bind. The reason zanidatamab is differentiated is that when they occur, when they’re positioned on the same antibody, what you get is binding of the two FAB fragments of the antibody on different receptors. And it causes receptor clustering, which enhances interference of signaling, whether that be through HER2 or interference of dimerization with HER3 and therefore interference of signaling with HER3, internalization and marking the cells for immune destruction. A lot of this experimental data was published in Nature Communications and includes some really nice data showing this clustering effect that occurs with the bipartopic antibody and showing that it induces complement dependent incited toxicity, which is unique amongst any HER2 antibodies, and also some experimental data comparing head-to-head to just combining those two antibodies separately.
So we think we actually have a differentiated drug that will be more effective than giving the combination. And our clinical data, by the way, support that. So we have activity in patients who have progressed on the combination of Herceptin and Pergola with breast cancer. So I think our preclinical data show the differentiated mechanism, and the clinical data are showing better results, whether it be in breast cancer or also in BTC, where we seem to have better results than when you give Herceptin, Pergola to BTC patients.
Operator: And we will take our next question from Charles Duncan with Cancer Fitzgerald.
Unidentified Analyst : Your line is open. Hi, this is Acia, on for Charles. We have a question on Epidiolex. So given the Phase III readout in the second half of this year, can you talk a little bit about the addressable market and opportunity in Japan compared to the opportunity in the US. And also you did mention additional market launches this year so I was wondering if you can provide a bit more color on this. Thank you.
Bruce Cozadd: Yes, Renee, let me turn that one over to you.
Renee Gala : Sure, yes, I’m happy to jump in there. So for Japan, we’re excited to be able to have made the progress that we have in that geography. There’s about 20, 000 patients across three different indications that we think provide quite an important opportunity in Japan obviously is the second largest pharmaceutical market in the world. We have now the opportunity, not only with Epidiolex, but also zanidatamab to be able to have meaningful opportunities in that market. So we do expect the top line results in the second half of this year, and we’re pleased also with the progress we’ve made to be able to see changes to the Cannabis Control Act underway, which will enable that eventual launch. And then in terms of outside the US, as we think about the progress that we’re making there, we’re already approved in more than 35 different countries.
We do have some additional launches and reimbursements anticipated through the end of 2024, and I would think of that as gradual updates as we go. We are already approved and reimbursed in the five main large markets in Europe. So what we’ve been doing over the course of ‘23 and ‘24 is really focused on ensuring we have the full indication set available in each of the countries. We’re continuing to be able to execute partnership agreements to ensure that either if we’re not going direct, we’re making the product available through our partners, and we’ll expect that to continue over the course of 2024. And given we’re now in a place where we’re annualizing at more than $900 million, we see the product as being very much on track for blockbuster status.
Operator: And we will take our next question from Jeff Hung with Morgan Stanley.
Michael Riad: Hi, this is Michael Riad on for Jeff Hung. Thank you for taking our question. On the high sodium authorized generics, what evidence generation is needed to support the long-term health messaging and drive patients towards the switch to low sodium? Or do you think that the majority of the narcolepsy and IH community are more or less aligned with the benefits given the need for lifelong treatment? Thank you.
Bruce Cozadd: Yes, I would say the evidence surrounding the impact of sodium on cardiovascular health pretty incontrovertible. I certainly underlined the original Orphan Drug Exclusivity Decision by FDA determining that Xywav was clinically superior to Xyrem on the basis of that lower sodium and the same thing could be said for Lumryz which has the same sodium level as Xyrem. That doesn’t mean there aren’t opportunities to bring out more data as we have already, including with our presentation at the neurology meeting last year that within a period of 180 days of starting high sodium oxybate therapy, we saw patients have a significantly increased either diagnosis of hypertension or getting antihypertensive med. So even in a short period of time, you see that impact on people, even if they aren’t already diagnosed as being hypertension patients, which is again why that original determination was that Xywav would be a safer product in all narcolepsy patients who are known to be at high cardiovascular risk to begin with.
Operator: And we will take our next question from Joel Beatty with Baird.
Joel Beatty: Hi, thanks for taking the question. For zanidatamab, how much of the $2 billion in peak sales potential projection comes from breast cancer? And are you able to give a sense of when we might see data in that setting from the I-SPY2 and MD Anderson collaboration trials?
Bruce Cozadd: I’ll take the first part of that and Rob, hand the data part of it over to you. We have not provided a breakdown of the opportunity set for zanidatamab which we believe is extensive and certainly in our slides you can see that while we have made the most commentary thus far on BTC and GEA and breast cancer, it certainly has potential beyond those indications as well, which is why we say north of $2 billion, we haven’t fully quantified how big the product could be as we determine where else to take it. We’ve got our near-term priorities work out and looking forward to sharing a little more information at our R&D day. But on timing of data, Rob, maybe I’ll turn that one over to you.
Rob Iannone : Yes, for the MD Anderson Neoadjuvant study, some data were already published. You may be aware of that December at San Antonio. That trial is ongoing and I would expect some updates. They haven’t indicated exactly when the updates will be published. On I-SPY, which is a little bit late, it started a little bit after that trial, really depends on the enrollment rate and the results and when that might graduate from that phase. And so we don’t have any specifics at this point. But we are pleased that the trials are ongoing and we’re excited to see how that may inform next steps in that early stage space where we think zani is particularly well positioned to provide a better tolerated option for women with curative breast cancer.
Operator: And, ladies and gentlemen, we have no further questions at this time. I will now turn the call back to Mr. Bruce Cozadd for closing remarks.
Bruce Cozadd: Thank you, operator. I’d like to close today’s call by recognizing our Jazz colleagues for their efforts and thank our partners and shareholders for their continued confidence and support. Thank you all for joining us today.
Operator: Ladies and gentlemen, this concludes today’s call. And we thank you for your participation. You may now disconnect.
