Jazz Pharmaceuticals plc (JAZZ) Earnings Call Transcript & Summary

Hi, everyone. Thank you for joining us at our Third Annual Neuropsychiatry Summit. I'm Joe Thome, one of the senior biotech analysts here on the team at TD Cowen, and it is my pleasure to have with me today the team from Jazz Pharmaceuticals. We have: President and COO, Dan Swisher; the Executive Vice President and Global Head of Research and Development, Dr. Rob Iannone; the Head of Neuroscience and Clinical Development, Phil Jochelson. Thank you all very much for joining us today, and congrats on the progress. Over the past year, we have a few exciting catalysts that we're going to get into throughout the discussion, but maybe I'll throw it over to the team, if you want to outline maybe some of the top recent progress, maybe on the neuroscience business, but overall as well, and kind of your outline goals for the next 12-months.

Yes. Thanks a lot, Joe. It's great to be here. Great to have this opportunity to talk more broadly about the business, but also about the pipeline. So, just some quick housekeeping notes as we discuss the business today. I'm going to remind everybody to consult our SEC filings, specifically refer to our recent second quarter earnings announcement on August 9 for additional information and risk factors. If I note guidance today, it's referring to 2023 guidance provided in the second quarter disclosures. We may also refer to some non-GAAP financial measures today. For a full reconciliation, please consult SEC filings. All right. So back to kind of your question, over the past several years, Joe, Jazz has undergone a significant transformation. We're really excited about our vision, continued growth, delivering shareholder value. And when I talk about transformation, we talk about it, it's really in 3 key areas: it's our Commercial business and the growth and diversification of that; it's in our R&D organization, again, sort of growth in build-out and readouts; and then it's our Operations, including operating leverage. So I'm going to start with a few comments on the Commercial side, and have Rob fill out on the R&D. If people look back just a couple of years ago to 2020, we were generating $2.4 billion in revenue. That was primarily 3/4 of it coming from one product, which was Xyrem, our sodium oxybate product. You fast-forward to the most recent quarterly earnings, 50% of our net product sales are coming from Oncology and Epidiolex outside the Sleep business. And then within the oxybate revenue, the majority of that is now coming from our low-sodium oxybate Xywav. Our revenue for the first half of 2023 was $1.85 billion. It's given us the confidence with the business to raise the midpoint of our full year revenue guidance to $3.725 billion to $3.875 billion. And a lot of that has to do with the strength of the neuro side of the Commercial business, and we're focused there on Xywav and Epidiolex. We raised our full year 2023 financial guidance for neuroscience to at the midpoint to $2.715 billion to $2.825 billion. In the second quarter of '23, we saw year-over-year growth, 39% for Xywav and 15% for Epidiolex. So on the Oxybate side, we continue to focus our efforts on Xywav growing a low-sodium oxybate. It's annualizing well over $1 billion, and we're really pleased with the continued adoption both in narcolepsy and in IH. We're well positioned for the Oxybate franchise to achieve our stated goal of $2 billion of revenue for Vision 2025. And so we expect, within that $2 billion that Xyrem is going to continue to decline with Xyrem AG adoption. But our increased 2023 guidance in neuroscience reflects the performance and growth of Xywav during the first half and our continued bullishness for the product going forward. And this is in a period where we've seen the introduction of the AG and other branded high-sodium oxybate competition. Epidiolex, just to touch on that very briefly, double-digit year-over-year revenue growth that we saw, and that's driven by a global launch, which is continuing to gain momentum with additional indications and markets, but also in the U.S., growth factors we're seeing in terms of the combination data with Clobazam, educating about reported outcome with caregivers beyond seizure control, delivering on education and promotion initiatives and an opportunity we're seeing in a less-penetrated patient segment, which is the adult side of things. And then importantly, that's the Commercial side of the business. On the R&D side, we're approaching now the 4 late-stage data readouts through 2024. And I'm going to have Rob touch on a few of those. So Rob?

Great. Thanks so much, Dan, and really happy to be here. So shifting over to R&D, we are advancing our pipeline toward meaningful catalysts with the potential for as many as 4 late-stage data readouts through 2024. All 4 of these programs are addressing areas of significant unmet need. Within the neuroscience pipeline, this includes multiple near-term data readouts: JZP-150 or FAAH inhibitor in PTSD will have a readout late this year; JZP-441, orexin agonist program will have an initial proof-of-concept in healthy volunteers also this year; Suvecaltamide, our [ CAP 3 ] inhibitor for essential tremor is expected to have top line data in the first half of next year. The Epidiolex trial in Japan is ongoing and progressing well, and we do have multiple other early-stage neuro programs that are either ongoing or planned. And then on the Oncology side, we have 2 important Phase 3 programs reading out in the near term. Zanidatamab, our bispecific, biparatopic HER2 antibody in gastroesophageal adenocarcinoma, the Phase 3 top line data are expected in 2024. And Zepzelca in first-line small cell lung cancer where the Phase 3 top line PFS data are expected as early as the end of 2024. I'd also say that underpinning our Commercial and R&D progress is a real focus on operational excellence. We have disciplined capital allocation that includes investing not only in our Commercial brands to drive the top line growth, but also investing in our pipeline to drive longer-term growth. And corporate development remains a priority where we are actively engaged in assessing opportunities. Corporate Development is a key part of our strategy, both to deliver sustainable growth and enhance value to our stakeholders. And we do believe there are a number of attractive on-market or near-market opportunities that would be really good strategic fits for our portfolio. Throughout the first half of 2023, we delivered strong Commercial results, advanced our efforts to unlock the tremendous potential of our growing pipeline and built on our record of driving operational excellence. And our focus remains squarely on execution in the second half of the year, as we continue to drive toward our Vision 2025. So that's a quick snapshot of the business, and maybe this would be a good time, Joe, to get into Q&A.

Sounds good. Thank you. Definitely a lot going on.

Maybe we'll start with the PTSD readout. Maybe, can you touch a little bit on the unmet need here. It seems like it's been a couple of decades since we've seen a new therapy kind of make moves here. So maybe how large can this market be? And maybe why haven't we seen successful therapeutics for PTSD being developed?

Yes, Joe, thank you for the question. Thanks for your interest. And we noted your landscape work as well, so -- which is largely consistent with the way we saw it when we started this work. Yes, it's a huge unmet need. The global public health problem is associated with significant morbidity and mortality, 8% of adults during their lifetime will experience PTSD, and that translates to 2 million patients in the U.S. with therapies that are suboptimal and have not really moved in quite some time over the last couple of decades. So, we're excited for the opportunity there, and we think we're well positioned with the study we have ongoing; and in particular, new mechanisms of action to tackle this disease. And maybe, Rob, you could just talk to the JZP-150 mechanism.

Sure. So as I mentioned earlier, JZP-150 is a Fatty Acid Amide Hydrolase. This is the enzyme that metabolizes anandamide and anandamide is an endocannabinoid. Stress and stress-related conditions such as PTSD have been shown to be associated with lower levels of anandamide. And by inhibiting the degradation of anandamide, we therefore, increase levels of anandamide. And this is believed to play a role potentially in improving PTSD symptoms. Specifically, JZP-150 is an irreversible inhibitor. So, it completely inhibits FAAH until the body synthesizes more enzyme, and we think this could provide better long-acting effect. We have confidence -- this is a proof-of-concept study, but we have confidence on the potential here based on prior studies that have been done with JZP-150, 2 separate trials: One was, a Phase 1b evaluation in healthy volunteers and what we call a fear extension model, that was about 60 randomized patients. There are also data in a completed cannabis use disorder study showing improvement in anxiety. And both of these trials support both with the underlying mechanism, but also evidence from these trials further evaluation of PTSD, which is ongoing.

And maybe can you touch a little bit on the ongoing study? What sort of patients are involved? Or did you exclude any certain patients? And is there a clear benchmark for what physicians want to see in terms of a clinically relevant reduction in the CAPS-5 score?

Sure. Let's -- Phil, why don't you tackle that one?

Great. Thank you, Dan. Yes. So, I'll start-off by saying, this is obviously our first study in the PTSD patient population that will clearly provide us important data with respect to the future development. As you mentioned, CAPS-5 is the primary endpoint for this study. And as Robert mentioned earlier, I think as well, and people know this is also where an endpoint that appears to be acceptable to the regulatory agencies. I will say that, yes, we're going to be looking at it as the primary and we'll be looking at this change in the CAPS-5, which is capturing multiple symptom clusters and disease severity across the 12-week period. And it's a placebo-controlled study with 2 dose levels, 2 active doses relative to placebo and is adequately powered to detect differences relative to placebo. Importantly, this PTSD is a 24-hour disease. And Rob talked earlier about having this irreversible FAAH mechanism, FAAH inhibition. We have the sustained levels of anandamide, which could translate into good disease control. So pharmacologically, it fits well with the type of disease that this is. So the target enrollment is a total of 270 patients, with the DSM-5 defined PTSD, these are DSM-5 classification of the disease, which outlines the diagnostic criteria. The CAPS-5 actually is built of their DSM-5, which captures many of those symptom clusters, as I had mentioned previously. And patients, as I mentioned, are randomized to either 0.3 dose or 4 milligram dose or placebo for the 12 weeks. We have top line data that, we're expecting to have in late-2023. And just to hit your point about who have been excluded, we did exclude combat exposure as this first foray into the PTSD population. I will start off by saying combat exposure is actually the minority of the PTSD population, although many people have awareness through it being a, through public domain, it seems to be more heightened. But in terms of the prevalence of the disease and where it actually occurs most frequently is actually the minority of patients. But the combat exposure have been shown to be probably the most treatment-resistant of all the other populations, historically. And we felt is our first proof-of-concept study that we wanted to get a clean result around the proof-of-concept to inform the development program, moving forward.

Perfect. And we've seen in some other trials of neuropsychiatric conditions like depression and schizophrenia that the placebo response can vary kind of substantially between different trial settings, I guess, is that also the same case with the CAPS-5? And are there ways that the company is looking to mitigate this?

Dan, do you want me to take that?

Please. Yes, just continue.

Yes, Dan. All good. Yes, great. Yes. So I think, it's important that to recognize that CAPS-5 is actually a fairly new endpoint, right, both of the new DSM-5 criteria. And there's been very few and limited sets of data that have actually emerged using CAPS-5 an endpoint. So we don't know a lot around a substantial amount of data that has emerged around placebo response. There has been some very recent publications around that. But I will say that we have a very adequate and well-controlled, randomized placebo-controlled study that we had designed with a lot of thought and input from the key opinion leaders around this to detect what we think will be adequate changes relative to placebo, assuming the drug is effective. We have taken into account what measures around, how that could mitigate placebo response. Understanding that in neuropsychiatry, you can't mitigate it completely, but we certainly take that into our design and with respect to our powering for the study to be able to give us a definitive readout for that study to inform future development.

And we recently saw some data from Lundbeck and Otsuka for brexpiprazole, where it looks like maybe the flex-dose worked and the fixed-dose trial didn't. I guess, is there anything that can be taken from that study, in particular as it relates to your program at all?

Yes. Go ahead.

One thing I would highlight, Joe, is that JZP-150 is really a distinct mechanism of action. So without going into details of the results of the study, I would say that it's a different opportunity to address what we think is an underlying pathophysiology around reduced anandamide levels in patients with PTSD. And so, I think there's room for significant improvement even with the slightest results, and pretty excited that JZP-150 with its novel mechanism of action has an opportunity there.

And when you think about the mechanism of 150 that we walked through before, is this applicable to other neuropsychiatric conditions as well outside of PTSD, if it works here? Are there other clear indications? Or are we thinking about a potential expansion if at all?

Potentially so. I mean, we know that other disease states have perturbed endocannabinoid physiology. An example of that in the literature would be Autism Spectrum Disorder where again, anandamide levels are known to be reduced. So there may well be other places that this mechanism could be active. But for the moment, we're focused on PTSD. We're excited to have a readout by the end of the year, and see where that takes us.

Perfect. And maybe we'll jump over to Tremor with Suvecaltamide. Maybe can you just talk a little bit on the mechanism here as well. Maybe what gives you confidence in the ongoing Phase 2? I know, when the drug was at Cavion, there was some supportive data, maybe some mixed data. So what did you take from that experience? And how do you think it's going to play out in the Phase 2 trial?

Go ahead, Rob.

Yes. So the underlying pathophysiology of Essential Tremor, and while it hasn't been fully elucidated, there's strong evidence to support the role of T-type calcium channels. And they're highly expressed in the tremor network in brain regions and they mediate a subthreshold oscillations and excessive rhythmicity, which is associated with tremor. Suvecaltamide is a highly selective, and importantly, a state-dependent T-type calcium channel inhibitor or modulator and may provide a better therapeutic index because of that state-dependent activity in modulating active calcium channels. As you mentioned, we had data from the Phase 2a TCOM study. That was a 4-week double-blind randomized placebo-controlled trial in Essential Tremor. And that established proof-of-concept, demonstrated the benefit in several clinically relevant end points, including the TETRAS activities of daily living, and supported further development in Essential Tremor. On the safety side, it was well tolerated. AEs tended to be mild, maybe moderate in severity, but occurred early and over titration tended to resolve continued treatment. We have conducted post-hoc analyses to really understand what we are observing in that study and the composite endpoint that we ultimately agreed with the FDA came in part out of the data showing that, that would be a good way to manage your patient benefit. The trial itself is robustly designed with 3 different dose levels, and placebo -- and we think it's targeting the right patient who have -- patients who have moderate to severe tremor, again, with the primary endpoint that's based on what we saw in the Phase 2 trial.

Perfect. And maybe a similar question for here. I guess, is there a clear clinically relevant reduction on the primary TETRAS endpoint and maybe how to physicians weigh the different items on the score, if differently at all? Is there something that's more important than others in the readout when you see it?

Yes. I mean I can take that as well. I mean we have clear feedback from patients and treaters in the community around what's important to patients. And the TETRAS ADL is, and it stands for activities of daily living, measures things that are highly relevant to patients, such as -- tasks such as drinking from a cup or utilizing a spoon, and the performance elements are more limited than the ADL elements, that have to do with drawing or making a spiral. There's also supportive secondary endpoints, such as the critical global impression scale as well as patient scale. And I think those will provide important supportive data.

And you touched a little bit on the mechanism, but maybe just to drill down in terms of a comparison versus maybe others on the landscape. We know Praxis has Ulixacaltamide. Maybe how does Suvecaltamide's calcium channel modular mechanism maybe compare? What are the key differentiating points in your opinion, if anything beyond what we talked about before?

Go ahead, Phil.

Yes. So importantly, Suvecaltamide is a very selective and highly selective and very potent [ CAP 3 ] modulator. And I think another important feature that we've noticed as part of the pharmacology is that it works -- it binds to a specific confirmation on the calcium channel, and that really results in what we call a state-dependent -- it works in a state-dependent manner. And what that really means is that when it works, when the channel is hyperexcited and excess calcium is coming through, but it actually doesn't really have is modulatory effect when the calcium channel is not hyperexcited or overexcited and allows for normal neuronal functioning during that silent period. As Rob may have alluded to as well, this is important is that it may have the potential to widen the therapeutic index. So it may translate to actually being able to achieve improved efficacy, while also being able to limit any of the safety, so we may be able to use higher doses to achieve that better efficacy as part of that widening of the therapeutic index. So, we think this is from a pharmacological point of view, a potential differentiator relative to other T-type calcium channel modulators.

Perfect. And maybe we'll spend some time on the Commercial franchise in Narcolepsy and then touch on maybe the Narcolepsy development path as well with the Orexin. But I guess just in terms of the back half of the year, obviously, in the first half of the year, we had the authorized generic launch. I know, the company has indicated the royalties from that are expected to pick up a little bit in the back half of the year. But we also had LUMRYZ launching as well. So maybe, can you just set the stage a little bit for what investors should be looking for? And how the company is thinking about maybe expanding and protecting the Narcolepsy and IH revenues, going forward? And maybe, how H2 could look a little bit different than H1, if at all?

Yes. No. Happy to sort of swing over to the Commercial side. And I will say just as we're leaving the Suvecaltamide. Yes, that obviously is a big market opportunity as well. And one of the reasons we targeted that with the mechanism and the study we're doing. It's the largest of the movement disorders, no new therapy in 50 years. So look forward as we're getting closer to the data readout to see more landscape around the Essential Tremor, which is a real debilitating and poorly-served market. So in Oxybate, we're very excited for where Xywav is. I mean, we've got now a full half of the year with the second quarter results with the AG, and we saw continued growth through that period. We have now some branded fixed high-dose or sort of the fixed-dose high-sodium oxybate competition with LUMRYZ. And we feel very good about our value proposition and the strength and durability of the oxybate franchise and Xywav continuing to be the oxybate of choice. Specifically, we expect, as we think about Vision 2025 that over $1 billion of the $2 billion will be Xywav, and Xywav is annualizing well over that. Of course, we are going to get the AG royalties as well. And the AG royalties, as we've indicated, they do step up in economics, and we expect the second half to be substantially higher than the first half. So, that will be a contributor as well. But in terms of where we are promoting, where we think the treatment of choice is and the continued growth into Idiopathic hypersomnia is the one and only approved therapy, it will be Xywav.

Perfect. And maybe going into the IH market a little bit because our physicians indicate this is a sizable population. So even though the drug has been doing well to-date, it looks like there's still a lot of room to run here. I guess, looking forward in the launch, are there any specific triggers the company can pull or sort of inflection points that investors should be aware of? Or is it really just grinding out, finding the patients and getting them on therapy anything you want to point to?

Yes. No. Good question. And we always said at the beginning of the launch that this is more of a new market development launch versus a Narcolepsy, where we had the pre-existing base and had built that market over 15 years. We think, of course, there's a strong overlap between IH treaters and Narcolepsy treaters and now the familiarity with Xywav, that development will go faster, but there's still a significant market development opportunity. So we're feeling quite good where we are with 2,200 active patients at the end of the second quarter. We're continuing to educate around how to diagnose appropriately and have confidence in the diagnosis and then seeking Xywav therapy. And it's really this 24-hour condition, we're treating well at night to provide significant daytime benefit. And that's -- obviously, we've landed that message well in Narcolepsy and that message needs to show that education has to come through on the Idiopathic Hypersomnia. But we see, in particular, that it's a rare multi-symptom 24-hour disorder, and the data we've got plus the real-world data and what we hear back from physicians and patients is it can be quite a transformative therapy for those patients. So it's identifying, it's getting them on, it's getting them titrated up to an effective dose, and it's continuing this market development expansion.

Perfect. Maybe we'll jump into the Narcolepsy pipeline with 441, the Orexin indicated we are going to see the healthy volunteer data by the end of this year. I guess, what should investors be looking for in that update? Obviously, we saw first-generation compounds have some AEs associated with them. What would give you confidence to take this forward from an efficacy and maybe -- or initial efficacy and maybe safety standpoint?

Yes. So for starters, I would just point out that we do not think that the limiting hepatic toxicity is a class effect. We think that's compound-specific, and we selected our compound for development, specifically to be from a distinct chemical class. Where we are with that program is, we have ongoing healthy volunteer studies. The first is a rising single-dose study that's actually dosed at night in healthy volunteers who are sleep deprived, so that we can get MWT data, sort of surrogate for efficacy. We also have an ongoing multiple-dose study and also in healthy volunteers, more traditional dose in the morning. And the goal of those 2 programs is to really hone down the dose that we would take into patient studies to then expedite the patient studies and also the multiple dose will provide the support we need for continued dosing in patients. We do expect to have proof-of-concept in healthy volunteers from the MWT study that I described this year. And we don't necessarily have plans to publish those data, right away, you're more likely to hear from us as we get the data we need to make that next pivot in the development program to hear us describe where we're going next in patient studies.

And you touched a little bit on the differentiation between some of the other compounds in the space. There are a couple of other companies with Orexins, maybe. Do we know yet how these products are differentiated? Maybe, how does Jazz think 441 is differentiated? And is there anything we can learn from their updates or that you can learn as a company from their updates?

Yes. I think, it is early days. We do know that liver toxicity was a challenge, at least for one chemical series. So that's certainly something to watch along with other safety data as these programs emerge from Phase 1 into Phase 2. I think, another critical factor is to have a drug that has the right pharmacokinetic properties so that you can dose it during the day and get enough of an effect during the day, but have it be washed out at night, so the patients can then have a night-time sleep that's not impaired by the orexin agonist. So, I think that's ultimately going to be a differentiating aspect as well.

Perfect. And maybe just to wrap up the time down. I know, you mentioned BD was a focus for the company as a whole, but maybe particular on the neuroscience side as well. So what are you looking for maybe in a potential candidate? You said you saw some things that are interesting out there. What is Jazz looking to do? If you can drill down on that a little bit.

Yes. I'm not going to reveal any names, Joe, so. But I'm going to just say, given our healthy cash flows and our strong balance sheet, we've got a lot of strategic flexibility. And as we think about the growth in the current business and the pipeline growth, we're in a really enviable position to pick and choose things that we think really fit well and can make a meaningful difference to the Jazz portfolio. So corporate development has been and always will be a core part of our strategy. I think it's a great sort of Darwinian approach to always make sure we've got the best program. Essential Tremor was a good example where we surveyed the landscape and we really went after the Cavion program knowing, and same thing in PTSD with a FAAH inhibitor. So we're well capitalized. We're evaluating unmet need, clearly, to fit into the neuroscience space, whether it's in the epilepsy sleep or related adjacencies as we've gone in now with Essential Tremor, PTSD or other areas of significant unmet need. On the Oncology side, we transitioned very strategically in the last couple of years from purely being hematology-focused to also solid tumor with the launch of Zepzelca and then Zanidatamab, which we see as a multibillion-dollar -- $2 billion-plus market opportunity. So, we've got a pretty large lens there. But we're also thinking about some areas like orphan or rare disease where it's a very efficient footprint from a Commercial perspective, but the agent we could bring in would really make a significant difference. And so, as Rob referenced, we're believing there's a number of good on-market or near-market opportunities which would fit well with our Vision 2025 objectives as well.

Perfect. And with that, we are at time. So thank you all very much for the discussion today, and thanks to the audience for tuning in. Please stay tuned in for our last session. It's the fireside chat with Xenon. Thank you very much.