Jazz Pharmaceuticals plc (JAZZ) Earnings Call Transcript & Summary

Hi. This is Kathee Littrell, Head of Investor Relations at Jazz. I want to thank you all for joining us for our Zepzelca Investor Update. Before we begin the webcast, I would point out that we will be making forward-looking statements today, including statements regarding our plans and expectations for the Zepzelca commercial launch in the U.S., potential Zepzelca revenue opportunity and our other development plans and opportunities. Our forward-looking statements are subject to risks and uncertainties described in our quarterly report on Form 10-Q for the quarter ended March 31, 2020, and our other filings with the SEC, and actual results may differ materially. We undertake no duty or obligation to update any forward-looking statements we make today. Finally, we are not confirming or updating any other guidance and actual results may differ. I remind you that you can send in your questions. So we'd appreciate if you would send in any questions, and you can do this at any time during the presentation, and we will address your questions at the end of the presentation. Please note that the slide deck from today's presentation will be available for downloading and is available for downloading on the Investors section of Jazz Pharmaceuticals' website, jazzpharma.com. With us today from the management team at Jazz are: Bruce Cozadd, Chairman and CEO; Dan Swisher, President and COO; Renée Galá, Executive Vice President and CFO; Rob Iannone, Executive Vice President, R&D; and Anne Borgman, Vice President, Hematology and Oncology Therapeutic Head. We are also very pleased to have Dr. Jacob Sands join us today. He is a thoracic medical oncologist at Dana-Farber Cancer Institute and an instructor of medicine at Harvard Medical School. I'll now turn the call over to Bruce.

Thank you, Kathee, and thank you everyone for joining our webcast today. We are very pleased that Zepzelca received FDA approval for the treatment of adults with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy. Zepzelca, with its strong efficacy and tolerability profile, represents an important addition to the treatment landscape for metastatic small cell lung cancer patients in the United States. I'm excited about the significant opportunities ahead for Jazz as we prepare 2 new product launches, advance and expand our portfolio and bring multiple new and differentiated treatment options to patients through both our internal efforts and corporate development transactions. We're off to a great start in 2020, with the European approval of Sunosi in January and launched in Germany last month, and the recent U.S. approval of Zepzelca with plans to launch in early July. We're also looking forward to our PDUFA next month for our low sodium oxybate candidate, JZP-258, which we expect to launch as early as the fourth quarter. We're also focused on continuing to advance our growing pipeline, including the potential to submit a BLA for JZP-458 in acute lymphoblastic leukemia as early as the end of this year. Corporate development continues to be a key priority for us and with our strong balance sheet and strong cash generation, we are well prepared to pursue a broad range of corporate development transactions to further diversify our portfolio and revenue base. We are focused on broadening our global pharmaceutical presence and leveraging our business and expertise to drive long-term growth while delivering differentiated products to patients. We began to develop our hematology/oncology therapeutics area in 2012 and have expanded our R&D portfolio with new molecules for hematological malignancies and a focused expansion into solid tumors. Our increasing R&D capabilities, approach to partnering to bring innovative assets into our portfolio and focus on being a partner of choice, are opening multiple opportunities for the expansion of the HemOnc therapeutic area. With our strong expertise, we are building a deep and broad pipeline from early to late-stage development. The addition of Zepzelca complements our growing portfolio of commercial assets in hematology and oncology and R&D portfolio in precision oncology and solid tumors. Zepzelca had a rapid path to FDA approval. PharmaMar submitted the NDA in December and received accelerated approval this week, 2 months ahead of the August PDUFA date. We are pleased with the rapid review and approval by FDA, which we believe underscores the tremendous unmet need for patients with metastatic small cell lung cancer. We are excited to launch this product next month and bring this important treatment option to patients. Since closing our exclusive U.S. license agreement with PharmaMar in January, we've made significant investments in preparing for early approval of Zepzelca. Our launch plans, which you will hear about in more detail from Dan, including reaching key small cell lung cancer prescribers through our expanded sales force, ensuring strong patient access and reimbursement. Our R&D priorities are focused on creating and executing a comprehensive Zepzelca development plan with PharmaMar. Next, I would like to thank Dr. Sands for joining us today to provide an overview of small cell lung cancer as well as highlights from the lurbinectedin Phase II study. Dr. Sands leads the small cell lung cancer clinic and clinical research program at Dana-Farber Cancer Institute and was one of the authors on the basket study leading to FDA approval of lurbinectedin. He serves on the NCCN Guidelines Committee for small cell lung cancer. Dr. Sands is also very active in lung screening, serving on the NCCN Guidelines Committee for lung screening, is a member of the International Association of the Study of Lung Cancer on the Screening & Early Detection Committee and is treasurer of the Rescue Lung Rescue Life Society. He is a media spokesperson for the American Lung Association and a scientific advisory board member of the GO2 Foundation for Lung Cancer. Thank you for joining us today, and I'll now turn it over to Dr. Sands.

Thank you so much. I'm happy to join this call, and I'm excited about the news with lurbinectedin. So we'll go through a discussion of small cell lung cancer and then the data from that basket trial. First of all, small cell lung cancer. This is -- the percentage is about 10% to 15% of patients with lung cancer have a small cell lung cancer. Different data sets, we see slightly different numbers, but essentially 10% to 15%. Small cell lung cancer is a very aggressive form of lung cancer. And so the course of things with small cell lung cancer is a bit different than non-small cell lung cancer. This is a disease with a rapid doubling time, a high-growth fraction. These patients need to start therapy quickly. And when they have resistance to therapy, that often ends up being a challenging scenario that requires urgent next-line therapy. Small cell lung cancer more commonly have paraneoplastic syndromes, and this is something that spreads quickly. The paradigm is different between non-small cell lung cancer and small cell lung cancer. In non-small cell, often we're encouraging patients that -- to allow us a little more time for a workup. That's when we do genomic testing, and that's when I really push with patients that I want to get them on the right treatment, not the first one. In small cell lung cancer, it's a different story. In small cell lung cancer, even when we're treating with curative intent, which is concurrent chemo and radiation, the standard is to start the chemotherapy immediately to prevent any delays in the time it takes to get the radiation going, which is just to say, this is a very active, very aggressive cancer. So U.S. estimated prevalence. You see here, as far as the staging, you see on the right, about 33% are limited stage; 67%, extensive stage. Again, there's some variation in those numbers. It might be a little bit more extensive in most people's perceived practice, but these are reasonable numbers. These are almost all smoking-related cancers. And I have a small cohort that I've kind of looked at of never smokers, and that I think is usually something else. So this is almost always a smoker's cancer, commonly older patients, 60s, 70s, 80s. People come in symptomatic. And so often, the discussion in advisory boards in the first-line setting or amongst academic conferences, the discussion is around how many of your patients end up getting treated in the inpatient setting. And that's because, again, this is an aggressive disease that once it causes symptoms, those symptoms progress rapidly. And it's not uncommon for people to end up in the hospital and starting their treatment there. So there's a lot of discussion around why it's so resistance and -- resistant and why it's so hard to treat. And in this cancer type, p53 and Rv1 are the most common areas of mutations, and we see loss of function of these. P53 and Rv1 are -- P53 is known as the guardian of the genome, but P53 and Rv1, both halt cells that have damaged DNA. They provide time for the cells to repair that DNA before going on in replication. And ultimately, if not repaired, lead to cell death. So when these are altered, you have cells that are proceeding on with their mutations without repairing the altered DNA and essentially trying to turn off these already off switches is a real challenge. When you have something where there's a switch that's turned on that is pushing the cell into replicating faster, then addressing that and turning off what is stuck on, ends up being a bit more feasible. So this is -- it's hard to treat. It's hard to target. And you see on the right there, there are drug class failures in second-line small cell lung cancer. Now some of these, I'm hopeful, will ultimately lead to something, and maybe it was just the wrong drug for those targets or those classes. But that being said, there are an array of failed drugs in this disease setting. So you see here the small cell lung cancer treatment paradigm, recently FDA-approved lurbinectedin, you see on the top right there. Topotecan is in that category as well. And you'll see below that in the NCCN Guidelines, topotecan relapse, less than or equal to 6 months. That being said, people with resistant disease or really early relapse after the first-line chemotherapy, topotecan really is not an option in those settings based on the studies with it. Clinical trial really has been the preferred option in many cases. If -- at a center with clinical trials, clinical trials ends up being the goal because there really hasn't been a great therapy available. So the clinical evidence for lurbinectedin, essentially setting the stage for the fact that in the second-line setting, this is a highly resistant, highly deadly diagnosis, for which we need more therapies, which is why clinical trials are so important in that setting. So this was a basket study. It's the first part and then it led to the basket study of enroll up to 100 patients there. We're going to discuss that specific for small cell lung cancer. And one other thing to highlight on that prior slide actually is that prophylactic use of G-CSF was not permitted. And so that will be part of our discussion going forward. So this is from the small cell lung cancer cohort of patients, 105 patients with small cell lung cancer, you can see that it included 8% with a performance status 2. So -- and that is something we absolutely see. These patients who clinically decline rapidly from their disease end up with a worse functional status. And also highlighting that the chemotherapy-free interval of less than 90 days, these patients that did not get a significant improvement from the first-line platinum-based therapy, end up really being exceptionally difficult to treat. And a number of these people have been placed on hospice, essentially, due to limited options. You also see other factors in here. I'll highlight that 30% of patients at their initial diagnosis were limited stage. The abnormal LDH ends up being a poor prognostic indicator, about half our patients had an abnormal LDH. So here are the response rates throughout the cohorts. You can see for all patients, the response rate was 30% to 35% by the IRC-assessed response or investigator-assessed response. When we break it into the less than 90 days or greater than equal to 90 days, we see a difference in those, which is expected. Those who have progression rapidly after first-line treatment, as mentioned, are difficult resistant diseases. So seeing some response in that setting is very meaningful. And then, of course, we see higher responses in those who had greater than 90 days of a chemotherapy-free interval. Here's the waterfall plot. We see a good portion of patients with meaningful responses, the dotted line at the bottom there representing the cutoff for a partial response, some patients with what's considered stable disease but some shrinking of tumor. In small cell lung cancer, stable disease is really meaningful. In non-small cell lung cancer, when we talk about a disease control rate, it includes stable disease, that can be -- it can be harder to know what to do with that. In small cell lung cancer, given the typical rate of progression, when you have stable disease in small cell lung cancer, that is meaningful, that is effective therapy in most cases. Here you see duration of response, again, separated by the less than 90 days or greater than or equal to 90 days in a chemotherapy-free interval. The median duration in that more challenging scenario being 4.7 months. And in the more sensitive disease being 6.2 months. Those numbers in itself, obviously, are not the full story. And what becomes really more meaningful in those with sensitive diseases, you see as you get further out on the curve, there are people at 9, 12 months and beyond that have an ongoing response to therapy. Here's the swimmer's plot, essentially demonstrating a similar thing. You see there, there was one patient that had 9.1 months duration of response, and that is somebody that's had a chemotherapy-free interval of less than 90 days. So this is typically a very challenging scenario, but long duration of response or in this disease, this really is considered a long duration. And those who had a longer chemotherapy-free interval, you see further out there on the swimmer's plot on the top of the swimmer's plot that goes out even beyond 12 months. As far as the safety profile, this is generally a very well-tolerated drug, fatigue there, 12% being Grade 3-4, and this is a patient population that often has symptoms from their diagnosis. So that being the highest, Grade 3-4, was fatigue. We see diarrhea and dyspnea as well. Again, this is a patient population that is high-risk for these kinds of side effects. But by and large, a generally well-tolerated drug from a patient experience standpoint. On the next slide, we look at the lab abnormalities. So the highest really being decreased neutrophils there at 46% Grade 3-4. And I'll point out that decreased neutrophils, 46%, seems like a lot of patients. A lot of drugs we give cause drops in cell counts that then recover by the time of their next line of therapy. So just a drop in numbers in itself isn't necessarily -- it doesn't necessarily impact the patient experience. At the bottom of that section, you'll see febrile neutropenia and that was 5%. Febrile neutropenia is a meaningful side effect, and it was only 5%. I'll also again point out that the patients in this study could not get primary G-CSF prophylaxis, but there were patients that did end up getting started on it secondarily. And then to highlight in that discussion, there were only 1.9% of patients that came off trial due to adverse reactions. You see the durations of response, again, highlighted at the top of that slide, again, generally well-tolerated drugs. Dose reductions and interruptions due to adverse events were in 25% and 30%, respectively. This was mostly due to neutropenia in the cohort. So some dose reductions, some dose interruptions, but rare to stop the drug due to adverse reactions. Thank you very much.

Dr. Sands, thank you so much. Let me just remind the listeners at this point, feel free to type in questions for Dr. Sands or any of the speakers today, and we'll address Q&A at the end of the presentation. I'd now like to turn the call over to Dr. Anne Borgman, our Hematology and Oncology Therapeutic Area head. Anne is an experienced oncology drug development physician with 20 years of industry experience. And she'll now provide an overview of the Zepzelca label and MOA.

Thank you, Bruce, and thank you, Dr. Sands. Zepzelca or lurbinectedin was approved just 2 days ago on June 15. And it's indicated for the treatment of adult patients with metastatic small cell lung cancer, with disease progression on or after platinum-based chemotherapy. This indication is approved under the accelerated approval mechanism based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial or trials. The recommended dosage of Zepzelca is 3.2 milligrams per meter squared IV over an hour, every 21 days until disease progression or unacceptable toxicity. And Zepzelca is supplied as a 4 milligrams lyophilized powder in a single-dose vial for reconstitution prior to IV infusion. In terms of the U.S. prescribing information, the tolerability and warnings and precautions, permanent discontinuation due to an adverse reaction occurred in a very low number of patients, only 2 patients for a 1.9% discontinuation rate, which, again, is quite low. Dose reductions due to adverse events occurred in approximately 1/4 of patients. And dose interruptions due to adverse reactions occurred in about 30% of patients. In terms of the warnings and precautions in the label, the main safety signal was myelosuppression. In the safety data set of over 550 patients, 40% had -- about 40% had Grade 3-4 neutropenia; 17%, anemia; and 10%, thrombocytopenia. In terms of the other warnings and precautions, hepatotoxicity occurred in a minor percentage of patients. AST and ALT elevations were in a 6% and 3% at the Grade 3 level and less than 1% at the Grade 4 level in this large safety set. And embryo-fetal toxicity is included in the warnings and precautions based on animal data. Patients receiving Zepzelca of childbearing potential and partners will be advised to use effective contraception during and for prescribed period following Zepzelca treatment. Lurbinectedin is a selective inhibitor of oncogenic transcription. Cancer frequently occurs due to degradation of transcription factors, and small cell lung cancer is a transcription-dependent disease. Lurbinectedin is an alkylating agent that binds to the -- and I'm talking now on the left side of the slide, that binds to the guanine residues in the minor groove of DNA, which forms adducts and results in a bending of the DNA helix toward the major groove. This adduct formation triggers a cascade of events that actually can affect the subsequent activity of DNA-binding proteins, including transcription factors and DNA repair pathways, which results in a perturbation of the cell cycle and eventual cell death. Lurbinectedin, now looking at the right side of the slide, actually inhibits active transcription in tumor-associated macrophages, leading to down-regulation of IL-6, IL-8, and CCL2 and VEGF. IL-6 activates oncogenic pathways which are known to be deregulated in cancer, and IL-8 plays an important role in tumor progression and metastasis. CCL2 monocyte chemoattractant protein-1 is a chemokine that attracts and activates mononuclear cells, which has growth-promoting effects that the tumor cells secrete. VEGF, of course, is a very well-known and important agent implicated in a variety of solid tumors. To sum, lurbinectedin's novel mechanism of action will play a very important role in the treatment of small-cell lung cancer. Now I will turn the presentation over to Dr. Rob Iannone, to cover -- to further discuss some of the lurbinectedin clinical data.

Thank you very much, Anne. I'd like to start by discussing the ATLANTIS trial. And as you can see on this slide, the ATLANTIS trial was based on Phase I/II data that was generated with lurbinectedin in combination with doxorubicin. And these data actually came before the data with lurbinectedin as monotherapy and before a decision was made to pursue an accelerated approval based on the lurbinectedin monotherapy data. So let me start by describing this data. You can see on the left that 21 patients were treated with a regimen of 4 milligrams of lurbinectedin in combination with a standard dose of doxorubicin. And this combination produced very encouraging results overall with response rates of 58% and a median progression-free survival of 4.1 months. Overall, it was well tolerated with the main toxicity being myelosuppression, which was transient, reversible and manageable through typical supportive care measures. The other toxicities were also atypical of doxorubicin in combination with lurbinectedin. You can also see in this slide that amongst those patients who are considered platinum-sensitive, there was a particularly strong response rate and durability of response. So it was on this basis that the ATLANTIS trial was conceived, again, before the data from the basket trial with lurbi monotherapy was available. You can see that in this trial, patients were eligible if they had one prior platinum-containing regimen. They needed to have an ECOG Performance Status score of 2 or better. And patients were allowed to have received prior immune checkpoint inhibitors. One thing that's noteworthy is that patients were eligible only if they had a platinum-free interval or chemotherapy-free interval of at least 30 days, and this was based on the data that was observed where they're showing that patients were particularly sensitive if they -- to lurbinectedin-DOX combination, if they had platinum-sensitive disease. It was a one-to-one randomization. Lurbinectedin, importantly, was started at a dose of 2 milligrams per meter squared, which was a conversion from a 4-milligram standard dose, but they were allowed to continue at the standard monotherapy dose of 3.2 milligrams per meter squared once they completed the combination of doxorubicin. It was randomized to a choice of either topotecan or CAV, cyclophosphamide, adriamycin and vincristine. The primary endpoint was overall survival. Secondary endpoints included PFS, ORR by RECIST Version 1.1. And as you know, this trial is still ongoing. Let me now shift the gears to describing how tumor types were selected for the basket trial. This slide presents preclinical data that were available before the initiation of the basket trial. On the left, you can see in cell lines that lurbinectedin inhibited growth of cells -- tumor-derived cells across a whole host of different tumor types. And in the middle, you can see that when lung cancer cells were exposed to lurbinectedin, that they demonstrated rapid apoptosis, consistent with the mechanism that Anne described. And to further support lurbinectedin's activity, it was evaluated in xenograft models such as the one depicted on the right, where it inhibited tumor growth. On this slide, you see the tumor types that were evaluated in the basket trial. Obviously, this was the trial that supported the accelerated approval with lurbinectedin and included 105 patients with small cell lung cancer, as Dr. Sands described, but it also included a number of other tumor types, including endometrial cancer, neuroendocrine tumors, biliary tract cancer, head and neck cancer, carcinoma of unknown primary, breast cancers that included BRCA1 or 2 mutations, germ cell tumors and the Ewing family of tumors. This trial has actually completed enrollment and some of the data from certain tumor types have been published at various congresses. Now shifting to our thinking on next steps. We received FDA approval in June of 2020 for second-line small cell lung cancer. We, as I mentioned, have the ongoing ATLANTIS trial to Phase III trial with the results expected in the second half of 2020. In that second-line small cell lung cancer combination space, we also have 2 investigator-initiated trials. These are trials in combination with either pembrolizumab or atezolizumab, which are both PD-L1 inhibitors. And based on the mechanism that Anne described, there are a number of other promising combinations that we are considering exploring. I also want to spend some time, before leaving small cell lung cancer, talking about first-line small cell lung cancer. As you may know, PD-L1 antagonists such as atezolizumab or durvalumab have now been approved in the first-line setting and in the United States are considered standard of care. This has been a significant advance for small cell lung cancer. But despite that, the overall survival is still, unfortunately, relatively short, with the median of 12 or 13 months, depending on which study you refer to. Virtually all patients eventually progress and die. And so this highlights the significant unmet medical need in this segment. So we are giving consideration to the potential to add lurbinectedin into the setting, potentially as a switch maintenance design to an add-on therapy. Based on the basket trial results that I mentioned previously, we continue to be very interested in expanding on signals in some of the tumor types that I mentioned previously, but also to explore additional tumor types based on the mechanism of action and the potential for combinations. So with that, I'd like to turn it over to Dan Swisher, President and Chief Operating Officer.

Thanks, Rob. I look forward to providing a commercialization strategy landscape overview. So starting with the launch plan. So we've got an excellent integrated launch plan that I'll give you some detail on and why we're really confident that this is an important new treatment option for small cell lung cancer. We had anticipated actually that the FDA action could come early. So we are launch-ready. And in fact, with day 1, June 15, we moved rapidly from plan to call-to-action. And we had our field force already contacting our targeted HCPs. We're arranging appointments, aware of interested -- interest among the physicians and also patients already being identified. I think most of the engagements are going to be virtual for the next couple of months. Importantly, the small cell lung cancer patients were continuing to get treatment even through the height of COVID. And we will start to engage in the field toward the end of this month as local restrictions enable that. But we're ready to go, sort of through whatever effective means of communication possible. And we can tell that there's quite a bit of interest for new therapies. In terms of what's on this graph, now that we've got a final price, we're getting that listed, and that's just more perfunctory, but that will get listed. With the finalization of the cartons and packaging and package insert, we're rapidly moving our product through the final supply chain. And we'll have that to our specialty distributors and then be ready to go with -- importantly here, GPOs, so since a significant portion of the patients are treated in the community, GPOs are actually important. And we can leverage an initiative we had underway with Vyxeos and really just sort of add-on to those relationships. And so those should be in place in early July, and we'll do everything we can to have product available soon after the July 4 weekend. In terms of the product profile, as you've heard from Dr. Sands and Anne and Rob, we definitely feel that the market research and virtual ad boards we've had, validate the product profile that we've seen from the basket trial that supported the lurbinectedin package insert. There's definitely been changes in innovation that's gone on in the front line, particularly with the adoption of checkpoint immuno-oncology therapeutics. But very little has gone on in second line. It's been more failure than success. And so given the profile from the basket trial, there's a lot of interest in post-platinum therapies. Something like Zepzelca that's got a strong and durable response rate across the patient segments, it's got a novel mechanism of action and it's got a very manageable tolerability and ease of administration. So that's a type of product that folks are looking for. In terms of the market opportunity, 30,000 patients per year are getting diagnosed. Of those, most of those are getting treated. Unfortunately, most of those do progress. In terms of -- in second line, currently, 17,000 of the 25,000 are being treated, and they're split between a little more disease-resistant or treatment-resistant versus treatment-sensitive as measured up above by the CTFI. Importantly, we showed good profile in both. And so we do think lurbinectedin or Zepzelca will be taken up in those segments. Importantly also, though, because of the lack of innovation in the treatment options that are currently available, many patients opt out of ongoing treatment. And so we do see growth opportunity in the 8,000 untreated patients. And then to the extent that we don't have a chance to treat patients in second-line post-platinum, there's an opportunity for Zepzelca to be treated in the third-line setting, of which there's 3,000 to 5,000 patients. In terms of the snapshot of what the current therapies are, and this is dynamic. You'll see -- we've got sort of I/O exposed and I/O naive and there's an increasing portion of patients that are going to become I/O exposed, most extensive-stage disease patients will. And depending on the outcomes of some clinical trials, it could become standard of care, and limited as well. Topotecan, which you've heard kind of the profile is not very engaging for most of the physicians, it's still the majority. And that is the only approved therapy in second line and something we feel we've got a very good profile compared to, but also the other therapies, it's -- we have an opportunity as well to establish uptake there, including, again, as I said, the second-line patients. In terms of the prescriber universe, it's fairly concentrated. On the right side, even though it's 3/4 treated in the community cancer clinics, 1/4 in the academic, the number of treating physicians is 6,000 medical and thoracic oncologists. We've sized our field force to be able to cover 5,000 target prescribers, which represent close to 90% of current small cell treatment. Importantly, at the beginning of the launch, we're going to be super-focused or, I should say, laser-focused on the top 1,500 physicians. These account for 63% of the treatments. And those are the 1,500 that we're already in contact with to arrange appointments and to engage. In terms of the prescriber distribution, there's a heavy concentration in the Northeast and Southeast, somewhat going along with the heavier tobacco use. What we've done to make sure we've got the resources to support this commercial launch is we've taken our existing adult oncology field force of 44, and we've added 28 additional sales representatives. They're largely on board now. They've -- most of them have been trained. Many of them actually come from recent lung cancer experience. And so combined with our Vyxeos field force, which many have solid tumor experience as well and this will be a primary focus for the field force, we feel very good about the firepower we can bring to raise awareness and support adoption, trial and usage with those top 1,500 docs. In terms of on the Medical Science Liaison group, we've had 10 existing ones that have been out there and educating and engaging with the KOLs and treaters, and we're hiring an additional 10, which are largely in place and trained to be solid tumor focused. And then just to support all the community centers in terms of reimbursement, we've been adding to our field-based reimbursement specialists and that will be a combined force for our adult group of 13. In terms of the payer landscape, it's pretty straightforward here, given that it's generally a disease in the 60s and 70s, as Dr. Sands referenced, not surprisingly, close to 2/3 are Medicare-funded. And given that this is going to be an outpatient infusion, it will mostly -- it will fall under Medicare Part B, which is a very straightforward ASP plus reimbursement system. I know there's some question about sort of the importance of NCCN Guidelines in this setting. It's really the on-label indication in the package insert which will drive initial reimbursement. And so we think we're good to go there. In terms of the commercial plans, this is not a very managed patient category. It's relatively few. Treatment options are not very good. I/O is very rapidly taken up in frontline. And so we don't anticipate significant barriers in either the commercial plans or the government plans. In terms of the product and how it's packaged, it's a lyophilized powder, highly concentrated. And this is our packaging. The API and initial launch supplies are being provided by PharmaMar. And so those are now moving over to our final packager and into the supply chain. Going forward, Jazz will have responsibility for the supply chain. API will continue to be manufactured at scale by PharmaMar. And then we've got a couple of contract manufacturing groups, one of which would be the majority, we've got a pre-existing relationship with and have good success with. So we're feeling good on the supply side. And then lastly, I just wanted to wrap up on the successful launch strategy that we're putting in place here. So the first portion is adoption, laser-focused on the top physicians that have the bulk of practice and really raise awareness, ensure good trial adoption with those clinicians. And as we get to that, start to expand then to the universe of 5,000. And there, we're positioning Zepzelca as really the important new treatment option, post-platinum, post-first line and really, our goal is that it should become the standard of care across all those patient segments. And then as Rob has mentioned, we're already working very closely with PharmaMar on our next set of indications and data generation. We see great opportunity to move Zepzelca, because of its combinability, into first line to explore combinations, including the ongoing ATLANTIS trial, but additional combinations in other segments of small cell lung cancer and then moving into other tumor types and ensuring a good steady data generation plan to support Zepzelca as the treatment of choice for small cell lung cancer. And so with that, I'd like to hand the call over to Renée.

Great. Thank you, Dan, I'm happy to be joining everyone today. So stepping back -- if we could do the next slide, please -- stepping back, as we reflect on our broader corporate strategy and upcoming catalysts, we are really excited about the opportunities ahead for Jazz. We're focused on expanding and diversifying our portfolio with multiple potential upcoming launches as we strive to provide innovative and life-changing medicines for patients through both our internal efforts and corporate development transactions. Being a partner of choice is important to us, and we will continue to aggressively evaluate opportunities to acquire external innovation through partnerships and transactions that align with our mission and strategy. And so in light of this, our licensing agreement with PharmaMar for the exclusive U.S. rights to Zepzelca across all indications is an ideal fit. In the United States, there are approximately 25,000 small cell lung cancer patients who progress to second line and for whom there has been no new therapy approved in over 20 years. So with a lack of good therapeutic choices in this second-line setting, approximately 8,000 of those patients who progress after first-line therapy make the difficult choice not to receive any further treatment. So given this important need, we're really excited to be able to bring this new treatment option to these small cell lung cancer patients with disease progression during or after receiving platinum therapy. We're pleased that PharmaMar viewed us as a partner of choice for this important product. They recognized our oncology expertise and knowledge across both commercial and R&D as well as our demonstrated commitment to making this therapy, its development and second-line small cell lung cancer patients a priority. We expect Zepzelca to be a multi-hundred million dollar net revenue opportunity in the first indication. Dan's talked about our preparation to launch this new therapy across the treating community where we expect it to be viewed as an important treatment advance in the second-line setting. And given the dissatisfaction with existing treatments, we do expect that after an initial period where we gain inclusion in the NCCN Guidelines and raise awareness through medical education and promotion, that the uptake will grow into peak for the current indication within a 3- to 5-year period. The next slide. Turning to cost of treatment. The wholesale acquisition cost or WAC of Zepzelca is $6,633 per vial. Zepzelca is dosed at 3.2 milligrams per square meter of body surface area or BSA every 21 days. So based on an average BSA and median number of cycles observed in the Phase II monotherapy trial, this would translate to approximately $53,000 per course of therapy, with 4 cycles of 2 vials. And the total cost of therapy, of course, will vary depending on the size of patient and the treatment duration. The price was determined through extensive pricing research and analysis, including detailed feedback from physicians, pharmacists and payers. And as the first-approved medicine in this line of therapy in over 20 years, we believe Zepzelca represents a clinically significant therapeutic option as a second-line treatment for small cell lung cancer and an important advancement for patients. So turning now to a summary of the key deal terms. You'll recall that we paid a $200 million upfront milestone to PharmaMar in January of this year. And following the FDA accelerated approval of the product, PharmaMar became eligible to receive a milestone payment of $100 million, which we expect to pay this month. In addition, PharmaMar may receive a milestone payment of up to $150 million upon the achievement of full regulatory approval of Zepzelca and that's approval before midyear 2023. If it's afterwards, it will be a slightly less amount. On the commercial side, there are up to $550 million of milestones. And while we are not providing the specific breakout, I'll just say that at the higher end of the potential milestones, this would represent a very large number of patients and a significant associated revenue stream. And all milestones occurring post accelerated approval will be capitalized and amortized over their estimated useful life. So PharmaMar will also receive royalties in the high teens to 30% range, which we will record under cost of goods sold. I'll also remind you that Jazz has the opportunity to co-fund any pivotal trials in new indications or pay a milestone on FDA approval of those indications, either of which can be offset against the future commercial milestones. And we expect gross-to-nets will be in the range of 20% to 30%, and this reflects cost primarily related to government rebates, distributor fees, GPO discounts and patient services. So to summarize, we are very excited to be launching Zepzelca. There's a significant unmet need, given the number of patients in the second-line population, with 8,000 currently being untreated. As the first new treatment in second-line small cell lung cancer in more than 20 years, this fits very nicely in line with Jazz's mission to bring life-changing medicines to people with limited or no options. And we're committed to further development, as Rob mentioned, both in the small cell lung cancer space as well as in other tumors. We plan to leverage our existing capabilities and infrastructure in the hematology/oncology space to reach the key 1,500 prescribers who treat over 60% of these patients and whose opinion and experience will have an important positive impact on the behavior of the broader treatment community as well as the patients they serve. And also importantly, this product and the underlying transaction with PharmaMar provides Jazz with another meaningful diversification opportunity with revenues in the multi-hundred million dollar range. So in closing, this is quite a catalyst-rich time for Jazz. We have a diverse portfolio of commercialized products with multiple growth drivers lined up in 2020 and 2021, 2 of which have been unlocked with the approval of Sunosi in Europe and the approval of Zepzelca in the U.S. We are preparing for the potential approval and launch of JZP-258 with a PDUFA date of July 21 of this year as well as the BLA submission for JZP-458 as early as the fourth quarter of this year. With our strong balance sheet and cash generation, we remain focused on disciplined capital allocation. We're expanding and diversifying our R&D portfolio through internal efforts and corporate development transactions, and we continue to enhance our capabilities with a focus on strong operational efficiency and globalization of our business. So I'll now turn the webcast back to Bruce.

So thank you, Renée. We'll begin the Q&A now. And I think I'm going to prioritize questions that are aimed at Dr. Sands first, and I'll act as the questioner and I may combine a couple of questions if they're -- seem very similar to me. So Dr. Sands, given some patients may have missed a treatment session during the COVID pandemic, would you ever consider retesting these patients with a first-line therapy if they progress? Or would you move straight to second-line therapies such as Zepzelca?

So this is where small cell lung cancer is different than most other cancers. Small cell lung cancer, we really didn't skip doses, didn't really delay doses even, except for really at the height of surge, potentially in some centers, so in the cities where the surge was most. This disease is too deadly, too rapid. So there are very few people that fit this, but for those that do, know if they've had progression, the likelihood of going back to something earlier is very unlikely. And as I said, these people, if they are delaying in any kind of a way, it's brief. You don't delay for a long time.

Great. Next question. Zepzelca was approved for disease progression following platinum-based therapy. Given that I/O plus platinum-based therapy is the de facto first-line treatment, is it safe to assume that this will be used following any of these first-line treatments?

That's correct. I don't think the addition of checkpoint inhibitors in the frontline, it changes any of the data that has been presented. If anything, we see in some trials where those who had previously gotten checkpoint inhibitors seemed to maybe have a better response. And the life -- or the half-life of the checkpoint inhibitor is pretty long. The effects of it stick around. If anything, there might be some synergistic benefit to that. So certainly, it does not diminish the results, does not challenge the results. I think approval of lurbinectedin has happened, knowing that, that is the standard of care. So I don't expect any surprises in that arena.

Dr. Sands, how do you see use and uptake by oncologists once Zepzelca becomes available, slow, modest or rapid? And do you foresee any differences in uptake in the academic versus community setting?

So this is maybe the most nuanced -- that requires the most nuanced answer of all of those questions thus far. I think -- and actually, it's interesting to see you highlight this in your slides, that the prescribing of drugs for small cell lung cancer, there are some who prescribe a lot, and that's a subset of people. And I think that, that really speaks to the fact that this is such a deadly disease. The drop-off from second line to third line as well that you highlighted on the slide, also, I mean is more a reflection of the lack of treatment options than I think patients refusing treatment. Second-line treatment, there was an FDA approval. Third line, anything that had prior FDA approval on third line is now first line with the checkpoint inhibitors. And then failed against topotecan as well in the second line. So there just isn't -- there just aren't a lot of great options. So that -- along that -- those lines then, I think you've got various oncologists across the country who end up consistently putting people on hospice even in the second-line setting and others who really try to treat everybody. The uptake on this, those who are already prescribing are really the ones that I think are most likely to now use a drug that appears to be, on cross-trial comparison, appears to be better tolerated than topotecan and a bit more efficacious as well. So it's a win in both of those arenas. I think the uptake will be easier in that group. The challenge is going to be in the people who end up not providing other -- not providing treatment to patients who have progression where their disease seems the most challenging, is to then encourage those people to give lurbinectedin a try and see what happens in those communities. This drug, I think, is still an unknown to a lot of oncologists. This was a basket trial. Of course, there is a publication in a well-respected journal, but that was a single-arm study. So some of it is going to be -- there are oncologists that are still going to just learn about the drug at all. And those are more likely the people that are not really prescribing much in the way of next-line therapies. So I expect uptick to be more in the academic setting and then more in the community docs that are prescribing already and then will -- depending on the rate of uptake and the discussion level as far as how quickly that trickles to others, so it will be variable.

Great. I appreciate the nuanced answer to that. That was a lot of information that I think will be very helpful. Dr. Sands, how much emphasis do you put on patient quality of life when treating these patients? And how will you measure the quality of life differences for these patients in practice versus those you put on topotecan?

So this is -- I mean this is of the utmost importance to patients. And I'll tell you, a lot of people are under the impression that oncologists give people drugs that help them to live longer but harm their quality of life in the process. And so I am often explaining to patients that, that would be -- that, that is not what I'm interested in doing, and that will be the worst job, to just prolong people's suffering. And that being said, in the second-line setting of small cell lung cancer, I think that's what we've been looking at, is topotecan can be rough on people. And so to give a drug that hurts people's quality of life, and then in many cases, ends up not being effective enough, I think is just enough to really limit the amount of use. And that's why we see people more commonly using other drugs in some settings. So some people within the oncology community end up more commonly using weekly paclitaxel or even temozolomide, these are not approved drugs, but -- not approved in small cell lung cancer, but don't have the same kind of side-effect profiles. So to have a drug that is now FDA-approved that for the majority of patients was -- the side-effect profile does not affect their experience so much, so cell count they don't feel, febrile neutropenia highlighted because people feel that. But in many cases, it's not a side-effect profile they feel. So even in the cases where the drug ends up not being effective, you haven't kicked them on the way down, so to speak. That's really the worst-case scenario, is when you have people that -- where the drug wasn't effective and you really harmed them in the process. So to have a drug that ends up being effective, I think this is effective enough to make a strong case for use. And a side-effect profile that doesn't really hurt people, that is extremely meaningful. The quality of life is the thing that patients consistently highlight. So that question is spot-on in asking about quality of life. That is extremely important.

Great. How would you describe the potential impact of positive ATLANTIS data on the future prospects of Zepzelca in terms of its uptake by the oncology community?

I think a positive result will be extraordinarily meaningful for a couple of reasons. One is it somewhat validates lurbinectedin as being a meaningful therapy in small cell lung cancer to see a second trial utilizing that drug that ends up being positive, ends up being really reassuring to that. But on top of that, this is going to be the first time that a lot of oncologists hear about lurbinectedin. I think getting the word out there is a bit more, given how rapid the course has been for this drug. So people are now going to hear the name of this drug. And therefore, that the ATLANTIS data will also register quite a bit more. People will notice that a bit more. So a positive result would be very meaningful. And then the question would become whether you give it as a single drug or the combination, I suppose, would end up really being the debate.

Do you expect average treatment duration with real-world use to be similar to what was seen in the basket study?

We -- I think we, across the board, tend to see outcomes in the real-world setting tend to be a little bit worse than what we see in clinical trials. And I think we can expect that. Part of that is that people who don't qualify for the trial end up getting treated on the drug as well. So -- and we see that across various trials. I mean if this is second-line setting or maybe people that wouldn't have qualified for this trial, maybe someone whose functional status was worse, but it's just been a rapid decline due to their disease. So if we can reverse the course of their disease and get a response, then maybe their functional status improves. Well, they wouldn't have qualified for the trial, but let's give it a shot. That type of thing happens. Or people who have, for whatever other reason they didn't qualify for the trial, but they will get treated with this now approved drug. So clinical trial patients tend to be the better patients in general. So across the board, not just this trial but every trial in the oncology setting, we tend to see outcomes, I think, be a little bit -- not quite as good in real-world practice as they were in the trial.

Thank you. For Dr. Sands, since he's on the NCCN Guidelines panel, can you comment on when NCCN Guidelines could be updated to include lurbinectedin?

Well, I can say this is in the works of being addressed. I can't give you an exact time to that, but I can tell you that this is already a discussion.

Great. Aside from slow adoption of new drugs, are there reasons to use another chemo, platinum or non-platinum, such as a taxane instead of lurbinectedin in second line?

There may be people that do that. So paclitaxel, weekly paclitaxel, in particular, tends to be generally well tolerated. There are oncologists that are used to that, that have been using that. And if that is their standard, the question in their minds is going to be, does this offer them more than paclitaxel. And some of it will be getting an experience then. In that setting, they're seeing patients weekly. So that is -- I mean they're getting -- with paclitaxel, it's often getting treated weekly, so they monitor those people closely. I think the goal of any of those oncologists that's using paclitaxel is going to be getting patients as many drugs as they can. So even if they're not using this in a second-line setting, they would likely try and then use it in the third-line setting. Like I said earlier that, that 3.5% is in part because of such a lack of viable options. At the same time, there could be people that really clinically decline enough where next-line treatment is not an option. So I'm not trying to suggest that every patient getting second line would get third line. The fact that this is FDA-approved, for a lot of people, if they're on the fence, FDA approval often ends up being the choice. And I've certainly heard in discussions where there was a debate, people said, "Well, look, this is the FDA-approved option." And so that absolutely carries weight. At the same time, clinical experience does and so there will be some individuals probably that continue with paclitaxel and are a little slower to adopt this drug. But like I said, those are usually people that are actually treating quite a bit of small cell. And those are people getting their hands dirty with second-, third-line therapy. So they're going to want to keep providing a next-line option. I think this is still something that they would want to make sure patients get an opportunity with.

Great. And I think that brings us to the last question specifically aimed at Dr. Sands from the ones that have been submitted. How long does treatment continue after response is lost? (Duration of response, 6 months; overall survival is 9 months.)

I'm sorry, can you ask that question again?

Yes, the question was how long might treatment continue after response is lost? So if the duration of response is 6 months, but overall survival is 9 months, would continue potential -- would treatment potentially continue after the response is lost?

So once there's progression on the drug, treatment with that drug wouldn't be continued, you'd go to next-line therapy. The fact that the overall survival is so close behind the progression-free survival is just a representation of the aggressive disease. But you'd want to get them a next-line option and your time to get them on that is limited because the disease is so rapidly progressing.

Terrific. Dr. Sands, thank you for your presentation and for answering these questions. Before I offer you the opportunity to exit the call, I'll just open it up. Are there any other points you think haven't come up that you'd like to make before you have the opportunity to sign off?

Well, I'll just underline, I guess that -- first of all, thank you for having me on this call. This has been interesting to listen to in the other aspects as well. I think in the small cell lung cancer setting, it's exciting to have a treatment option added to the armamentarium. We are pretty limited as it is with a disease that is rapidly progressive and kills a lot of people. So to have something in there to utilize, is exciting to see that. So thank you.

Yes. So Dr. Sands, on behalf of all of us at Jazz, and also small cell lung cancer patients, thank you so much for your time today.

Thank you.

And so Anne Borgman, maybe I'll come to you with a question next. Can you talk to any early data or hypotheses for lurbinectedin's utility in other tumor types?

Yes. Thank you, Bruce. Some intriguing data have been generated already from the basket trial. And we are working with PharmaMar regarding which additional tumor types to pursue further, which could include, for example, endometrial carcinoma, mesothelioma sarcoma and some of the DNA repair challenge tumors like the BRCA1, 2 or MMR tumor types. And these are all areas of highest need where there's the potential for a straightforward regulatory path. Naturally, we are considering exploring other tumor types as well based on preclinical data and Zepzelca's mechanism of action where it might appear nicely. And lastly, and importantly, in addition to the promising mechanism of action, a strong attribute of Zepzelca, which was mentioned previously by Dan and by Dr. Sands is -- and Rob, is its safety profile, its general tolerability really lends itself very nicely to combination therapy. So in addition to the ongoing combinations with the immune checkpoint inhibitors, we're going to work with PharmaMar to consider other rational combination strategies.

Terrific. Thank you, Anne. Rob, coming to you for a few questions, including some that are regulatory in nature. If the Phase III ATLANTIS trial fails as a confirmatory trial, do you expect to have to run a monotherapy confirm trial? How long would that take? And what in your estimation is the risk that FDA would withdraw the approval?

Thank you, Bruce. So I would just reiterate some of my comments during the presentation as context. So the ATLANTIS trial really was designed based on the Phase I/II data that I showed you. And it wasn't until after that trial was designed, initiated, that PharmaMar understood that the monotherapy signal from the basket is strong enough to pursue an accelerated approval based on that. So in that context, ATLANTIS wasn't designed per se to be a confirmatory trial or it might have had a monotherapy arm. Nevertheless, the FDA has said, depending on the results, that trial could serve as a confirmatory trial, meaning that the accelerated approval could be converted to a full approval. Ultimately, it will depend on the data, data confirming that lurbinectedin is active in that setting. But we don't think it necessarily has to be statistically significant but essentially confirming of the activity of lurbinectedin. In the case that it's not, we would expect that we would have to initiate a new monotherapy trial that would serve as the confirmatory. I think based on those trial design differences, the monotherapy data that resulted in accelerated approval would continue to stand on their own, pending another confirmatory trial. And I would mention that if we were to do another confirmatory trial with monotherapy lurbinectedin, that PharmaMar would be conducting that trial.

A slightly different angle on ATLANTIS, Rob, in the next question. What are the chances that ATLANTIS trial data, if positive, still may not be viewed as support of a full outright FDA approval?

Yes. So as I mentioned, the ATLANTIS trial is designed as a survival trial. And given that its control includes an arm that has doxorubicin in it, and given that DOX itself is not known to be highly, highly active in that setting, I think a survival advantage, a statistically significant "positive" study would be quite compelling.

And there's a similar question, but it's got a little bit of a twist in it, Rob. Has FDA seen any of the ATLANTIS data? And what will happen if the trial conclusion includes indications of benefit? I think you've got the second part already, but has FDA seen any of the ATLANTIS data?

No, the data, the trial is blinded. And so neither we nor the FDA has seen the data. The only view into the data has been through the independent data monitoring committee, which has met multiple times throughout the course, really to look at safety and to affirm that the trial could proceed without changes. And that in fact was the case. The trial proceeded based on safety data presented to the IDMC.

Yes. And just in case it's not clear to people, FDA hasn't seen the data, PharmaMar hasn't seen the data, and we haven't seen the data. So we're all on the same page there.

Yes, we have -- I was using 'we' to be Jazz and PharmaMar, but thanks for the clarification.

Yes. And Rob, I think this similar question went to Dr. Sands, but let me ask you, too: How is the outcome from the ATLANTIS trial expected to change how Zepzelca would be used, either positively or negatively?

Yes. I think Dr. Sands answered it well. It would provide another option, a combination with doxorubicin. And the data, of course, would be randomized and showing a survival benefit. So I think that docs would -- could be very compelled by that. The overall tolerability profile would be different. And so there may be certain patient subsets where lurbinectedin would be used as monotherapy as the best choice. For other patient subsets may -- docs might consider the combination.

So Rob and Anne, I'm going to do the same thing with you guys that I did with Dr. Sands, which is just give you, before I move on to Dan, any other comments you'd like or clarifications or additions or emphases you'd like to add to anything that's been covered thus far? Anne, maybe I'll go to you first.

Yes. Thank you, Bruce. The one thing that we are looking forward to in reviewing the ATLANTIS data when available, and assuming this study is positive, is to investigate what potential subgroups may benefit from treatment with the combination. These could be younger patients, for example, or patients with bulky disease. So I think that does potentially enhance the profile of lurbinectedin in the post platinum-treated setting. And also, I for one am excited to be working on this compound. This represents a huge milestone in the treatment of small-cell lung cancer as no agents have been approved in this -- in the post-platinum setting for 20 years. So it's very good news all around. And with that, I'll turn it over to Rob.

Thank you, Anne. And maybe what I would start with a follow-up on to one of the questions that was asked to Dr. Sands about uptake, for example. Dr. Sands described lurbinectedin as being very promising, but given that it was a relatively small trial, not many physicians have had experience directly with lurbinectedin. What we're finding as we talk to KOLs is that once doctors have been made aware of the data, that they're actually quite compelled by it and express that they want to try it in their patients. And so we are certainly planning to and have already initiated engagement with physicians both in the community and academic centers to really ensure that they're aware of the data and know that this is an option for their patients. And I think that will support rapid uptake in a context where the available treatments are really quite poor and not well tolerated compared to lurbinectedin.

Great. Thanks, Anne, and thanks, Rob. So let me go next -- Renée, there are a couple of questions maybe I'll toss your way. When does Zepzelca's U.S. composition of matter patent expire? And what could patent term extension extend it to?

Great. Thanks, Bruce. So the composition of matter patent expires in 2024. And then with that patent term extension, that would be extendable through 2029. I should also mention, though, that with patent applications for combo therapy pending, those, if issued, could extend us further to 2031.

Great. And a specific question around milestones. If full approval comes after mid-2023, you mentioned the milestone payable as being lower than $150 million. Could you guide to how much lower?

Yes, the amount would be less that $150 million. However, we have not disclosed that amount. You can appreciate with a partner, we make all of those disclosures together. And certainly, to the extent that amount and that scenario becomes relevant, I would expect us to be disclosing it.

And Renée, last specific question for you: What would you consider a good achievement from a revenue perspective for 2020 for Zepzelca?

Right. Great question, and I'm not surprised that we've received it. So we're not providing specific guidance for Zepzelca for 2020. In fact, in our guidance that we provided on May 5, we provided net sales guidance for hematology/oncology products combined, including Zepzelca. And that annual guidance at the time was $420 million to $510 million for the year of 2020, but we haven't provided it specifically for Zepzelca.

Okay. Terrific. Thank you. Dan, let me come to you now for some questions. Do you expect uptake from community oncologists prior to getting lurbinectedin into the NCCN Guidelines? And then I think we heard from Dr. Sands on this already, but the question was: Given this approval came early, where are you in terms of getting lurbinectedin into the NCCN Guidelines?

Yes. Let me address that one first. So on the NCCN Guidelines, we have provided a substantial data deck preapproval, just to make sure it was on the radar screen. And given there's been so few FDA-approved drugs, we wanted to make sure that would be rapidly evaluated and incorporated into the Guidelines. And I can say the day of approval, our medical affairs, scientific affairs team was ready to go with a full package. So we expect, as it is in the works, that we'll get a response fairly soon. And it's definitely helpful to have it on the Guidelines, so people can get it into their practice guidelines and just have confidence how to navigate through the different type of patient segments. That being said, Medicare will provide reimbursement to indication as will, from our research, most of the commercial plans for this patient segment. And given the breadth and strength of our indication, we don't think NCCN is rate-limiting. It's more just sort of a nice to have. And then particularly as we explore clinical data in frontline, in other patient types and other combinations, where you may not even have full approval but support for reimbursement through, NCCN can be very important there.

All right. Dan, there was another question on NCCN, but you've covered it. What is your expectation around the ramp and uptake of Zepzelca? Do you think any meaningful uptake near-term is gated by the full approval?

Yes. I'll take the latter part again first. No. I mean it's -- from what you've heard from Dr. Sands and from our clinical team, the clinical profile and the fact that it is FDA approved, which is a rarity for this indication, will not be at all rate-limiting. What is rate-limiting is the challenge we know we have in front of us, which is a good one for our commercialization team, which is to build awareness around the data and the indication and then insure as physicians and patients get access to the therapy, that the expectations are appropriately set and that they have a good experience and realize the full product potential across the multiple segments. We'll probably be getting some combination of patients who are truly very treatment-resistant. And any extension there we can give to quality of life will be good. The biggest impact, both in terms of the market and clinical impact, will be on those patients who have a longer chemotherapy-free interval and those are the ones that will get more cycles, will get more survival and benefit. And their responses are important, but even stable disease will enable us to continue to support the quality of life. And we would imagine that the drug would continue to be used up to the point of clinical signs of progression.

All right. Dan, I got 2 similar questions, so I'm going to read both of them and then let you answer. First, what percentage of small cell lung cancer is treated in the community versus academic centers? How much work will Jazz need to do to educate physicians in academic versus the community? And question two, given that these patients have progressed, what percentage of them are treated in a community oncologist setting versus an academic hospital or cancer center setting? Do you expect the academic hospitals to be those to adopt this treatment straightaway?

Yes. Good questions. And as I showed in the pie chart in the presentation, 75% is currently treated in the -- with the community. And it's in part -- it's not super complicated care, but also kind of the urgency of care is necessary there. Just to give some color to what we're doing in both the academic and the community centers, I had referenced that we've got the target list of 1,500 prescribers, which are really the top prescribers in both segments that we're highly focused on and we've got the multifunctional team, cross-functional team of MSLs and our sales representatives in an outreach effort there. Immediately post-approval, a series of e-mail blasts going out to those folks and through a variety of means to raise the awareness. We'll be hosting a launch webinar. There's going to be virtual speaker programs. So we're doing everything we can, both virtually and then in-person where possible, to communicate to both segments. And we see that there's an opportunity for a similar uptake in both community and academic. And the good news is, as I referenced, it's fairly concentrated. And with the 72 representatives and 10 MSLs, we should be well supported for a successful launch.

Okay. Dan, I think we've probably hit this one already, but let me just ask it for completeness. In your view, how important is it for lurbi to show overall survival benefit in ATLANTIS for its commercial adoption?

Yes. I mean I think for -- what Dr. Sands and Rob has said, it's always good to have additional trials and additional confirmation of benefit and additional treatment options. But we evaluated the drug primarily for this setting on the profile with the monotherapy data. And I think as people see the data, you'll see as patients are more sensitive and get more cycles of therapy, both the response, but even more importantly, the absolute survival, goes up. But that being said, I always like to see positive clinical trials. So hoping that's what we'll see.

Great. Dan, 2 related questions, so let me combine them. One, what is the potential for expansion of the second-line small cell lung cancer patient population treated with the availability of lurbinectedin? A similar question on the decision for pricing, which seems pretty reasonable for a course of treatment, how much of a factor was consideration to try to tap into the 8,000 who don't get treated second line in addition to the 17,000 that do get treated in second line?

Yes. So it's a really good question. And Dr. Sands touched on it a little bit. And I don't have all the profiling data in front of me. Clearly, the physicians who get experience and are using lurbinectedin to have -- or Zepzelca, to have a good experience there, know it's got a reasonable chance for good efficacy and more tolerable than some of the therapies they've been exposed to, I think in those treatment decisions and choices, we will start to some of the patients that would otherwise opt out of therapy consider. I think for the physicians and patients who are not as experienced in small cell, just take a little more surround sound and publication and education and maybe peer-to-peer from the other small cell lung cancer treaters to make sure we do get the word there. But again, we're also looking with patient advocacy and other means to make sure that patients who could benefit from the therapy are aware of the treatment option.

Okay. And Dan, I think your last specific question, which I love the way it's phrased. Notice I'm not saying which analyst asked which question. Multi-hundred-million-dollar opportunity, that's quite a range, $200 million to $900 million. What indications does that contemplate? Is that just second-line small cell lung cancer? And thank you for taking my questions. Sorry I had so many. Although, again, you don't know who typed which questions, but there you go.

Yes. Without giving specific guidance, because I think I might not have a job tomorrow, so I will just stick with -- one way to think about the market potential is you take the 17,000 patients times the average course of therapy, $53,000, that gives you an immediately addressable market. And that's around $1 billion, not saying that's our guidance. And then we've got the 8,000 patients who are not being treated. So it all depends on how rapidly and what market share we end up with, the number of cycles. And then just the continued data generation that will support Zepzelca, both as monotherapy and combination second line. And then obviously, we've got plans to move into the first line and into other tumor types. So we're really excited by what we've said is a 3- to 5-year ramp to peak revenue in second line, and we'll do everything we can with the tactics and awareness to be on the earlier side.

So maybe I'll take one other question that came in late, which is how does the combination patent provide additional exclusivity now that you have monotherapy approval? Obviously, we've got potential combination data/use/labels in the future, so I'll probably wait to comment on that until that's more relevant. In general, we don't comment on our plans for how we'd defend IP, but we are always glad to have more IP. Let me give Renée and Dan the same opportunity I gave all the other speakers, to see if there are any other clarifications or additions you'd like, having heard the totality of the questions. So maybe Renée, I'll come to you first.

I would just reemphasize some of the comments that I made regarding business development and corporate business development. Seeing how this transaction that was done with PharmaMar progressed to a product approval early in an area with a significant unmet medical need, I think, is a great example of how the company is working to really leverage external innovation and then, in turn, work to leverage our internal capabilities and infrastructure, and I'm really excited to see this new option for patients.

Yes. And Bruce, I'd just add, it's fun to be actually in a license where we've got a midsized company on the other side, and we can truly demonstrate that we're the partner of choice and hopefully, that positive word-of-mouth will get out to other pharma companies as well. But it's also part of our growth strategy, which is to take an existing therapeutic area, which had been hematology/oncology, it turned out, we had a lot of solid tumor experience there, bring in additional people, and we really benefited from some people with recent experience in small cell. Add to the team, be very agile, nimble, integrated and be ready to go 2 months ahead of PDUFA. So proof is in the pudding, and we look forward to demonstrating the results.

Terrific. So maybe I can thank all of our speakers and just add a comment to go back to where I started, which is to say we're very excited about the Zepzelca approval and launch, but also really excited about how 2020 and 2021 are shaping up on the product approval side with the approval of Sunosi in Europe, the approval of Zepzelca in the U.S., an upcoming PDUFA date and potential launch of JZP-258 this year. And a hope to get a BLA in as early as the end of the year on JZP-458. Of course, as both Renée and I emphasized, we're excited about continuing corporate development activities. And then we've got some upcoming developments in our pipeline as well. We've mentioned that we completed the Phase III enrollment early on the idiopathic hypersomnia trial for 258. We're looking to move into Phase IIb on JZP-385, our essential tremor program in the first part of next year. Obviously, we've got the ongoing conduct of the Phase II/III pivotal trial for 458, data on Defitelio for prevention of acute GvHD. And then as referenced in this call, ATLANTIS Phase III top line data in the back half of this year. So lots upcoming. And with that, Kathee, I'll turn it back over to you.

Thank you, Bruce, and we want to thank each of you for taking time to join the webcast today. This will now end the meeting.