Welcome to the Jazz Pharmaceuticals plc fourth quarter and full year 2018 earnings conference call. Following an introduction from the company, we will open the call to questions. I will now turn the call over to Kathee Littrell, Head of Investor Relations at Jazz Pharmaceuticals.
Thank you, Glenn, and thanks to those of you joining our investor call today. We reported our fourth quarter and full year 2018 financial results and provided financial guidance for 2019. The press release and slide presentation accompanying this call are available in the Investors section of our website. On the call today are Bruce Cozadd, Chairman and CEO, Matt Young, CFO. Joining for the Q&A session are Daniel Swisher, President and COO, Mike Miller, our Executive Vice President, U.S. Commercial, Allen Yang, Head of Clinical Development and Acting CMO, and Jed Black, Senior Vice President, Sleep and CNS Medicine. I'd like to remind you that some of the statements we will make on this call relate to future events and performance rather than historical facts and are forward-looking.
Examples of forward-looking statements include those related to our future financial and operating results, including 2019 financial guidance and goals, corporate development efforts, future growth and growth strategy, product sales and volumes, supply challenges, product launches, regulatory approvals, ongoing and future clinical trials, data readouts, and other product development and regulatory activities, and the timing of these matters. These forward-looking statements involve risks and uncertainties that could cause actual events, performance and results to differ materially. They are identified and described in today's press release, in the accompanying slide presentation, and under Risk Factors in our Form 10-Q for the quarter ended September 30th, 2018, and our Form 10-K for the year ended December 31st, 2018, which we will file shortly. We undertake no duty or obligation to update our forward-looking statements. On this call, we will discuss Non-GAAP financial measures.
We believe these measures are helpful in understanding our past financial performance and potential future results. They are not meant to be considered in isolation or as a substitute for comparable reported GAAP measures. Reconciliation of GAAP to Non-GAAP financial measures discussed on this call are included in today's press release and slide presentation found in the Investors section of our website. I'll now turn the call over to Bruce.
Good afternoon, everyone, and thank you for joining us. 2018 was a year of significant progress across our sleep and hem-onc therapeutic areas. The expansion of our R&D capabilities over the past few years has been instrumental in accelerating and diversifying our pipeline. In sleep medicine, we've established a framework to enable us to realize the long-term value of our oxybate franchise through our continued investments in the development of new options for patients with sleep disorders. Key among these is our plan to deliver an improved and safer therapeutic option for patients with our oxybate product candidate JZP-258 that contains 90% less sodium than XYREM. We look forward to top-line data from our phase III study of JZP-258 in adult narcolepsy patients this spring.
We also advanced other key R&D programs and executed on multiple regulatory objectives, the approval of XYREM for pediatric narcolepsy and an MAA submission for Solriamfetol. For hem-onc, we are working on new drug discovery and development in cancer utilizing our CombiPlex platform and partner collaboration technologies, including exosomes and antibody-drug conjugates. With our expanded internal and partnered expertise, we are growing the breadth and depth of our hem-onc pipeline and product portfolio with multiple pre-clinical to late-stage programs, balancing innovative new product candidates with programs aimed at generating new data and indications for current products. We are generating new data for VYXEOS in a broad range of AML and MDS patient populations and pursuing new indications for defibrotide. We also continued our global expansion with the EU approval and rolling launch of VYXEOS.
In 2019, we will continue to focus on operational excellence and scalability as we grow and evolve as a global biopharmaceutical company, and we expect to deliver growth on both the top and bottom line. 2019 will be a year of significant investments in our commercial portfolio and R&D pipeline as we execute on our long-term strategy. Additionally, expanding our commercial portfolio through corporate development remains a key priority. After providing details on some of our key commercial, regulatory, and R&D activities, I'll turn the call over to Matt to update you on our financials. Let's start with VYXEOS. We made progress in growing VYXEOS sales with a sequential increase over the third quarter of 2018 and a year-over-year increase from the fourth quarter of 2017. While we are still in the early stages of driving adoption of VYXEOS, we expect meaningful growth this year.
The introduction of eight new products in less than two years has led to a crowded and noisy AML commercial market and increasingly complex treatment paradigm. In this environment, positioning VYXEOS as the essential backbone treatment for secondary AML remains critical. In the U.S., we continued physician education initiatives to support the use of VYXEOS in appropriate patients fit for intensive chemotherapy. Our initiatives emphasize VYXEOS' MOA and efficacy and the importance of intensive chemotherapy in secondary AML to provide patients a better opportunity to proceed to a transplant which can offer the potential for a cure. We were pleased to see first-time community hospital accounts ordering in the fourth quarter, demonstrating increasing interest in VYXEOS and use of consolidation in the outpatient setting.
We also observed first-time orders in academic centers, which still represent the highest volume of AML patients. For 2019, our U.S. commercial focus will expand into additional community hospitals and infusion centers while continuing to drive broader adoption in key academic centers. On the reimbursement front, NTAP, or new technology add-on payments, began in October for in-hospital Medicare patients and has been well-received by hospital pharmacies. Also, a permanent product-specific J-code went into effect in January, which should help speed reimbursement payments to hospitals. Both the VYXEOS NTAP and J-code should provide additional reimbursement confidence, support our customers, and reduce barriers to adoption. We began our rolling launch of VYXEOS in the E.U. in September. Following the NICE positive recommendation in early November, commercial sales commenced in England and Wales.
As in the U.S., our E.U. team is focused on medical education and outreach to AML-treating physicians and centers. In Germany, we received a positive NUB I status recommendation in late January, which is an inpatient add-on payment for hospitals, allowing hospitals to apply for reimbursement for new and innovative treatments. We expect sales in Germany through this process to begin during the first half of the year. We continue to navigate the complex country-specific pricing and reimbursement environment in Europe. We are also devoting substantial resources to advance our multipronged development program to support the safety and efficacy of VYXEOS in combination with other agents in standard, high risk, and relapsed refractory AML patients at different doses, in patients fit or unfit for intensive chemotherapy, and in pediatric through adult patients with AML and MDS.
Our program is designed to optimize understanding of the benefit and value of VYXEOS as the treatment backbone of AML and potentially for other hematologic malignancies. Initial data from the Cincinnati Children's Hospital on the use of VYXEOS in relapsed refractory pediatric patients was presented at ASH in December, and we expect data from another cooperative group study in a similar pediatric patient population later this year. Initial data from combination studies in fit adult AML patients from our collaboration with MD Anderson is also expected to be available later this year. Turning to Defitelio, we're pleased with the performance of Defitelio and the continued growth and penetration into adult treatment centers in 2018. We believe our educational and promotional efforts have improved physician awareness, early recognition, and more rapid interventional treatment of VOD.
We are making substantial progress with our defibrotide development program, which includes our phase III study for the prevention of VOD and three phase II studies evaluating safety, tolerability, and efficacy in prevention of acute graft-versus-host disease or acute GvHD, prevention of CAR T-associated neurotoxicity, and treatment of TA-TMA. The phase III study for the prevention of VOD has enrolled well, and we expect the predefined interim analysis in 2019 to determine the final enrollment goal of either 400 or up to 600 patients. The phase II study for the prevention of acute GvHD is also enrolling well, and we expect to complete enrollment this year. In 2019, we expect to begin enrollment in the phase II study for the prevention of CAR T-associated neurotoxicity and initiate the phase II study for the treatment of TA-TMA.
For Erwinaze, we experienced significant global supply outages in 2018 that were more extensive than in previous years, negatively impacting product availability, including in the fourth quarter. We will continue to experience multiple supply disruptions during 2019 since demand for the product exceeds the supply that we expect to receive from the manufacturer, PBL. We remain focused on delivering all available Erwinaze to as many patients as possible given the importance of asparaginase in treating ALL. Earlier this month, we received the notice of termination from PBL related to our current Erwinaze supply and license agreement. If the parties do not reach a new agreement, we will lose our license from PBL to Erwinaze at the end of the current term of our agreement on December 31st, 2020, with the exception of the right to sell certain Erwinaze inventory for a 12-month period following contract expiration.
As the BLA holder for Erwinaze, we've made significant investments in the product, and we devote extensive resources to the global commercialization of Erwinaze to maximize patient access to this essential therapy. We believe we are the best commercial partner for Erwinaze, and we hope to ultimately reach agreement with PBL to enable us to continue to commercialize the product after the expiration of the current agreement. In the unfortunate event that an agreement can't be reached, we expect to be an essential party in a negotiated transition of Erwinaze to a new licensee. We continue to make progress in our early-stage recombinant crisantaspase-based program aimed at developing a new asparaginase product candidate with a reliable supply chain and a potentially improved target profile. We expect to provide updates on this program later this year. Now on to our sleep therapeutic area, starting with Solriamfetol.
As we announced in December, the Solriamfetol PDUFA date was extended to March 20, and we are working with FDA toward a final label. We expect a DEA scheduling decision within one quarter following FDA approval. We look forward to launching this meaningful treatment option for patients living with excessive daytime sleepiness or EDS due to narcolepsy or OSA. Our commercial team continues to prepare for launch, including the expected salesforce expansion after approval. The combined sleep salesforce would cover both XYREM and Solriamfetol. In the fourth quarter, we submitted Solriamfetol's EU marketing authorization application. Timing of the EU regulatory process can vary, but our current estimate is that we could receive EMA approval as early as the end of this year. On the development side, we have unblinded the phase II proof of concept study in Parkinson's disease. The primary objective of this study was safety and tolerability.
Solriamfetol was well-tolerated in this patient population up to the highest dose. Efficacy assessments in this study were exploratory and included measures of the ability to stay awake and excessive sleepiness. On the ability to stay awake, we observed dose-dependent effects based on the Maintenance of Wakefulness Test that separated Solriamfetol from placebo at the highest dose. We also observed reductions in excessive daytime sleepiness on the Epworth Sleepiness Scale, or ESS. However, a large placebo response on the ESS precluded a statistically significant separation of Solriamfetol from placebo. We look forward to presenting the full data in May at the American Academy of Neurology meeting. We are currently in the process of prioritizing multiple development opportunities for Solriamfetol, and we'll provide further updates on our plans later this year. XYREM.
We're pleased with the strong XYREM performance in the fourth quarter and full year 2018, with bottle volume growth of 10% in the fourth quarter and 9% for the full year compared to the same periods the prior year. The average number of active XYREM patients increased to 14,300 in the fourth quarter of 2018, up 6% compared to the same period in the prior year. In January, we refreshed our disease awareness program, which will run throughout the year. The morethantired.com website had approximately 350,000 unique visits in the first month of 2019, more than double the average monthly site visits in 2018. Importantly, we observed a doubling of the number of unique visitors completing screening tools such as the Epworth Sleepiness Scale and Swiss Narcolepsy Scale.
We also observed an increase in the rate of newly diagnosed narcolepsy patients in the U.S. in 2018 and are confident that continued disease education efforts can result in further increases in narcolepsy diagnosis. As a separate initiative, our account reimbursement managers continue to educate healthcare providers' offices on effective interactions with payer utilization management tools. We expect to fully launch in the pediatric narcolepsy indication later this quarter after we finalize the addition of information for pediatric narcolepsy patients and their caregivers in the XYREM REMS . On the development front, we completed randomization in our phase III study of JZP-258 in adult narcolepsy patients in late 2018 and began enrollment of patients in our phase III idiopathic hypersomnia study in the fourth quarter. We are looking forward to sharing top-line results from the JZP-258 narcolepsy phase III study this spring.
We have received many questions about the study design as we approach the unblinding. The JZP-258 phase III study is a randomized withdrawal study and has a primary endpoint measuring the change in weekly number of cataplexy attacks and a key secondary endpoint measuring the Epworth Sleepiness Scale score from the end of the stable dose period to the end of the randomized withdrawal period. We have included a slide in our earnings deck illustrating the study design. In closing, 2018 was a very productive year. We are starting 2019 with a strong foundation to support global growth with four key marketed products, one near-to-market product, more than 20 active R&D studies, access to innovative platform technologies, and a strong balance sheet with $2.4 billion in available capital. We expect to advance our preclinical and clinical pipeline and achieve multiple clinical development milestones.
Generating strong returns for shareholders and diversifying our pipeline with highly differentiated novel therapies remain a priority in 2019. Finally, we look forward to launching XYREM for pediatric narcolepsy and Solriamfetol for the treatment of EDS in patients with narcolepsy and OSA following FDA approval and DEA scheduling. Matt, now I'll turn the call over to you.
Thanks, Bruce, and good afternoon, everyone. We are pleased with our strong year-over-year growth as we continue to execute on our business model. We made significant progress in 2018, delivering double-digit growth in our top and bottom line. In 2018, total revenues were $1.9 billion, an increase of 17% over 2017. Revenues in the fourth quarter of 2018 increased 9% to $476 million, compared to $436 million in the fourth quarter of 2017. XYREM net sales for 2018 were $1.4 billion, up 18% from $1.2 billion in 2017. Net sales of XYREM for the quarter were $375 million, up 20% from $312 million in the fourth quarter of last year.
Our XYREM net sales guidance for 2019 is in the range of $1.53 billion-$1.57 billion, representing expected growth of 10% over 2018 at the midpoint. The guidance reflects the 7% price increase that we took in early January on our expectation of a return to formalized volume growth in the mid-single digits for 2019, absent the tailwind of 2018. We are looking forward to continued growth in XYREM and expect our oxybate franchise to be a key contributor for many years. As a reminder, as with many specialty products, net sales can be impacted by typical industry payer churn in the first quarter. Turning to Erwinaze, net sales for 2018 were $175 million, a decrease of 11% compared to 2017.
Fourth quarter net sales were $24 million, a decrease of 49% compared to the fourth quarter of 2017. Our Erwinaze net sales guidance for 2019 is in the range of $160 million-$195 million. We experienced supply disruptions in early 2019 and the wide range of our guidance reflects our expectation of further supply disruptions throughout the year. In 2019, we also expect some quarterly variability, depending on the timing and extent of those disruptions. Defitelio net sales in 2018 increased 12% to $149 million compared to $134 million in 2017. Fourth quarter Defitelio net sales were $38 million compared to $36 million in the same period of 2017.
We believe our commercial initiatives in 2018 positively impacted Defitelio's performance. 2018 U.S. sales were $55 million, up 43% compared to 2017. Our guidance for Defitelio net sales for 2019 is in the range of $155 million-$180 million, which at the midpoint represents year-over-year growth of approximately 12%. VYXEOS net sales in 2018 were $101 million compared to $34 million in 2017. VYXEOS was launched in the U.S. in August 2017 and in the EU in September 2018. 2018 results included minimal EU sales. For the quarter, net sales were $26 million compared to $24 million in the same period last year.
We were pleased to see double-digit growth in the U.S. sequentially from the third quarter of 2018, as well as contribution of sales from the EU. Our VYXEOS net sales guidance for 2019 is in the range of $120 million-$150 million, representing a 34% increase over 2018 at the midpoint. This guidance reflects continued growth in the US and an increasing contribution from the EU. As we make positive progress on price and reimbursement, we estimate EU sales contributing up to 10% of our 2019 VYXEOS sales. For Solriamfetol, we have included minimal net sales contribution in our 2019 revenue guide. This guidance assumes a U.S. launch mid-2019.
For 2019, we expect continued strong top line growth with estimated total revenues in the range of $2.05-$2.13 billion, an increase of 11% compared to 2018 based on the midpoint of the range. Turning to operating expenses, we've been strategically increasing our investments in R&D and SG&A, both in absolute dollars and as a percentage of revenues as we expand our development pipeline and prepare for and execute multiple product launches. In 2018, adjusted SG&A expenses increased 21% to $549 million or 29% of revenues compared to $455 million or 28% of total revenues for 2017.
Adjusted SG&A expenses for the fourth quarter of 2018 increased 17% to $142 million or 30% of total revenues compared to $121 million or 28% of total revenues in the fourth quarter of 2017. In 2018, the increase included expenses related to pre-launch activities for the anticipated approval of Solriamfetol in the U.S. and the rolling launch of VYXEOS in the EU. For 2019, our adjusted SG&A expenses are expected to be in the range of $620 million-$650 million or 29%-31% of 2019 revenue guidance.
The increase in adjusted SG&A expenses in 2019 is driven in the most part by our investment in the pre-launch and launch activities of Solriamfetol in the ex-US and EU, as well as continuing EU launch of VYXEOS and the launch of XYREM for pediatric patients in the U.S., as well as pre-launch activities for JZP-258. The incremental spend for these key growth initiatives is in the range of $70 million-$80 million, and we would expect a return on these investments in the coming years. As a reminder, Solriamfetol is our first retail product requiring a significant upfront investment. While OSA is a large market opportunity, currently less than 10% of patients are drug-treated with wake-promoting agents. As a result, a key portion of our initial investments is focused on building the market through disease awareness as well as other educational efforts.
Adjusted R&D expenses for 2018 increased 21% to $197 million compared to $162 million in 2017, or 10% of total revenue in both periods. Adjusted R&D expenses for the fourth quarter of 2018 increased 19% to $51 million or 11% of total revenue compared to $43 million or 10% of total revenues in the same period of 2017. The increase in adjusted R&D expenses in 2018 reflects our continued investment in internal and partnered R&D programs and our EU regulatory submission for Solriamfetol.
For 2019, our adjusted R&D expenses are expected to be in the range of $235 million-$265 million, or approximately 11%-13% of 2019 revenue. This guidance includes expenses related to our early and late-stage development programs, including our JZP-258, Solriamfetol, VYXEOS, defibrotide, and asparaginase programs, the continued support of our partner programs, and IND-enabling work with our CombiPlex platform. The adjusted effective tax rate for 2018 was 15%, principally reflecting favorable impacts of FIN 48 and valuation allowance releases. Without these favorable impacts, the adjusted effective tax rate in 2018 would have been approximately 18%, which is consistent with our expected normalized rate.
We expect that our 2019 adjusted effective tax rate will be in the range of 17%-19% based on our current business. Adjusted net income for 2018 increased 24% to $839 million or $13.70 per diluted share, compared to $677 million or $11.04 per diluted share in 2017.
Fourth quarter 2018 adjusted net income increased 22% to $220 million or $3.64 per diluted share, compared to $180 million or $2.95 per diluted share for the fourth quarter of 2017. 2018 and fourth quarter 2018 adjusted net income included the benefit of a lower tax rate and lower net interest expense, higher invested cash balances. As a reminder, during the fourth quarter, we made significant share repurchases, which positively impacted fourth quarter 2018 adjusted EPS. These share purchases will also benefit our 2019 adjusted EPS, which we estimate will be in a range of $14.30-$15, or year-over-year growth of approximately 7% at the midpoint.
Please note that our guidance assumes weighted average diluted shares outstanding of approximately 58 million. In 2018, we generated $799 million in cash from operations versus $693 million in 2017. During 2018, we returned $524 million of capital to shareholders through the repurchase of approximately 3.5 million shares, including $447 million in the fourth quarter of 2018. As of December 31st, 2018, the remaining amount authorized under the share repurchase program was $379 million. As of December 31st, we had $825 million in cash equivalents, and investments, borrowing capacity under our revolver of $1.6 billion and $1.8 billion in outstanding principal balance of our long-term debt.
In 2019, we expect to pay up to $81 million in milestones related to Solriamfetol approval and DEA scheduling. These payments would be capitalized on our balance sheet as an increase in the value of our intangible assets and amortized over an estimated useful. Over the past several years, we have consistently delivered strong top and bottom line growth for shareholders while making considerable investments in the future of the company. With approximately 40% of our top line revenues flowing through to after-tax profits, we expect to continue to make significant investments in our business, including a focus on key value drivers and the scale-up of our R&D programs over time.
We also plan to maintain ample capital for corporate development transactions as we identify opportunities to further diversify our commercial and R&D portfolios consistent with our strategy and commitment to deliver short and long-term growth for shareholders. Thank you for joining us on the call today, and I'll now turn the call back over to Kathee.
Thank you, Matt. We kindly request that you limit yourself to one question during this call so that everyone has an opportunity to ask a question. We will gladly address any additional questions after the call, or you can reenter the queue. With that said, operator, please open the line for questions.
Thank you. Ladies and gentlemen, if you have a question at this time, please press star and one. If your question has been answered or you wish to remove yourself from the queue, please press the pound key. Our first question comes from Brandon Folkes from Cantor Fitzgerald. Please go ahead.
Hi. Thanks for taking my question, and congratulations on the good results. Firstly, is there anything in the settlement agreements with XYREM generic filers that would be triggered if you had a hard switch there to 258? Secondly, as we look to the 258 results later this year, are there any key study differences that we should keep in mind compared to the XYREM studies? Thank you.
Brandon, on your first question, is there something in the existing settlement agreements that would be specifically triggered by a hard switch itself? I think the answer is probably no, but there are provisions that relate to a potential decline in sales of XYREM, generally, and clearly that would have an impact on that, but not specific to that. On your second question, which is differences in study design, maybe I'll refer that over to Jed Black.
Yes. Each of the three randomized withdrawal studies that have been conducted have some differences. The first was an adult study many years ago. The second was a pediatric study recently. The third is an adult study again. The patient population may vary a bit given the time difference between the two adult populations. The study design has some nuances that are different, but the overall theme is the same.
Okay, great. Thank you very much.
Thank you. Our next question comes from Akash Tewari from Wolfe Research. Please go ahead.
Hi. Our understanding is that your current collaborations with Spanx on a next gen Erwinaze, you don't really have to disclose where they are until you kind of enter phase II, III. Can you help us understand, in a best-case scenario, what's the earliest you could get those products onto market? Frame to us the kind of clinical development path ahead. Thanks.
Yeah. You know, we've disclosed only limited information about our progress on that program. We did say today we'll provide updates as we go through this year. You know, you're generally right that we're not obligated to make disclosures until we're farther along. On the clinical development, you asked specifically when we would get to market, and we can't answer that question right now without giving more color on the development programs. But it's our goal to get to market as soon as we possibly can. You know, particularly in a situation where the current Erwinaze product has periods when it's not available and patients need therapy, we'd like to do everything we can to make that product available just as soon as possible.
On the clinical development and regulatory pathway, I think we've said before that the key objective in that program would be to demonstrate that we successfully deliver ac-
At an appropriate level, and that we do that safely. That is different from doing a long-term outcome study where you're actually measuring, you know, multiyear survival rates, because the regulators clearly understand the impact of that sufficient level of active enzyme and what that does in the treatment of. Think of it almost as a PK and safety endpoint. You're trying to make sure you're, in fact, delivering active agent safely at the appropriate levels to these patients.
Thanks so much.
Thank you. Our next question comes from Umer Raffat from Evercore ISI. Please go ahead.
Hi. Thanks so much for taking my question. One's a quick clarification for Matt and one perhaps for you, Bruce. Matt, I noticed the low end of the guidance doesn't include any solriamfetol as per my math. Am I not doing my math right, which is very possible? Bruce, I noticed the 258 trial has 4 different groups of narcolepsy patients based on their prior treatment status. Presumably, the design was in consultation with FDA. My question is FDA interested and/or focused on seeing consistency in the trends across these groups of prior treatment status? Because in theory, given the small size of this trial, you could expect some variability across, let's say, a XYREM naive versus XYREM experienced, et cetera. Thank you very much.
Yeah. Matt, you wanna take the first part?
Sure, Umer. The first part, you are correct. You didn't miss anything. Given some of the timing uncertainties related to approval, ultimately scheduling and when we would be launching. Then also with that, payer negotiations, which, you know, are not, you know, perfectly determinable in terms of timing, the low end of guidance would contemplate effectively no sales for solriamfetol. But there are some minimal sales in there in the guidance range.
On your second question, maybe I'll have Jed take that one as well.
Sure, yeah. The FDA is interested in efficacy and safety. However, as you highlighted, this is one of the differences in this adult study with two five eight versus XYREM that I referenced in the prior comment. The goal here is to evaluate all potential patients that might be appropriate for a two five eight treatment. We've included them in the study.
Thank you very much.
Thank you. Our next question comes from Ronny Gal from Bernstein. Please go ahead.
Thank you for taking my question. Just a quick question about your obligations and not to launch a competitive program if your agreement with Porton does not renew. Essentially, you do have a different formula and other manufacturing process you already got from Phoenix. Can you bring that one to market if your agreement expires? And second, now that we have both settlements and we know when XYREM generics are coming to the market, are you regulatorily barred from buying a competitive product? Or, from perspective of the FTC as you understand it, you may buy a kind of like a pre-commercial product from a competitor in the same market.
Yeah. Ronny, on the first question, we do have the freedom to move our recombinant crisantaspase-based program all the way through to the market. On the second question, I think I'm gonna decline to answer. You know, you're essentially asking a question about what's deemed competitive and what's not, and that's a complex question. You know, we do have a strong commitment to the therapeutic areas we're in, and we think we're an excellent developer and commercializer of medicines for serious sleep disorders. Where appropriate, you know, we'll seek outside opportunities as well as our internal development pipeline to continue being a leader in the area, but I can't comment on a specific opportunity.
Thank you.
Thank you. Our next question comes from Gary Nachman from BMO Capital Markets. Please go ahead.
Hi, good afternoon. Now that volume growth has been accelerating nicely for XYREM, do you plan on stepping up any of your DTC efforts even further to improve awareness and diagnosis rates? Just comment on how much more you can do there. When do you expect you'll start to see a real benefit from the pediatric indication? How long will that take? Thanks.
A couple comments, Gary. I think you know, I think as Matt commented on his guidance for 2019, you know, we expect to return to a more normalized mid-single-digit volume growth rate for XYREM. Remember that we had a little extra growth in 2018 that we don't think recurs in 2019. We're very pleased with that volume growth. To be clear, the trends are all good, but I don't wanna overstate that case. On your question about DTC, I'll just point out, you know, technically we're doing disease awareness efforts there. We're not doing product-specific DTC. But maybe I'll turn it over to Mike to talk about what we see as the impact of that initiative and his comments on the pediatric indication.
Thanks, Bruce. Yeah, we're gonna continue our disease awareness campaign for narcolepsy in 2019. We've committed to that. We have seen an increase in diagnosis, and we're especially pleased with the traffic to morethantired.com and the screener completions that we've witnessed. We're excited about that, and we continue to see good early demand indicators.
On the pediatric front, we will launch in late Q1. We are notifying payers now around some of the payers have policies around age, and we're educating them around our indication, but we will kick that off at the end of Q1.
Okay. Thank you.
Sure.
Thank you. Our next question comes from Ami Fadia from SVB Leerink. Please go ahead.
Hi, good evening. Maybe two quick questions from me. You talked about some minor design differences between the prior XYREM studies and the JZP-258 study, as well as some of the four subgroups, in the JZP-258 study. Would the efficacy results be comparable across these studies given these differences? And secondly, could you remind us of any key data sets that we should be watching out for the VYXEOS program, some of the combination studies you're doing, in 2019? Thanks.
Jed, maybe I'll have you address the question about would you expect to see or is it important to see comparable efficacy across groups or trials?
Yes. I think there was a comment made previously that suggested that one could anticipate some difference in response depending on what prior treatment a patient was on. This is information that is definitely possible. We are expecting, and the study was designed and powered to show efficacy, and we're expecting to see efficacy.
Allen Yang, maybe I could have you comment a little bit on upcoming data generation.
Sure, sure.
for VYXEOS.
Yeah. I think you asked specifically around data generation, combination studies, et cetera. You know, our strategy for VYXEOS is remains unchanged. We believe in the product. We believe that it's an excellent product for patients with AML and high-risk disease. You know, our strategy is unchanged. You know, in terms of combinations with other agents, there's a lot of noise, a lot of new agents approved, which is exciting for AML patients. There are already two venetoclax studies listed on ClinicalTrials.gov. Expect additional studies in that area, both internal and external collaborations. Of course, FLT3 combination studies will come online this year as well, and then IDH or IDH1 and IDH2 inhibitor studies as well.
more importantly, expect that we'll be generating the data to make this the backbone of AML therapy. Expect collaborations with cooperative groups looking at standard risk AML, younger populations of AML, and then sort of comparative data in MDS as well as, against HMA or hypomethylating agents. I believe that sort of suite of studies or those sort of groups of studies will sort of establish VYXEOS as the backbone of AML therapy.
I guess just a clarification. When could we see any of this data in 2019 or 2020?
Yeah. Some of the data will come online. Last year at ASH, there was the release of the University of Cincinnati IST looking at VYXEOS in relapsed/refractory pediatric AML study, in AML, pediatric AML. There is a cooperative group study, the COG study, which we believe is fully enrolled and the data has matured, and we've seen that data, and we're excited about that as well. In addition, the University of Cincinnati has announced a combination study as well with venetoclax following their initial pediatric relapsed/refractory AML study. There's this ongoing collaboration we have with MD Anderson, and they've announced studies in combination with gemtuzumab and venetoclax.
We can't control how fast they enroll those studies, but they traditionally roll them very quickly, and they're smaller studies, so there could be interim data later this year.
Thank you.
Thank you. Our next question comes from David Amsellem from Piper Jaffray. Please go ahead.
Just a couple of quick ones on Solriamfetol. You talked about the EDS data in Parkinson's patients. Realize you still have decisions to make here, but you know, is there anything we can glean into that data regarding your willingness to pursue other EDS populations and maybe talk to what your latest thinking on that is? Secondly, regarding DEA scheduling, assuming it gets a Schedule IV designation, which I believe is what you're aiming for, can you tell us what that means in terms of what you can and cannot do in terms of sampling and branded DTC and whether that's the latter is in the cards? Thanks.
On your Solriamfetol question, maybe I'll have Dan take that one.
Yeah. Thanks. Yeah, on Solriamfetol, I mean, we remain very enthusiastic about the product profile and what we've seen across all the studies, including in narcolepsy and OSA. We're prioritizing, you know, a range of areas where excessive sleepiness or fatigue could be key factors. We're just putting that in line with what we know about Parkinson's and where are the biggest market opportunities, where are the best sort of return for investment, probability of success, et cetera. Obviously near-term, we're looking to get to approval and launch, but we'll be updating on our development strategy later this year.
On scheduling and approach, Mike, you wanna take that?
Yeah, sure, Bruce. Just a reminder that DEA assigns the scheduling to the product, and then it's really the State Board of Pharmacy that directs how those scheduled products should be handled in respective states. Generally, as you suggested, a schedule four, you could do DTC, you could do sampling, that would not be restrictive.
Thank you.
Thank you. Our next question comes from Jason Gerberry from Bank of America. Please go ahead.
Hey, good evening. Thanks for taking my questions. Just one for me, maybe Bruce or Matt. Just sort of curious on the M&A front, as you kinda look back on 2018, if you can just give us a general sense of maybe what are one or two biggest reasons, you know, that maybe has held up the company from being more active on the M&A front and doing a larger transaction to address sort of the XYREM concentration issue? Just trying to get a sense of, is it valuation? Do you feel like it's just the assets that you're looking for, maybe predominantly in hem-onc, you know, the value arbitrage opportunity is not quite there yet.
Any color that you can give us in terms of sort of maybe what's been the hang-up from the M&A perspective would be helpful. Thanks.
Sure, Jason, it's Matt. I'd say the biggest thing is just timing's difficult to predict. I think we've had a lot of ongoing engagement and continue to feel really good about the companies we're involved with, you know, whether that be in the context of partnerships or acquisitions of varying stages of development or proximal to commercialization. That continues to be a robust dialogue. As we've said many times, you know, predicting exactly when you'll see, you know, value, risk and the right proposal align where there's the right complementarity is really hard to predict for. Most of all of our dialogues that have resulted in transactions have been the product of years of discussion.
I'd say the biggest issue is just, it's difficult to predict that and, you know, I feel very good about the opportunity in front of us today, as we said last year. That said, we did take the opportunity, given we did deploy less capital than we had anticipated over the course of the year to buy back more stock, with some of that excess liquidity, which, you know, I think we'll be pleased that we've done that. You know, we will continue to look both within the hem-onc domain, where there is obviously a lot of targets, but as you can see with the Codiak collaboration, we're looking broadly in precision oncology across sleep and relevant adjacencies in the CNS world.
We'll, as we said before, look beyond that. I think there's plenty of opportunity out there for us to execute on bringing in new assets to the company.
Got it. Thank you.
Thank you. Our next question comes from Annabel Samimy from Stifel. Please go ahead.
Hi, thanks for taking my question. I just want to go back to VYXEOS. You mentioned, given the complexity of the AML treatments, there's clearly an urgency to establish the backbone, but it seems like a lot of this is gonna require, you know, meaningful readout of studies. You have a few coming out this year. To what extent does your guidance include some expansion to these other populations? How much is the survival data from SOHO really helping this growth right now? Does your guidance include any expansion to other populations other than the well-studied population? Is this growth maybe better use in consolidation? Like, what's driving the growth right now? Thanks.
Maybe I'll turn that one over to Dan.
Yeah. Okay, thanks. Yeah, I think just broadly, there's plenty of opportunity for us to penetrate further into secondary AML, and now we can penetrate not only in the U.S., but internationally as we're getting very nice initial outcomes from pricing and reimbursement in the major European countries. I think we're facing two, you know, issues in the market. One is, for 40 years, people have used 7+3, and that's been their standard therapy. We have to really get the message across about the superior profile of our drug relative to 7+3, which is, you know, you look at the study and it's very clear. If you haven't read that and you haven't thought about it's easy just to think of it as a reformulated 7+3.
We really have to land the message that to change medical practice, which just takes repetition, medical education, you know, a fair amount of that, and it's coming at a time when eight new products are in the market and there's a lot of noisiness. It takes more voice and more impact and more repetition to land that. We're very confident with the data we have in hand and the outcomes we're seeing in the marketplace for those who've adopted the therapy, that we have plenty of growth. The growth in the current indication is what's driving our guidance.
Is it also coming from increased use in consolidation?
Yes. Yeah. Importantly, making sure there's a continuum of care, that people are getting sufficient induction therapy, sometimes requiring two, and then going on for consolidation therapy as well.
Okay, great. Thank you.
Thank you. Our next question comes from David Risinger from Morgan Stanley. Please go ahead.
Yes, thanks very much. I don't know if I missed it. I did hear the instruction to ask just one question, so I'll do that. With respect to the next gen asparaginase, what's the timing of that? I mean, when you know, what will be the pathway to a filing with the FDA, and then when can you launch that product? Thank you.
Yeah, David, we did address that question a little bit earlier, so we'll follow up with you after this call and just make sure you've got that. You know, short answer is we haven't given a date, but we're pursuing what we think is, you know, the fastest possible path to making that product available to patients, particularly given the ongoing inability to supply enough Erwinaze to satisfy demand. We think we've got a clinical regulatory strategy that accomplishes that.
Thank you. Our next question comes from Jessica Fye from J.P. Morgan. Please go ahead.
Great. Thanks for taking my question. Mine's for Allen. Just following up on Ami's question. Can you talk a little bit more about the MD Anderson study evaluating the combination of VYXEOS and venetoclax in both relapse refractory and untreated AML? It sounds like you can't comment on things like exactly how many patients we might be able to see at ASH. But can you maybe speak to what you would consider encouraging in each of those groups, relapse refractory and newly diagnosed, from a CR rate? And then can you also just help us understand that study design a little better? How many relapse refractory patients are targeted for the lead-in, versus expansion cohort A and then the cohort B in de novo AML?
Yeah. I'll tell you as much as I know about the study, and, you know, I have to admit that I'll have to refer to a lot of the details around my team around this. But it is a collaboration. It's just one of many studies that we plan to do with MD Anderson. I think more exciting than the study itself is our collaboration and sort of the novel approach that we're taking there to do studies quickly with them. If I remember correctly, it's 46 patients. There's no sort of dose escalation phase. There's a sort of safety run-in phase as well, and it's looking at both frontline patients as well as relapse refractory patients as well. I think, you know, the complexity at MD Anderson, having trained there, is it's a huge referral center for patients with AML.
Depending on what their previous treatment was, their condition status, there can be variability in sort of what you would expect as the response rate, you know, whether they were secondary AML, first relapse, second relapse, whether they've had a transplant or not. MD Anderson has very large databases, so they can sort of gauge what they think the relative expected outcome will be. Whether they'll release that is up to them. Again, we're collaborating closely with them. Again, it's not the only venetoclax study that we plan to have. I mean, the University of Cincinnati has announced one for relapse refractory AML in the pediatric population. We expect to have our own studies, and, you know, it's an area of huge interest. All the investigators would like to do that study.
I think there's challenges in trying to get both of the products to do a study, but we've been very cooperative and open to working with investigators to do combination data, not only with venetoclax, but other agents as well.
Okay. Maybe just following up on that, maybe recognizing that, there might be wider differences depending on the specific profile of the relapsed refractory patients that end up in this study and maybe the, even by virtue of the fact that they're being treated at MD Anderson. What about for the de novo AML patients? What would be kind of encouraging data for that combination in those patients?
Yeah. Again, I think it depends. Let me back up and sort of talk about the, what you would expect to see in patients, right? If you go back to the original Lancet publication in JCO from last year, I think what people often forget, in that pivotal phase III study, it was a very high-risk population. If you ask, clinicians what they would expect the standard CR rate for frontline AML is, they may quote numbers as high as 80% for adults. That includes low risk and standard risk patients. Now, this was a high risk population, therapy-related AML, secondary, AML, and the CR rate for 7+3 was only 25%. Now, with VYXEOS, where you actually gave the same two drugs at about a third or less dose, the CR rate jumped to 37%.
I mean, this is phenomenal data, and I don't think that everybody fully understands that, and that's an important message that we have to get across. You know, I think the challenge with venetoclax is that it adds on to chemotherapy. The single agent activity is somewhat limited, and when you add it to a hypomethylating agent or low-dose cytarabine, it seems to increase the response rate. But what it is inhibiting the BCL-2 in apoptotic pathway, so you're gonna add some toxicity, some myelosuppression. What is that therapeutic window you can adjust? You know, I think depending on the population, you would see, you would expect to see significant increase, but would it be significantly increased beyond what the CombiPlex technology is adding to 7+3? I think that's still unknown yet.
Okay. Got it. Super helpful. Thank you.
Thank you. Our next question comes from David Maris from Wells Fargo. Please go ahead.
Hi. Bruce, can you describe the current state of the Porton discussions? In your comments, you mentioned you used the word hopeful, but in their press release, they say that the effort was to pursue better value for money, which sounds like they just want more of the pie. How did you get to this point? To help investors put things in perspective.
Is it fair to say that Erwinaze has a lower margin than the overall operating margin when you include the current profit share? Thank you.
Yeah, David, good question. In terms of the current state, they've delivered the termination notice, and they've essentially said they're gonna run a process. Our hope is to participate in that process. Until we hear different from them, that's our assumption about what will play out in the period ahead. As to where that'll end up, both in terms of who the partner is and on what terms, you know, too early to say. We are hopeful that we'll be an active participant in that process and continue to believe partner on multiple dimensions. It is a lower margin product. I'm not sure if it's our lowest margin product, but it probably is, given the structure of that arrangement. I think your assumptions there are correct.
Thank you very much.
Operator, this will be our last question coming up.
Sure. Our last question comes from Esther Rajavelu from Oppenheimer. Please go ahead.
Thank you for squeezing me in. On Defitelio, when is the interim analysis? Apologies if I missed this earlier. What should we expect from you in terms of communication after the interim?
Yeah, we haven't given a precise timeline for that interim analysis other than to say, based on successful enrollment, we do expect to hit that predetermined interim analysis this year. In terms of what you'd hear, you know, we said we'll use that interim analysis to decide ultimate study sizing as to number of patients. You know, we'll be back to you with telling you where we're gonna end up on that and what that implies about timeline, but after the interim analysis.
Got it. Thank you very much.
Thank you. This concludes our Q&A session. At this time, I'd like to turn the call back to Kathee Littrell, Head of Investor Relations at Jazz Pharmaceuticals, for closing remarks.
Okay, thank you, Dylan. Thank you again for joining us today. We will be participating in the upcoming TD Cowen Healthcare Conference. This now ends our call.
Thank you, ladies and gentlemen, for attending today's conference. This concludes the program. You may all disconnect. Good day.