Welcome to the Jazz Pharmaceuticals plc fourth quarter and full year 2016 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, Sandra, and thanks to each of you for joining our investor call today. We reported our fourth quarter and full year financial results and 2017 financial guidance in a press release. The release and the slide presentation accompanying this call are available in the Investors section of our website. With me for today's call are Bruce Cozadd, Chairman and CEO, Matt Young, Chief Financial Officer, Russ Cox, Chief Operating Officer, Mike Miller, Head of U.S. Commercial, and Karen Smith, our Global Head of R&D and Chief Medical Officer. Following some remarks, we'll open the call for your questions. I'd like to remind you that some of the statements we will make on this call relate to future events and future performance rather than historical facts and are forward-looking statements.
Examples of forward-looking statements include statements related to our 2017 financial guidance and goals, potential FDA submission approval and launch of Vyx, our corporate development efforts, future product sales and volume, future litigation and intellectual property-related events, our expectations with respect to a potential launch of a generic version of Xyrem, future inventory and supply challenges, future legislative changes, ongoing and future clinical trials and other product development activities, including study initiations and completions, top-line data readouts and other clinical and regulatory events, and the timing of such events and activities. These forward-looking statements involve numerous risks and uncertainties that could cause actual events, performance and results to differ materially.
These risks and uncertainties are identified and described in today's press release, the slide presentation accompanying this call, and under Risk Factors in our Form 10-Q for the quarter ended September 30, 2016, and our Form 10-K for the year ended December 31, 2016, which we will file shortly. We undertake no duty or obligation to update any forward-looking statements we make today. On this call, we will discuss several non-GAAP financial measures, including historical and expected 2017 adjusted net income and the related per share measures and historical and expected 2017 adjusted SG&A and R&D expenses. We believe that these non-GAAP financial 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.
Reconciliations of GAAP to non-GAAP financial measures discussed on this call are included in today's press release and the slide presentation accompanying this call. Both are posted 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.
2016 was a busy and productive year as we drove strong organic growth of Xyrem and Defitelio, including a U.S. Defitelio NDA approval and launch, completed enrollment of 3 JZP-110 Phase 3 clinical studies and the Phase 3 study of Xyrem in pediatric narcolepsy, advanced key projects in the R&D pipeline, including announcing two oxybate product candidates that have the potential to offer new and improved treatment options for narcolepsy patients and initiating a Phase 3 study of defibrotide in the prevention of veno-occlusive disease in high-risk patients post-stem cell transplantation, initiated the rolling NDA submission for VYXEOS in the U.S., received regulatory approval and began shipments of Xyrem from our Athlone manufacturing facility, and executed multiple corporate development transactions, including the acquisition of Celator, the agreement with Pfenex around hematology assets, and the investment in Arrivo that has the potential to add future innovative products or product candidates to our portfolio.
In 2017, we are looking forward to delivering solid top and bottom-line growth, expanding our commercial portfolio with potential FDA approval and U.S. launch of VYXEOS, executing on R&D, including multiple expected clinical trial initiations, completions, results, and regulatory submissions, as well as continuing to diversify our portfolio through corporate development activities. I'll now provide an update on key commercial, legal, regulatory, and clinical development activities and highlight some key events that we expect in 2017. I'll then turn the call over to Matt to review our financial results for the quarter and full year and provide 2017 financial guidance. In our sleep therapeutic area, Xyrem delivered strong sales growth during the fourth quarter and full year 2016. Full year 2016 and fourth quarter 2016 bottle volume growth for Xyrem was 6% compared to the same periods in 2015.
Following completion of enrollment of patients and prescribers in our current REMS in August, second half 2016 volume growth was approximately 7% compared to second half 2015. The average number of active Xyrem patients grew to approximately 12,925 in the fourth quarter. For 2017, our growth efforts are aimed at increasing disease awareness and accelerating diagnosis, focus sales targeting efforts on physicians with high narcolepsy patient volume and low Xyrem share, and reducing payer burdens through our field reimbursement team. On disease awareness, we have further analyzed insurance claims databases to assess the impact of our larger 2014 narcolepsy disease awareness TV campaigns. Following this campaign in 8 metropolitan areas across the U.S. We observed a statistically significant improvement in Multiple Sleep Latency Test use and narcolepsy diagnosis rate in the test cities compared to controls.
In light of a general slowing in growth of overall narcolepsy diagnosis, earlier this year, we kicked off a narcolepsy disease awareness campaign leveraging network and cable TV, as well as social and digital media platforms, which, based on the test market results, should accelerate the rate of diagnosis of this debilitating condition. Our Xyrem field reimbursement support team, which launched in August, has reached approximately 250 target accounts across the U.S., and we have observed measurable success on the prior authorization, or PA, approval rates in this target group versus the national average. After assessing the positive impacts of the field reimbursement team, we plan to expand the size of this team from five to 11 this year to allow more consistent national coverage, to reduce denials of PAs in key accounts, and to reduce the time to first prescription.
Next, I'll highlight our R&D plans for Xyrem and other oxybate-related programs. We anticipate submitting a Xyrem supplemental NDA later this year, which will include data from the pediatric study and the study report for the FDA pediatric written request that we received in 2014. We are advancing development of JZP-507, our product candidate that has a 50% reduction in sodium content compared to Xyrem and has demonstrated bioequivalence to Xyrem in a pilot study. We are not planning to conduct our previously anticipated pivotal BE study because we believe that we have a more efficient path to obtain the data necessary to complete the NDA submission. We are evaluating our plans to complete this submission by the first quarter of 2018, including the potential for earlier submission.
We are also moving forward with another product candidate, JZP-258, that has a 90% reduction in sodium content compared to Xyrem. We plan to initiate a global phase 3 study of JZP-258 in narcolepsy patients this quarter. We expect to complete the study in the second half of 2018 to support a planned NDA submission in 2019. Turning to a brief legal and intellectual property update on Xyrem. Patent litigation continues in the District Court in New Jersey. The trial with Roxane is scheduled to commence on May 1 with respect to our Xyrem formulation patents and two of our patents related to the drug-drug interaction with divalproex sodium. The judge recently bifurcated and stayed the four REMS-related patents in the Roxane case. A separate consolidated case that includes the remaining and the litigants is also proceeding, but no trial date has been set.
With respect to challenges to our patents through the U.S. Patent and Trademark Office Patent Trial and Appeal Board, we recently filed a notice of appeal of the IPR decisions regarding six restricted distribution system patents that were considered unpatentable by PTAB. The Federal Circuit appeal process usually takes 12-18 months. Finally, we anticipate a decision next month on the pending IPR involving three claims of an additional restricted distribution system patent. Last month, Roxane received FDA approval for generic Xyrem, and two other ANDA filers, Ranbaxy and Amneal, received tentative approvals. However, we do not expect any launch prior to resolution of the intellectual property issues that are currently being litigated. FDA granted Roxane a waiver for a separate new generic sodium oxybate REMS with the condition that the new generic sodium oxybate REMS be open to all future ANDA or NDA sodium oxybate products.
Although we do not believe the REMS waiver reflects the best approach for the safety of patients and the public, we were pleased that FDA concurrently granted our citizen petition affirming that FDA will not approve any sodium oxybate ANDA that does not include in its package insert information related to the drug-drug interaction with divalproex sodium. Turning to our development program for JZP-110, we completed enrollment in our two phase three OSA studies in the third quarter and expect preliminary data next month. We completed enrollment in the phase three narcolepsy study in the fourth quarter and continue to anticipate preliminary data from this study next quarter. Subject to the results of these phase three trials, we are planning to submit an NDA late this year for excessive sleepiness in OSA and narcolepsy.
We have received a number of questions from investors on the design and statistical plan for the Phase 3 studies. We believe that the Phase 3 study in narcolepsy is de-risked due to the large body of evidence generated from the Phase 2 studies, where we observed robust efficacy and an adverse event profile in line with other wake-promoting agents. Our Phase 3 narcolepsy study also includes a lower 75 mg dose to allow us to characterize the minimum effective dose. As a reminder, JZP-110 has not previously been studied in patients with OSA. However, data from other studies done with wake-promoting agents suggests that agents such as JZP-110 should have a therapeutic effect in OSA. Our Phase 3 studies are known as the TONES studies for the treatment of OSA and narcolepsy excessive sleepiness.
Study 14003 or TONES 3 is a Phase 3 12-week double-blind placebo-controlled randomized study evaluating the safety and efficacy of JZP-110 in the treatment of excessive sleepiness in patients with OSA. The co-primary endpoints in this study are the change in the mean sleep latency on the maintenance of wakefulness test, an objective measure of the ability to stay awake. The change in the Epworth Sleepiness Scale score, a subjective measure of sleepiness. The key secondary endpoint in this study is the Patient Global Impression of Change. For the study to be considered successful, it needs to show a statistically significant improvement at the 0.05 level on both co-primary endpoints.
Our hierarchical testing strategy for these endpoints will start with the co-primary endpoints at the 300 mg dose and will step down to the key secondary endpoint at the 300 mg dose before proceeding to the co-primary and key secondary endpoints at lower doses. The second phase 3 OSA study, 14004 or TONES-4, is a six-week study in which patients are first titrated to a maximal dose that is tolerated over two weeks and then continue on that dose for two weeks in a stable dose phase. Patients who report much or very much improvement on the PGIC scale and who show numerical improvements on the MWT and ESS at week four are then randomized to receive the same dose of JZP-110 or placebo for two weeks.
We're evaluating patient outcomes combined across dose 75, 150 and 300 milligram on the co-primary endpoints of MWT and ESS, measured from the end of the stable dose phase at week four to the end of the randomized withdrawal phase at week 6. We expect to share the top-line results in OSA next month. Finally, earlier this month, we began enrolling patients in the Phase 2 study evaluating JZP-110 as a potential treatment for excessive sleepiness in adult patients with Parkinson's disease. Excessive sleepiness is a common non-motor symptom and contributes significantly to the disease burden of Parkinson's disease. We expect to enroll approximately 50 patients. Now on to the Hematology Oncology franchise. Erwinaze sales were up in the fourth quarter of 2016 compared to the same period in 2015. However, performance was negatively impacted during 2016 by continuing supply challenges.
While FDA has been extremely responsive to our request to facilitate release of product as quickly as possible, due to manufacturing issues at our supplier, we experienced multiple supply interruptions during the second half of the year. We continue to expect that we will experience inventories and supply challenges in 2017, which we expect will result in temporary disruptions in our ability to supply certain markets, including the U.S. Last month, Porton Biopharma Limited or PBL, the manufacturer of Erwinaze, received a warning letter from FDA that generally noted issues with quality, sterile aseptic manufacturing, and lack of change control and implementation of certain working cell banks. As the BLA holder, we are accountable, along with PBL, to maintain the quality of Erwinaze manufacturing and be in compliance with cGMP. We have been working closely with PBL to develop a well-defined compliance action plan.
We are highly focused on resolving FDA concerns in the warning letter to PBL and consistently delivering high-quality product to the patients who need it. We expect PBL will submit the warning letter response to FDA in March. Now I'll turn to Defitelio. The launch of Defitelio in the U.S. continues to progress well, with 117 accounts having ordered product. These accounts represent approximately 74% of the total transplant volume in the U.S. We continue to observe growing demand with the addition of 12 new accounts and 71% of accounts reordering product in the fourth quarter. We held 79 regional disease and product awareness educational events in the fourth quarter, and we're pleased to see new adult centers ordering for the first time following these events.
As we look at known pediatric and adult accounts, approximately 78% of pediatric accounts have ordered product since launch, and just over half of adult accounts have now ordered. Our U.S. sales initiatives remain focused on educating healthcare providers for adult patients on the recognition of signs and symptoms of VOD, the diagnosis and treatment of VOD with multi-organ dysfunction, and the clinical benefits of Defitelio. This remains an important growth opportunity in the U.S. market. In the EU, our team is focused on ensuring that physicians, key hospital administrators, and pharmacists are aware of the clinical and health economic benefits associated with the administration of Defitelio. On the R&D front, we have started enrolling patients in the phase 3 study of defibrotide for the prevention of VOD in high-risk adult and pediatric patients following HSCT.
The study is expected to enroll 400 patients from 100 sites globally, and depending on the results from the interim analysis, enrollment could increase up to a maximum of 600 patients. As we've mentioned previously, we are interested in investigating defibrotide in other settings and announced this quarter that we intend to start a study later of defibrotide for the prevention of acute graft-versus-host disease in transplant patients. That's later this year. We continue our efforts on Defitelio geographic expansion with our new drug submission for Defitelio in Canada, which was accepted in January. We estimate the review of this regulatory submission may be completed mid-year as it received priority review. As we prepare for our planned U.S. launch of VYXEOS and consider the importance of healthcare providers treating adult HSCT patients, we have expanded our U.S. hem/onc sales team from 35 to approximately 55.
The hemonc sales force will focus on Defitelio and Erwinaze until Vyxeos receives marketing approval. We've reorganized the hemonc sales force to focus on either physicians specialized in treating pediatric patients or adult patients. We believe that this approach will allow us to more efficiently reach treaters of adult patients undergoing HSCT and developing veno-occlusive disease with multi-organ dysfunction and treaters of adult AML patients while maintaining our strong relationships with clinicians who specialize in pediatrics. Following the Celator acquisition, the preparation of a high-quality NDA submission for Vyxeos has been our priority, and we continue to anticipate completing our NDA submission by late next month. Vyxeos has breakthrough therapy designation and fast track designation in the U.S., and we plan to request priority review. We anticipate submitting our EU marketing authorization application later in the year following the required pre-submission regulatory meetings.
Our clinical development team is actively evaluating future development opportunities for VYXEOS as well as opportunities for the CombiPlex technology platform. We anticipate providing more information on our plans later this year. We're looking forward to an exciting 2017 with multiple clinical development, regulatory, and other milestones, including announcement of the preliminary data from the phase three JZP-110 studies evaluating excessive sleepiness in OSA and in narcolepsy with a planned NDA submission by year-end. Submission of an sNDA for Xyrem to include the pediatric phase three study results and the submission of the report meeting the requirements for the pediatric written request. Completion of the VYXEOS NDA submission by the end of March and potential FDA approval and launch in the U.S. this year. Submission of the marketing authorization application for VYXEOS in the EU. Initiation of enrollment in the JZP-258 Phase 3 study this quarter.
An evaluation of potential acceleration of our NDA submission timeline for JZP-507 and potential corporate development transactions. Through 2017, we expect the President and Congress will continue to focus their efforts on revisions to the Affordable Care Act, exploring the potential for reducing drug prices, increasing manufacturing in the U.S., and reforming tax laws. We don't know how rapidly these events will evolve or the nature or extent of any changes, but we remain focused on delivering important products to patients who have unmet medical needs. We believe that our business model, which is to develop and commercialize clinically important and differentiated products that provide value to patients, payers, and society, will continue to be a successful and sustainable model.
We believe our continued investment in our R&D pipeline and commitment to bringing meaningful products into the portfolio through corporate development activities provides the potential to generate strong mid and long-term growth for shareholders and to further diversify and expand our commercial and development portfolio. Matt, let me now turn the call over to you.
Thanks, Bruce, and good afternoon, everyone. We are pleased with our financial performance in 2016, which was a great year for us as we continue to expand our business. Total revenues increased 12% compared to 2015, driven primarily by higher sales of Xyrem and Defitelio. Net sales of Xyrem for 2016 were $1.108 billion, up 16% from $955 million in 2015. Net sales of Xyrem for the quarter were $291 million, up 16% from $252 million in the fourth quarter of last year. Our Xyrem net sales guidance for 2017 is in the range of $1.22 billion-$1.25 billion, representing expected growth of 10%-13% over 2016.
This guidance reflects the price increase of approximately 6.5% that we took in early January and our expectation of mid-single-digit volume growth for 2017. As we look forward to 2017, I'll remind you that there is a fourth quarter, first quarter pattern that we see in Xyrem volume related to payer churn in the industry and higher gross to net adjustments that typically occur in the first quarter. Turning to Erwinaze, worldwide net sales for 2016 were $201 million, down 1% compared to net sales of $203 million in 2015. In 2016, we continued to experience supply interruptions, which at times led to our inability to supply certain markets and resulted in quarterly variability in our reported net sales.
In the fourth quarter, we experienced out-of-stock periods which caused fluctuations in inventory levels. We were able to resupply the market in the U.S. and E.U. in late December. At the end of the fourth quarter, our U.S. distributor had 13 days of inventory as compared to 9 days on hand at the end of the fourth quarter of 2015. Fourth quarter worldwide net sales were $57 million compared to net sales of $50 million in the fourth quarter of 2015. For 2017, we expect that inventory levels will continue to fluctuate and that inventory will be depleted from time to time, which may lead to inter-quarter variability. Given our expectation of continued supply disruption in 2017, our Erwinaze net sales guidance for 2017 is in the range of $205 million-$225 million.
Total worldwide Defitelio net sales for 2016 were $109 million, an increase of $38 million or 54% from $71 million in 2015. Fourth quarter worldwide net sales were $30 million, an increase of $11 million or 61% from $18 million in the fourth quarter of last year. The increase in Defitelio net sales was primarily driven by the April 2016 launch of Defitelio in the U.S. U.S. sales were $26 million in 2016 and $10 million in the fourth quarter of 2016. As a reminder, physicians in the U.S., particularly those that treat adult transplant patients, are less experienced in recognizing, diagnosing, and treating VOD, which is an ultra-rare disease. Dosing of Defitelio is weight-based, varying significantly between pediatric and adult patients, all of which can increase inter-quarter variability in Defitelio net sales.
Our Defitelio defibrotide net sales guidance for 2017 is in the range of $130-$150 million, with estimated U.S. sales of $45-$55 million. Prialt net sales for 2016 were $29 million, an increase of 10% compared to $26 million in 2015. Fourth quarter net sales in both 2016 and 2015 were $6 million. For 2017, we expect solid top-line growth with total revenues for 2017 anticipated to be in the range of $1.63 billion-$1.70 billion, up 9%-14% from 2016.
Our guidance assumes potential FDA approval and US launch of VYXEOS in 2017, with estimated net sales in the range of $10 million-$20 million. Turning to operating expenses, adjusted SG&A expenses for 2016 were $405 million compared to $355 million in 2015, or 27% of revenue in both periods. Adjusted SG&A expenses for the fourth quarter of 2016 were $108 million, or 27% of revenue, compared to $87 million, or 26% of revenue in the same period of 2015.
For 2016, the increase in adjusted SG&A was primarily due to the expansion of our business, including higher headcount, expenses related to the launch of Defitelio in the U.S., and the launch preparation for VYXEOS, as well as a contract termination fee of $12 million in the fourth quarter to eliminate a potential future royalty obligation for VYXEOS. For 2017, our adjusted SG&A expenses are expected to be within the range of $440 million-$460 million, or 26%-28% of 2017 revenue guidance. Adjusted SG&A expenses are expected to increase primarily due to investment in the planned launch of VYXEOS in the U.S., including a recent expansion of the U.S. Hematology Oncology sales force and other business-related expenses.
Also, I'll remind you that when we look at fourth quarter to first quarter adjusted SG&A trends, our adjusted SG&A expenses have historically increased due to our typical pattern of spending during the first quarter. Adjusted R&D expenses for 2016 were $146 million, or 10% of revenue, compared to $97 million, or 7% of revenue for 2015. Adjusted R&D expenses for the fourth quarter of 2016 were $40 million or 10% of total revenues compared to $26 million or 8% of revenues in 2015.
For 2016, the increase in R&D expenses was primarily driven by an increase in costs related to the development of JZP-110, our oxybate-related R&D programs, the defibrotide prevention of VOD study, the VYXEOS rolling NDA submission, and an increase in headcount required to support these activities. For 2017, our adjusted R&D expenses are expected to be in the range of $165 million-$180 million, or approximately 10%-11% of 2017 revenue guidance. The expected increase in R&D expenses is primarily due to multiple planned regulatory submissions and ongoing investments in our expanding pipeline.
Adjusted net income for 2016 was $627 million or $10.14 per diluted share, compared to $595 million or $9.45 per diluted share for 2015. Our 2016 adjusted net income and EPS reflect our increased spend in R&D as we advanced projects in our pipeline, as well as the overall expansion of the business, including the Celator acquisition. 2016 adjusted EPS also increased by $0.10 due to our early adoption in the fourth quarter of an updated accounting standard related to share-based compensation accounting.
Fourth quarter 2016 adjusted net income was $166 million or $2.71 per diluted share compared to $177 million or $2.81 per diluted share for the fourth quarter of 2015. The year-over-year change reflects in part tax changes in certain jurisdictions that resulted in a net tax benefit in the fourth quarter of 2015 that lowered the adjusted effective tax rate compared to the fourth quarter of 2016. We anticipate our 2017 non-GAAP adjusted EPS to be in the range of $10.70-$11.30 per share, which represents growth of 6%-11% compared to 2016.
As of December 31, the outstanding principal balance of our long-term debt was $2.1 billion, and we had a total of approximately $426 million in cash equivalents and investments, as well as $400 million in undrawn revolver. During the fourth quarter, we made a $150 million payment toward our revolving credit facility and spent $18 million to repurchase shares at an average cost of $105.71 per ordinary share. Corporate development transactions continue to be a high priority, and we are enthusiastic about multiple opportunities that could further diversify our portfolio. We believe that our strong cash flow, low leverage ratio, and flexible capital structure allow us to continue to meaningfully invest in our portfolio.
Our capital deployment strategy seeks to optimize the allocation of capital between R&D, commercial products, corporate development opportunities, and the repurchase of shares with a focus on optimizing return on investment for our shareholders. In closing, 2016 set the stage for an exciting 2017, when we expect top-line data from 4 phase III trials, initiation of multiple studies of new product candidates, as well as initiation of clinical studies for new indications for our current products, multiple regulatory submissions, 2 potential regulatory approvals for VYXEOS in the U.S. and Defitelio in Canada, the potential for more clarity around Xyrem exclusivity, and multiple opportunities to further diversify our product portfolio.
We remain focused on executing on these opportunities to drive mid to long-term growth through our sustainable business model with the goal of delivering meaningful therapies to patients while building shareholder value. Thank you for joining us on the call today, and I'll now turn the call over to Kathee.
Thank you, Matt. We request, as per our usual, that you limit your questions to one at a time, and then feel free to reenter the queue if you have further questions. With that said, I'll turn the call back to the operator to open the lines up for your questions today.
Ladies and gentlemen, if you have a question at this time, please press star, then one on your touchtone telephone. 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 the line of Marc Goodman with UBS. Your line is now open.
Afternoon. I guess I could slip into one just on SG&A, if you could just expand a little bit on what all the money is being spent on, as you move into next year, the incremental spend. Just on Defitelio, if you could just give us a little more flavor on what's going on. It just doesn't feel like that product is increasing as fast as we all thought it would. Thanks.
Yeah. Let me have Matt talk about SG&A.
Sure. As it relates to SG&A, most of this increase in spend there is gonna be related to product expansion activities, so new launch or launch preparation. Remember, we launched Defitelio in April of 2016, so that's increasing through the course of 2016 and then through this year as it goes into its second year of launch, and then also preparation for the launch of VYXEOS this year. We took the opportunity early in the year to expand both our sales force and to make increased investments in medical related to MSLs, health economic outcomes, research, education, and awareness. Commensurate investments across regulatory, technical operations with supply chain and other commercial operations to support the launches of those products.
That said, we're still talking about a relative percentage of sales that's consistent with last year. I think we've been able to absorb this increased investment with respect to margin, but would expect that to be leverageable in future years. When you look at base SG&A, there is some increase this year just given the impending trial on the legal side and some increase in facilities costs as well as again, we've increased headcount in particular associated with R&D as that activity has picked up over the last couple of years.
Marc, on Defitelio, I would say we're experiencing good growth ex-US, where the product's been on the market a little bit longer, double-digit growth. In the US, still early in the launch. We think there's substantial opportunity to grow on the adult side. We're making the investment we think is necessary to do that. Longer term, I'd remind you, we now have a trial going in prevention of VOD. We're getting ready to start a trial later in the year on prevention of acute GVHD in transplant patients, and we're talking about pursuing other indications as well. We're early in the life cycle for Defitelio, and I think making good progress.
Our next question comes from the line of David Amsellem with Piper Jaffray. Your line is now open.
Thanks. You include VYXEOS contribution in the guidance. I just wanted to get a sense, and I know it's a small number, but I just wanted to get a sense of, you know, the extent to which you think some of that could just be pent-up demand. Just looking into 2018, what's your sense about how widely or how broadly the product will be used, at least initially, in its commercial life in the AML setting? Thanks.
David, I'll take the first part of your question. Included in our guidance is some amount of revenue from VYXEOS this year. That represents obviously only a partial year and the startup of that commercial effort. It would include some stocking, although I don't think that's a huge impact for a product like this. As to the adoption of VYXEOS as therapy late this year and next year, let me have Mike Miller address that.
Sure, Bruce. The adoption for VYXEOS will be certainly guided by the label and the indication that we receive from the FDA. The specificity around the patient population would be one look at it. The other is how NCCN guidelines look at the drug and the data in terms of their treatment guidelines.
Our next question comes from the line of Annabel Samimy with Stifel. Your line is now open.
Hi. Thanks for taking my questions. Just really quickly, on the NCCN guidelines, what is the process by which they start to look at that? Is it something that you do in parallel to the FDA? I guess what's the timing of its potential inclusion or exclusion from those NCCN guidelines? Just going back to the Defitelio question, I guess the question revolves around why it seems that Europe is somewhat flat. Was there any FX going on, or were there any fluctuations in inventories? Can you just talk about a little bit what's going on in Europe? Thanks.
Mike, do you wanna take the NCCN piece?
Sure. The NCCN guidelines, once the product is approved, it is submitted to a guideline committee. They look at the,
The quality of the data and give it a weight based on their criteria. From that, they actually drive guidelines for treatment going forward that most cancer centers and payers will follow. That takes a review and then they publish those, but that happens post-approval.
Russ, you wanna talk a little bit about Defitelio in Europe?
Sure. We're actually very pleased with Defitelio in Europe this year. You know, in terms of the overall revenue generation, you know, we don't see that as a flat performance in Europe this year. We actually saw a really nice double-digit growth this year.
I guess flash on a quarterly basis.
As it relates to 2017, we continue to expect, and the guidance assumes double-digit volume growth in Europe this year. I think we'll continue to see growth there. It does incorporate some lower FX just as we've seen the euro move. You know, on the average FX last year was you know, roughly 5% higher than it would be this year. Again, on a bottom line basis, we're relatively neutral, but we would see some headwind on the FX side for Defitelio.
Okay. Thanks.
Our next question comes from the line of Bill Tanner with Cantor Fitzgerald. Your line is now open.
Hey, Bill, are you on mute? Okay, maybe go to the next question.
Our next question comes from the line of Gregg Gilbert with Deutsche Bank. Your line is now open.
Yes, I was curious on JZP-110, whether the company views one indication as higher risk than the other from a probability of success standpoint. Do you need both indications, in your opinion, for regulatory success? I'm sorry, Matt, if I missed this, what tax rates in your guidance, and what's the cash tax rate you're assuming for the year? Thanks.
Yeah, Gregg, on the relative risk, I mean, we'll have Phase 3 data readouts this quarter, next quarter. I think that will tell us a lot. You know, as I highlighted during my comments, we believe excessive sleepiness and narcolepsy is a little more de-risked just because we had the two phase 2 trials already conducted in that patient population. Whereas this is our first time in OSA patients, but we are following other agents that have been tested in OSA. We'll have the data soon, and I think that will give us a good sense. Our goal is to get the product, you know, initially for treatment of excessive sleepiness in these two disease states.
You know, we've all already talked about starting down the road in Parkinson's, and there may be the opportunity to go into other patient populations as well in the future, but we'll be back to you after the initial readout. Matt, you wanna take the tax rate? Yeah, sure. Greg, you didn't miss it. I didn't give the tax rate directly, but it's a rough band of 22%-24%. We don't really report a cash tax rate anymore as we've moved into you know, following the SEC guidelines as it relates to non-GAAP.
While our number would have been in the, you know, very high teens, 19%-20% historically on a cash basis and still would be under the, you know, comply with the SEC guideline, it's roughly 22%-24%. I will say we could see more interquarter variability or volatility associated with that because that does include some balance sheet related adjustments, and we alluded to some of those even in the fourth quarter here this year that can swing the tax rate up or down from that line, but are not, again, cash taxes.
Thanks.
Our next question comes from the line of Ken Cacciatore with Cowen and Company. Your line is now open.
Hey, guys. Just wanted to ask Bruce about Xyrem and the litigation now that the PTAB for the inability to carve out the label has been ruled on. Just trying to better understand kind of what are the outstanding issues in terms of things that you don't really know or they don't really know, just trying to see where the parties are in terms of information that would be necessary to kind of come to an agreement. Then secondly, on orphan oncology, I'm just not as familiar with that area. Can you just give a little bit of a thought on business development in that area?
Is pricing in orphan oncology as attractive as other orphan indications, or is there anything unique that wouldn't allow you to get pricing as you can kind of look at the business development in that area? Thank you.
Ken, on the first part of your question, you know, as time has gone on, we've learned, we and Roxane have each learned more, you know, there have been regulatory developments, there have been court developments, there have been PTAB developments. There may still be some of all of the above going forward. You know, I mentioned the upcoming PTAB ruling, you know, for one thing. But, you know, we know a lot more now than we did a few months ago. Just had a Markman hearing recently. You know, we're getting rulings on motions occasionally. But I, you know, I won't say there's any one big thing that I'd point to. Just continuing discovery and pretrial activities as we move toward the May first trial start.
On biz dev, on the oncology side, you know, maybe I'll let Matt comment. You know, in general, when you ask a comment on pricing, I would say pricing really always should relate back to how effective is the product, how serious is the disease, and what's that product impact relative to other available treatments. You know, one of the things I think we've been highly focused on in the products that we have as part of our portfolio are finding products that really make a difference for patients, in a way that's differentiated from other products. Matt, you wanna talk generally about corp dev in this space?
Yeah. I think, Ken, we've been able to be successful here in the recent past in a series of at least three transactions recently and continue to see the opportunity to find products that we see may need some help in terms of education and awareness and making sure that, you know, how to use them in an evolving treatment paradigm is well understood. We believe there is an opportunity for us to both identify and enhance value of products in this space. Like a lot of BD across the industry, it can be competitive for attractive products, but we believe we have a path to be successful in securing additional assets in that area.
Great. Thank you.
Our next question comes from the line of Jason Gerberry with Leerink Partners. Your line is now open.
Good evening. Thanks for taking my questions. I guess, Bruce, just on the Xyrem legal front, I just wanted to make sure, have you and Roxane technically entered into an agreement for them not to launch prior to the outcome of the patent trial? I just wasn't sure if there was anything formal on that front. Just secondly, I think I heard for 507, the potential to file that potentially sooner than 1Q18. Can you talk about some of the variables and scenarios under which you could file sooner? Thanks.
Jason, on the first part of your question, you know, we've made comments in the past, again at the time of FDA approval of the Roxane generic and again today, that we don't believe there will be a product launch short of some resolution of the intellectual property litigation that's ongoing. That comment is not specific to Roxane. It's not tied to a specific agreement. It's just our assessment of the situation, which has remained unchanged for quite some time. On JZP-507, I would say having made the determination internally that we've got a clearer path forward without doing the study we had talked about earlier.
Our team is looking at resource requirements, work to be completed to put together a high-quality submission and, you know, relative prioritization, and we'll be back to you with, you know, a final determination on that later. We're still gonna say for now by first quarter 2018, but we know there's the potential that we could do it faster than that.
Okay. Thank you.
Our next question comes from the line of Gary Nachman of BMO Capital Markets. Your line is now open.
Hi. Just following on generic Xyrem, Bruce, have there been any conversations yet regarding how different pharmacies might be able to talk to each other between you and the generics based on the REMS waiver Roxane received? How would that actually work?
Gary, my answer is probably not gonna be particularly satisfying to you on this front. You know, as we said before, we were not a party to the discussions about the creation of an ultimate approval of a waiver REMS for the generics and exactly how that would work itself or would relate to our REMS. That's not a conversation we were part of, and I would say we're still evaluating our views on what that system would look like in reality and how well it would work. We continue to think our system represents a safe way of distributing this product and haven't completed our analysis of what was approved last month.
Okay. Maybe I could just squeeze in a quick one on JZP-110. Just any updates on conversations with managed care in terms of how they would potentially reimburse that product? Thanks.
Yeah. This is Mike. We look at this, and we probably see a Tier 3 formulary placement by most PBMs.
Okay. Thanks.
Our next question comes from the line of Louise Chen of Guggenheim. Your line is now open.
Hi. Thanks for taking my question. Just back on VYXEOS, curious how we should think about the market opportunity to Jazz and if you see any label expansion opportunities. For example, do you think the drug could be used in MDS? And then what are you thinking of charging for the drug, or how do you think about that? Thanks.
On pricing, I'll take that one and say we'll have more to say on that when we have an approval and when we're launching the product and probably not before. On potential for expansion of the applicable use of VYXEOS over time. Mike, Russ, Karen, who wants to jump in on that?
Yeah, I think that based on what we know of the molecule, there's certainly the potential to take it into other myelodysplasias or other myelodysplastic disorders, but we have not defined what they would be at this stage.
Just on an AML basis, there's about 20,000 cases in the U.S. About half of those are considered chemo fit and fall into that treatment paradigm. Probably you take another haircut by patients going into clinical studies till you get to a treatable eligible population of about 8,000, and about 40% of those are high risk AML.
Okay, thank you.
Our next question comes from the line of Jessica Fye of J.P. Morgan, your line is now open.
Hey, guys. Thanks for taking my question. Mine's on Erwinaze and just how you have confidence in giving guidance for Erwinaze growth this year given the supply challenges experienced last year.
Yeah. Jess, I would say, you know, our prediction is we will have continued supply constraints in 2017, or put another way that we think demand will exceed supply. That doesn't mean we aren't trying to grow supply at the same time. We in PBL certainly are working on initiatives that will expand effective capacity, ability to produce more product, you know, in a calendar year. And you know, I would say, simply put, we'll be able to sell what we can supply. But both things may be true. We may grow the product in 2017 by having more supply than we had in 2016 and still have periods where we can't keep up with total demand.
Okay. Thank you.
Our next question comes from the line of Umer Raffat of Evercore ISI. Your line is now open.
Hi. Thanks so much for taking my question. I just wanted to drill down on the statistical hierarchy for a minute. Just so I have it right, on the 6-week OSA trial, is it pooled doses versus placebo for a p value 0.05? I just wanna make sure I got that right. If you could give us the same for the narcolepsy trial, should we assume it's 300 milligrams versus placebo on the co-primary, and then we work our way down on doses? The MWT, is it measured over 4 or 5 trials? Thank you.
Karen?
Sure. Yes, it's a step-down procedure, it's a hierarchical testing to control for the multiple testing specifics in each of the different studies. You have to hit on the co-primaries, the ESS and the MWT, before you then step down onto the secondary, which is the PGIC, and then you step down from that into the next dose, so from the 300 down to the 150. In terms of the number of trials, it was four across the MWT.
Yes, pooled across doses in the-
Yeah. Yes, of course. Yeah.
Thank you.
Step down in the sixth week as well.
Your next question comes from the line of David Maris with Wells Fargo. Your line is now open.
Good afternoon. Bruce, on business development, it sounds like you're pretty excited about the things that you may have in front of you that you're choosing among. With so many launches and filings in the next couple of years, how much of the debate internally is finding something that's complementary but not distracting versus finding something that's maybe another therapeutic area? 'Cause to me it seems like one of the biggest risks is distracting from what's already a really good pipeline.
Yeah, David, really, really great question, and I think you've got to look across our business units and across our geographies to make that determination. You know, never say never, but I would say our U.S. hemonc business unit is really busy. We're still in launch phase with Defitelio. We're managing through a difficult Erwinaze situation. We're gearing up for VYXEOS launch. We've increased the size of our sales force to get ready for that. We've restructured our sales force. If Matt came along and dropped another hemonc launch on the team, would we figure out a way to do it? Maybe. But that would, to your point, represent a distraction from other things we're doing, and we'd think about that really hard. I think that's less of an issue in other parts of our business.
I think that's less of an issue in Europe. I think that's less of an issue in the Sleep BU. I think that's less of an issue in the Pain BU. So I certainly think we have the opportunity to be busy, and that all is if we're discussing commercial products. Of course, we're looking at interesting development opportunities as well.
Great. Thank you very much.
Our next question comes from the line of Douglas Tsao of Barclays. Your line is now open.
Hi. Good afternoon. Thanks for taking the questions. Just a couple quick ones. First, on Defitelio, I noticed that the penetration into pediatric is much higher than adult centers. Just maybe talk a little bit about the adoption curve within those respective sort of patient populations and how we should think about growth there. Then also, Bruce, you know, it seems like there's a little bit more. Or JZP-386 seems to be coming back a little bit more in terms of company presentations. Just maybe a little bit of an update in terms of where things might be in terms of that formulation work.
Yeah, Mike, you wanna take the first part of the question?
Sure, Bruce. With respect to pediatric adoption of Defitelio, first and foremost, we have established relationships into the pediatric centers by way of our MSLs. When we launched, we knew our way around those centers, and that helped. VOD actually happens at a higher rate in pediatric patients. The pediatric transplanter is much more attuned to looking for the early signs and symptoms, and will aggressively treat that patient who develops those signs and symptoms, more so than the adult patient, where there can be a wait-and-see approach. We feel very good, as Bruce spoke, that we have expanded our sales team on the hem-onc side to include a lot of adult expertise in preparation for VYXEOS, but more importantly, to drive Defitelio adoption in adult centers.
We feel like we're already getting that traction, so we feel very good about it.
Doug, on once-nightly oxybate, we are continuing work in that as well. We've been featuring more in our comments the lower sodium versions recently because I think those are closer to moving all the way to regulatory submission. We are continuing our work on once-nightly, including, you know, the potential that that also ought to be a lower sodium load than the current Xyrem product.
Okay, great. Thank you.
Our next question comes from the line of Liav Abraham with Citi. Your line is now open.
Good afternoon. Just a follow-up question on business development and capital deployment. You partly addressed this during your answer to David's question, but perhaps if you could elaborate further. I'm curious as to, when thinking about business development, how you think about approaching commercial versus R&D stage assets, particularly given how busy you are on the R&D front, and I guess basically what is your capacity and bandwidth to increase R&D activities at the moment?
Yeah. Thanks, Liav. We're definitely looking at that in a balanced way, and as I think Bruce alluded to in the previous comment, are thoughtful about what part of the organization we may stress with new opportunities. We've certainly grown our investment in R&D, both programs and people, pretty dramatically. I think we'll always look at what can we take on directly, what can we leverage a partner for, what can we leverage outside resources for. We do believe there's capacity across our organization to continue to add development programs, taking those factors into account.
I think we look at both and operating lines as it relates to that in terms of capacity constraints as well as a financial line to sort of balance what we believe is achievable and doable in the best interest of shareholders. We're definitely very active looking at a combination of commercial and R&D opportunities.
Thank you.
Our next question comes from the line of Irina Koffler with Mizuho. Your line is now open.
Hi. Thanks for taking the question. Can you remind us about the opportunity in pediatric narcolepsy and what the incremental value there is? Is it people are taking it now off label that are pediatric, and it would just be an easier formulary approval process, or is it actually a few hundred new patients that you can add to the current patient mix? I have a quick follow-up on the once-nightly oxybate. I just wanted to clarify, if you get the formulation right, can this product go directly into phase 3 from the phase 1 work where it is now? Thanks.
Irina, I'll take that second question first. We haven't yet talked about exactly what our regulatory path would be on a once-nightly program, probably premature to do that at this point. On the pediatric opportunity, let me just step back and frame it a little bit and then maybe I'll ask Mike to make some comments. You know, we're certainly aware that narcolepsy can emerge in childhood. We often talk about it emerging in adolescence and young adulthood. But if you talk to patients who were diagnosed in adolescence and early adulthood and ask them when symptoms emerged, they often can go back, they or their parents can go back and talk about symptoms emerging earlier.
We're certainly aware that there are pediatric patients who are in fact diagnosed with narcolepsy and are in search of effective treatment. This trial has given us the opportunity to go collect real data in this patient population about dosing, about efficacy, about tolerability, and I think making that data available to physicians who treat this disease in pediatric patients will be very helpful. Mike, in terms of market opportunity?
Yeah, I think, in terms of, you know, there's probably some spontaneous use, currently, but, since, most payers really guide by label, and the label does not include pediatrics, the product is not used currently in pediatric patients.
Our next question comes from the line of Ken Trbovich with Janney. Your line is now open.
Thanks. Just quick question on Erwinaze. Can you give us a sense as to how much the manufacturing setbacks at PBL have impacted the contribution margin for the product? Give us an update on the status for efforts to perhaps have alternatives to PBL.
Yeah, maybe I'll take the first half of that and then let Russ talk a little bit about where we're going longer term. You know, it's hard to quantify, Ken, exactly what the total impact is. In part because you can imagine that we've cut back on our efforts around Erwinaze. We're not out trying to generate demand we can't meet. We've long said there's a greater opportunity, I think, to improve use of asparaginase containing regimens in adolescent and young adult populations. I think that would be a good thing for patients. You know, honestly, we're doing less work in talking about that right now out in the medical community than we would be doing if we had more supply of product.
There's both the current demand we can't supply, which is particularly painful to us, but there's also demand beyond that that we're not helping to generate because of supply constraints. So it's, you know, it's a meaningful impact now. And you know, if you extrapolate that over time, we understand the importance of solving this problem quickly because we'd like to get back to not only making the treatment available to all current patients, but in fact helping more patients get the best therapy over time. Russ, you wanna talk about some of our other efforts to longer term?
Yeah. Some of the ongoing efforts that exist, as you know, we started some time ago with doing what we call 24/7 shifts so that we could have an increase in capacity as a result of doing more shifts on a regular basis. That has been able to bear some fruit over time. We've also brought in an efficiency expert who's analyzed every possible way to increase efficiencies within PBL. We're pleased with some of the recommendations that are coming out of there. We also know that some of those will take some time to actually generate additional supply.
If you were to look at what are some of those things, some of the decoupling efforts that are required on the front end and the back end, I would also say that, you know, looking at how we maximize some of the efficiencies that we've had with stoppers and then, ultimately, making sure that we're in a position to, you know, do some things that are, you know, longer term to, maximize how we can, build inventory. If I step back and say, you know, we have some things that are working, we have some things that are in play and some things that we think will, you know, kick in probably end of this year and more probably in the 2018 timeframe.
Just as a reminder, we certainly have efforts underway as well to look at whether there are other asparaginase related development efforts that could yield better products for patients, whether that's longer half-life, so less frequent dosing, whether that's reduction in immunogenicity, or other things that could actually result in a better product offering for patients. We've had efforts like that underway for years. I just wanna remind you we continue to be active in that area.
Okay. Thank you.
Operator, this will be our last question please.
Our final question will come from the line of Bill Tanner with Cantor Fitzgerald. Your line is now open.
Hi. Can you guys hear me?
Yes, we can.
Yeah.
Thanks for circling back. I don't know what happened. Didn't pay our phone bill or something. Anyway, Bruce, just on JZP-110, just on the expectation for the data. You know, if you look at the Provigil, Nuvigil labels for OSA, the MWT, it's a decrement of about 10% 'cause it's a couple of different baselines, but for both of the products, it's about that. So I'm just curious, you know, is that a reasonable magnitude, you know, to expect? And I guess the extension of that would be approvable. Then just the other one was, you know, as it relates to JZP-507 and maybe JZP-258, the contemplation of a review time for both of those would be what I'm assuming six months, but anyway.
Let me have Kathee take the first part of that, which is expectations around review timeline on the low sodium oxybate programs.
Bill, those would be one year.
And then-
Okay.
Bill, on your other question, I'd sort of answer it in a couple ways. You know, we certainly know what we've seen in earlier clinical trials with respect to JZP-110's efficacy on both the objective and the subjective endpoints. It's been strong efficacy. It's not been head-to-head against Provigil or another wake-promoting agent, but it's been done in similar patient populations with similar endpoints, and certainly the magnitude of effect looked you know more significant than we've seen with some other agents. I would separate that comment from what it would take to be approvable. You know, I think approval gets down to efficacy and safety, right? Benefit, risk.
I think commercially, we'd say it's important that the product be differentiated, that in fact it have a profile that's different from what you've seen with other agents. That really has more to do with our expectations for what would make a successful product as opposed to just what would be an approvable product.
Would there be an expectation or at least a hope, I guess, that you might have a better side effect profile? I mean, those products have some, you know, pretty high incidence of headache, nausea, maybe less so nervousness.
Yeah. I think our real goal is to see a different benefit risk trade-off, whether that's more efficacy at the same tolerability or, you know, there are different ways you can look at it, but that you would offer a benefit to patients that is different from what they can get from other patients on the efficacy or tolerability side.
Got it. Okay. Thanks very much.
That does conclude today's Q&A session. I would now like to return the call to Ms. Kathee Littrell for any further remarks.
Thanks, Sandra, and thank you all for joining us today on this call. We will be participating in the Deutsche one-on-one day, the Cowen Healthcare Conference, the Barclays Healthcare Conference, and the J.P. Morgan Healthcare Conference next month, and we hope to see many of you there. This ends our call.
Ladies and gentlemen, thank you for participating in today's conference. This does conclude the program, and you may all disconnect. Everyone, have a great day.