Jazz Pharmaceuticals plc (JAZZ) Q1 2014 Earnings Report, Transcript and Summary

Katherine A. Littrell - Vice President of Investor Relations Bruce C. Cozadd - Co-Founder, Executive Chairman and Chief Executive Officer Matthew Young - Chief Financial Officer and Senior Vice President Russell J. Cox - Chief Commercial Officer and Executive Vice President Jeffrey K. Tobias - Chief Medical Officer, Executive Vice President of Research & Development and Head of Research & Development

Louise Alesandra Chen - Guggenheim Securities, LLC, Research Division William Tanner - FBR Capital Markets & Co., Research Division Annabel Samimy - Stifel, Nicolaus & Company, Incorporated, Research Division David Amsellem - Piper Jaffray Companies, Research Division Jason M. Gerberry - Leerink Swann LLC, Research Division Gary Jay Nachman - Goldman Sachs Group Inc., Research Division Ken Cacciatore - Cowen and Company, LLC, Research Division Jonathan Eckard - Citigroup Inc, Research Division Douglas D. Tsao - Barclays Capital, Research Division Daniel Brims - Brean Capital LLC, Research Division John L. Newman - Canaccord Genuity, Research Division Difei Yang - R.F. Lafferty & Co., Inc., Research Division Marc Harold Goodman - UBS Investment Bank, Research Division Patricia L. Bank - DISCERN Investment Analytics, Inc

Ladies and gentlemen, good afternoon and welcome to the Jazz Pharmaceuticals First Quarter 2014 Earnings Conference Call. [Operator Instructions] And now I'll turn the call over to Ms. Kathy Littrell, Vice President of Investor Relations at Jazz Pharmaceuticals.

Thank you, and thank you, all, for joining our Investor call. Today, we reported our first quarter financial results and reaffirmed and updated our 2014 financial guidance in the press release. The release and the slide presentation accompanying this call are available on the News & Events section of our website. With me for today's call are Bruce Cozadd, CEO; Matt Young, CFO; Russ Cox, Chief Commercial Officer; and Jeff Tobias, our 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 our future performance rather than historical facts and are forward-looking statements. These statements include future financial results and commercial development and regulatory plans, expectations and projections and the potential timing of future events. Examples of forward-looking statements include our 2014 financial guidance; anticipated growth prospects for our products; planned commercial efforts, including the rolling launch of Defitelio in Europe; and related pricing and reimbursement approvals expected and potential interactions with regulatory agencies regarding Xyrem and other products and product candidates; anticipated regulatory submissions, anticipated litigation-related events and the timing of planned and ongoing trials, including enrollment in and results from those critical trials. 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-K for the year ended December 31, 2013, and our Form 10-Q for the quarter ended March 31, 2014, that we expect to 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 2014 adjusted net income attributable to Jazz and the related per share measures and 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. Reconciliation 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 News & Events section of our website. I'll now turn the call over to Bruce.

Thank you, Kathy. Good afternoon, everyone, and thank you for joining us. We're pleased with our financial performance in the first quarter of 2014 and our progress toward achieving our corporate goals. We have continued to strengthen our commercial portfolio and expanded our global infrastructure through the acquisition of Gentium and the commercial launch of Defitelio in Europe. Our late-stage R&D pipeline is expanded with the acquisition of JZP-110 for excessive daytime sleepiness and narcolepsy and in obstructive sleep apnea, as well as the addition of defibrotide through the Gentium acquisition. Our achievements in the first quarter have further contributed to our goal of building a sustainable and diversified company that generates long-term shareholder value. Our total revenues increased 26% to $247 million compared to the first quarter of 2013, driven by increased sales of our key products, Xyrem and Erwinaze, in addition to revenues from sales of defibrotide. We realized adjusted net income attributable to Jazz of $101 million in the first quarter of 2014, reflecting the attractive margins in our business. GAAP net loss attributable to Jazz for the quarter was $93 million, primarily due to the $127 million upfront license fee and milestone payment for JZP-110. I'll now update you on our sleep and hematology/oncology franchises, including information on key commercial, regulatory and clinical development progress made during the quarter. Matt will then review our financial results for the quarter and comment on our guidance. Sleep medicine is a major focus area for Jazz, and we've strengthened this franchise through the acquisition of rights to our new product candidate, JZP-110, which joins JZP-386 in our R&D pipeline, as well as through further investments in our lead commercial product, Xyrem. In the first quarter, the average number of active Xyrem patients grew 8% to approximately 11,400 from 10,550 in the same period of 2013. During the first quarter, our volume growth was 5.4% year-over-year. We have frequently experienced a reduction in bottle volumes in the first quarter relative to the prior year's fourth quarter. The dip was more pronounced in the first quarter of 2014 than in 2013 due to a confluence of factors. First, the Xyrem central pharmacy experienced unusually high call volume, particularly in January. The inbound call volume was approximately 50% greater than average historical levels, and there were longer-than-normal hold times on outbound calls to payers, causing a slowdown in processing claims for patients in the beginning of the quarter. Second, there were delays by some payer plans in the distribution of updated member list related to the implementation of the Affordable Care Act. There were also delays from standard drug utilization review tools. Finally, there were weather-related issues that impacted normal prescription refills and doctor visits, particularly in the northeast region of the country. These factors led to slower time to fill or refill prescriptions early in the quarter. We have implemented plans to handle the continuing higher call volumes at our specialty pharmacy, and we expect to deliver high-single digits to low-double-digit volume growth for full year 2014. Our efforts to expand Xyrem prescriptions written by our low- to mid-decile physicians have contributed to our sales growth year-over-year. We're continuing to educate physicians about the diagnosis of narcolepsy through our Narcolepsy Link programs and are planning further medical education programs during SLEEP 2014, the 28th Annual Meeting of the Associated Professional Sleep Societies in any Minneapolis. We're also focused on narcolepsy disease awareness efforts that we believe will, over time, increase the number of patients diagnosed with narcolepsy and may help reduce the time from disease onset to diagnosis. We further evaluated our pilot TV advertisements that were focused on driving consumer disease awareness of narcolepsy. These disease awareness advertisements in 2 test markets ran from October through December 2013. We previously mentioned that we observed a significant increase in use of the physician finder tool and request for additional information on narcolepsy through the narcolepsylink.com and checkmysleep.com websites for the test markets as compared to control markets. Market research indicates that there is a statistically significant increase in health care providers seeing patients who made appointments to discuss narcolepsy, as well as the significant increase in health care providers ordering both polysomnograms and multiple sleep latency test compared to baseline assessments and control markets. Based on this positive data, we plan to roll out an expanded narcolepsy disease awareness program in 8 additional cities this summer. Finally, we are pleased to inform you that we are initiating a pediatric narcolepsy study. As you know, in many patients, narcolepsy can begin during childhood and adolescence. There's limited information on treatment of pediatric narcolepsy patients with Xyrem. Given this unmet need, we have worked with the FDA and several thought leaders to design a clinical study on the treatment of pediatric narcolepsy patients with Xyrem. We plan to open clinical sites for this study in the second half of 2014. Turning to a brief legal update on Xyrem. Patent litigation against the 3 ANDA filers continues in the District Court of New Jersey. In the Roxanne case, the District Court recently granted our motion to bifurcate and indefinitely suspend the portion of the lawsuit related to our patents covering the distribution system for Xyrem. Although no trial date for the Roxanne case has been scheduled, we continue to anticipate the trial on the patents in the portion of the case that has not been stayed could occur as early as late in the fourth quarter of 2014. The court also recently issued an order consolidating the litigation against the other 2 ANDA filers, Amneal and Par, at their request. We anticipate the consolidated case schedule will generally be in line with the schedule that we would've expected for the Par case. The court's order confirmed that the Amneal 30-month stay date will be extended to coincide with Par's in May 2016. Turning to a brief regulatory update on the Xyrem REMS. On February 28, we initiated dispute resolution with FDA related to the conversion of the Xyrem deemed REMS to a final REMS. The current dispute process is a confidential administrative process under our Xyrem NDA. We expect to receive FDA's response to our initial dispute submission in the second quarter, and next steps will depend on the response from FDA. And now a broader regulatory update. We recently received an FDA Form 483 at the end of a pharmacovigilance inspection conducted by FDA. The Form 483 included observations related to the late submission of adverse drug experience reports for several products, including Xyrem, and our procedures for review and investigation of adverse events. In most instances, we have identified, investigated and addressed the observations reflected in the Form 483 prior to the inspection. We have responded to FDA with our plan to complete the remediation activities necessary to fully address the FDA's observations, and we plan to work with the FDA to promptly address any remaining concerns they may have. Next, I'll provide a few comments on the JZP-110 program. We're excited to inform you that the JZP-110 Phase IIb data have been accepted as a late-breaking abstract for oral presentation at SLEEP 2014 and will be presented by Dr. Jed Black on Monday, June 2. Also, we have requested an end of Phase II meeting for JZP-110 and expect to meet with FDA midyear. We continue to anticipate that we'll begin Phase III trial startup activities in late 2014 and expect to provide you with further thoughts on the Phase III development plans following our discussions with FDA. Finally, regarding JZP-386, our deuterium-modified sodium oxybate compound licensed from Concert, we are currently manufacturing clinical trial materials to support a first-in-human trial that we plan to commence this year in the European Union. Now onto the hematology/oncology franchise. We are excited about the addition of a new commercial product in the European Union, Defitelio, which we launched in the first quarter. The hematology/oncology franchise now consists of Erwinaze and Defitelio, including potential future indications for these products. In addition, JZP-416, or 416, formerly known as Asparec, a PEGylated recombinant Erwinia asparaginase, and Leukotac, a monoclonal anti-CD25 antibody, are in development. First, let's turn to Erwinaze, which continues to perform well. We are pleased that we added over 20 new accounts in the first quarter. We also continued our efforts to educate health care providers and centers, including adult centers, with asparaginase usage on identifying hypersensitivity reactions to asparaginase in acute lymphoblastic leukemia. We will continue our medical education programs and are planning to host an event at The American Society of Pediatric Hematology/Oncology meeting in the second quarter entitled Building on Asparaginase Therapy to Improve Outcomes in ALL. The sBLA for administration of Erwinaze intravenously was accepted for filing, and our PDUFA date is December 28. We anticipate that our Erwinaze young adult study will be open for enrollment this quarter. We plan to enroll approximately 30 patients in this study. On JZP-416, we are pleased to announce that we are working with the children's oncology group and have completed the design of a first study of JZP-416 in children. We expect to initiate this study later this year. We launched Defitelio commercially in Europe in the first 2 countries, Germany and Austria, on March 24, and in the U.K. earlier this month. In April, Defitelio became reimbursable by the Italian National Health System under Law 648. We expect to launch Defitelio in additional European countries on a rolling basis during 2014 and 2015 and are engaged in pricing and reimbursement submissions as applicable. The official Defitelio European launch event took place at the European Society for Blood and Marrow Transplantation Congress, or EBMT, in Milan from March 30 to April 2. There was strong interest in Defitelio at EBMT and over 450 physicians and 250 nurses attended Defitelio-focused symposium. The disease registry required as a post-approval commitment for Defitelio was developed in collaboration with the EBMT and opened in late April. Going forward, our near-term emphasis in Europe remains on establishing solid pricing and reimbursement in order to maximize access for patients in need. We also met with FDA early in the second quarter to discuss the possible submission of a new drug application for defibrotide in the treatment of severe hepatic veno-occlusive disease in patients undergoing hematopoietic stem cell transplant therapy. The FDA meeting was very useful and helps clarify the requirements for the NDA submission. We now believe that it may be possible to submit an NDA without the need for data from an additional clinical trial, but we are continuing to address FDA's comments and questions and plan to have further meetings with FDA prior to finalizing our submission strategy. Matt, let me now turn the call over to you.

Thanks, Bruce, and good afternoon everyone. We are pleased with our performance in the first quarter as we saw total revenues increased by 26% and adjusted EPS attributable to Jazz increased by 18% year-over-year. We expect strong top line growth for 2014, driven by growth in sales of Xyrem, Erwinaze and Defitelio defibrotide. We are reaffirming our guidance for total revenues, total product sales and adjusted EPS for 2014. Net sales of Xyrem for the quarter were $160 million, up from $118 million in the first quarter last year. We are reaffirming our guidance for Xyrem net product sales in the range of $755 million to $775 million for 2014. As a reminder, first quarter net sales partially reflect a 12% price increase on February 3. Turning to Erwinaze. First quarter worldwide net sales were $47 million, up 12% from the same period in 2013. First quarter net sales of Erwinaze reflect the 3% price increase on January 3. We are reaffirming our guidance for Erwinaze net product sales in the range of $185 million to $200 million for 2014. For Defitelio, first quarter worldwide net sales from the January 23 closing date of the Gentium acquisition include sales of defibrotide under the expanded access program in the U.S. and on a named patient basis elsewhere. These sales were $12 million. Pro forma net sales of Defitelio defibrotide were $15 million in the first quarter of 2014 compared to pro forma net product sales of $9 million in the same period of 2013. As we've mentioned, the European launch will continue to roll out over the course of 2014 and 2015 as the product becomes commercially available in additional countries. We are maintaining our previous defibrotide net sales guidance at this time, primarily due to the early stage of the launch and continuing launch-related uncertainties, such as outcomes of pricing and reimbursement efforts on a country-by-country basis and the transition from named patient basis access to commercial product. Net sales of Prialt were $4 million in the quarter and were $5 million for the same period in 2013. The decrease in net sales of Prialt was due in part to timing of shipments to the exclusive wholesale distributor and pharmacy in the fourth quarter. Turning to operating expenses. Adjusted SG&A expenses for the first quarter were $76 million or 31% of total revenues compared to $57 million or 29% of total revenues for the first quarter of 2013. The increase in adjusted SG&A expenses reflects higher headcount and related expenses due to the Gentium acquisition and the Defitelio launch, Xyrem initiatives and expanded infrastructure. Adjusted R&D expenses for the first quarter were $15 million or 6% of total revenues compared to $6 million or 3% of total revenues for the first quarter of 2013. The increase is primarily related to increases in clinical study expenditures, outside services for new product candidates and increased cost related to the development of line extensions for our existing products. We anticipate investing approximately $5 million over the second and third quarter related to the narcolepsy disease awareness program, as well as increasing expenses around R&D for clinical programs and regulatory efforts. We are also maintaining our 2014 guidance on adjusted SG&A in the range of $315 million to $325 million, as well as adjusted R&D in the range of $55 million to $65 million. As of March 31, 2014, we had cash and investments of $251 million, current and long-term debt of $1.2 billion and available capacity under our existing revolving credit facility of $125 million. We continue to believe that we have significant financial flexibility to pursue corporate development initiatives, and we are continuing our efforts to identify and evaluate potentially attractive opportunities to expand our business. We acquired a controlling interest in Gentium in January 2014 and completed the tender offer in February, resulting in our ownership of more than 98% of Gentium. We plan to repurchase any remaining outstanding shares of Gentium to the extent possible. We also may repurchase our shares under our share repurchase program subject to market conditions and our assessment of alternative uses of cash. In closing, we're pleased with our financial results for the first quarter, our significant process in integrating Gentium and launching Defitelio and our execution of other important commercial and R&D initiatives in the first quarter, which we believe continue to support our short- and long-term growth strategy. Thank you for joining us on the call today, and I'll now ask Kathy to make a brief comment about our Q&A session.

Thanks, Matt. [Operator Instructions] And with that, operator, I will turn the call back over to you to open the line for questions.

[Operator Instructions] And our first question comes through from Louise Chen with Guggenheim.

The first question I had was on the issues related to the Xyrem volume in first quarter '14. Will they be resolved by the second quarter, or it will be more of a second half '14 timing on that? And then secondly, just on the market opportunity for Xyrem pediatrics, just wondering the timing of trying to commercialize that opportunity.

So Louise, let me hand those questions over to Russ.

So with -- as it relates to the timing of when we'll actually see the return of steady state as it relates to the call volume issues that we experienced with specialty pharmacy, I think it's clear to say that we're encouraged by what we're seeing so far from the specialty pharmacy of late. It's always one of those things that we're going to be watching very carefully. And we hope that by the end of the second quarter, we're talking about a perfect scenario again, but we have to watch and see.

And then on Xyrem pediatrics, I'd point out that we do know there is use of Xyrem in pediatric patients as we sit here today. Obviously, that's not on label and not something we promote. We believe that generating this clinical data will help physicians better understand how to use Xyrem in that population. Obviously, we're working with FDA on this study and look forward to submitting that data back to FDA at the end of the trial.

And our next question comes through from Bill Tanner with FBR Capital Markets. William Tanner - FBR Capital Markets & Co., Research Division: Bruce, just back on the Xyrem topic. I'm wondering, it's maybe kind of an unfair question, maybe difficult to do on the fly, but just curious if you could maybe tease out the impact, the relative impact of the factors that you did list. And I guess the point being that obviously ACA and weather kind of out of your hands, or out of Jazz's hands, where some of the other may not be. And then the second part of that would be sort of not withstanding, I guess, the dispute resolution on the REMS. Does this not suggest maybe that a second distribution -- distributor might be -- might make some sense.

So on the first one, Bill, tough to fully analyze the data in a way that gets you a precise answer. You may have noticed that in the call, I specifically flagged the growth in patients, which I don't usually do in quite the same way. And if anything, over the last months or quarters, we've seen volume growth slightly outpace the increase in patients. And you saw it go the opposite way this quarter, which really tells me that we are continuing to bring new patients on the Xyrem therapy. We just didn't process all the prescriptions, including retail prescriptions, the way we like to in the first quarter. So there was weather. I think everyone has seen that other companies have talked about that too, and I think that is real. But we have something far beyond that, which was this processing issue in the first quarter. On the REMS side, I hear your question. That's a smart question. I'm not sure that having an additional site would have changed anything. This was a processing issue that anyone would've dealt with. Some of it was on our side of the equation, and some of it was on the payer side of the equation. I don't know if any of the listeners on the call tried to contact a payer earlier in the year. But I don't think we were the only ones having trouble getting through, and so I'm not sure that really would've been affected by multiple distributors. And as you know, our rationale for having the single central pharmacy isn't just about processing. It's really about coordination and ensuring public and patient safety. William Tanner - FBR Capital Markets & Co., Research Division: And just reiterating the guidance, I mean, it does seem like the ground is going to be made up. So is it reasonable to sort of view perhaps the guidance that was given at the beginning of the year maybe a little bit more on the conservative side and now maybe a little bit more on the realistic side, I guess, given what happened in the first quarter?

Not sure I want to answer the question quite the way you asked it, Bill. But I'd say when we give guidance, we always want to give guidance that we believe we're confident we can deliver on. And while Xyrem growth in the first quarter wasn't what we might have hoped for coming into the year, our expectations for the year remain in line with our guidance. We're very pleased with how we got out of the gate with Defitelio defibrotide in the first quarter. Obviously, we're super early on in that process, but we're encouraged. And we were very encouraged by what we saw with Erwinaze in the first quarter. So as we look at our business overall, we're feeling really good, which is why we -- why we're reiterating the guidance we gave earlier in the year.

And next, we have Annabel Samimy with Stifel. Annabel Samimy - Stifel, Nicolaus & Company, Incorporated, Research Division: So I just wanted to be clear, the processing issue that you have was from increased patient adds. So technically, there should be a backlog and a catch-up in the coming quarters, and that should technically be a good sign if you're seeing higher call volume. I just wanted to understand the source of the call volume. Is this the increased advertising? Or it was just unusual call volumes for some other reason?

Yes, let me start that and then Russ, feel free to jump in. I wouldn't attribute it to the advertising. So call volumes to the pharmacy really comes after a patient has already received a prescription. The increased call volume had more to do with the fact that multiple calls were required to get things done in part, again, related to how well the pharmacy could handle the calls and how the pharmacy's outgoing calls were not being easily processed by payers. So it's not that we have a big backlog of patients. It's that patients didn't all get timely prescription refills. And remember that for almost all of our patients, they have to be refilled every 30 days, right, because of the controlled substance, because of the way a Xyrem program works. All of our patients ripple through that system once every month. So had we had a glitch like this in the first quarter and had a bunch of our patients on 60- or 90-day refills, the effect would've been much more muted.

I think that's accurate. And so think of this more as a delay to refill, and a day or 2 actually makes a big difference. Annabel Samimy - Stifel, Nicolaus & Company, Incorporated, Research Division: Okay. And then if I could ask you a separate question on Defitelio. You obviously had a meeting or you had a conference that was presented and it had some good attendance. Can you share with us some of the feedback that you're getting or initial reception that you're getting on Defitelio and how you feel the education -- how difficult that education might be in Europe?

So if the phone system is working from Europe, let me ask Jeff who's on from there to chime in on this one.

Sure. Well, it's very interesting at the EBMT meeting to see the reaction of the transponders there who had experienced for a number of years with Defitelio. So it's not like it's a new product for them. But what is new now is the availability, the type of research and information that they're being exposed to and there was a great deal of excitement on the investigator's point of view. I think there, if we look at the various guidelines that are published, Defitelio is now considered to be standard of care in the treatment of severe VOD. So here, again, it was very interesting because it was finally going from an experimental product to a real commercial product for them.

Next, we have David Amsellem with Piper Jaffray.

I joined late, so I apologize if you already addressed this. Just on the processing issues that you saw, should we be concerned that this is something that will rear its head down the road? Or can you take away some things that you've learned from this issue to keep it from happening again? And then secondly, on 386 with the human study starting, can you give us a sense of timing of data and then what potentially would be the next steps? In other words, could you potentially advance it into a pivotal trial if you get the safety and PK data that you're looking for, in other words, accelerate development?

David, this is Russ. Thanks for the question. I do think that we have learned a lot from this. The call volume is really just a numbers game more than anything else. And so it is something that you can get ahead of and you can actually plan for. Having said that, there are numbers of factors that can cause call volume to go up. And so as we stand here today, I don't see something happening in the very short term that would cause that to change, but there's really no way of knowing whether something down the road could increase call volume as well. I think we're in a position to deal with it going forward, and so I like the improvement that we're making today.

Yes, on JZP-386, David, consistent with what we've said before, our plan is to get data this year. I think we've generally said we'll come back to you and talk to you about the plans for further development once we've seen that data. Probably, it's a little too early to comment on that without seeing it. We're certainly aware that Concert has had other programs that move quickly into pivotal trials after initial data, so we know that's at least a potential. But what we'll do, I think, depends on the data we see.

Next, we have Jason Gerberry with Leerink Partners.

Just wanted to follow up on David's question about 386. Can you maybe just -- are there any -- I'm just kind of curious why the study hasn't started yet. I'm just kind of curious how you guys think about your development program versus the Flamel once a day program just in terms of timeline for development there. I would've thought maybe there'd be kind of an urgency to kind of get a once-a-day product to market ahead of that. So any commentary just on the Flamel product? And then just if you go down the pathway of an NCE with 386, is that -- could you also avail yourself of the 505(b)(2) pathway? Or are the 2 not -- the 2 not -- can you not do both at the same time?

So Jason, a lot of different questions built in there. I think I won't comment specifically on somebody else's development program. We've certainly answered some questions about that data. But if there's some urgency, I would say there's urgency in everything we do around Xyrem, whether that's our current efforts to treat our existing patient population, expanding that population, expanding physician education, expanding disease awareness and helping diagnosis, developing follow-on products. JZP-386 is something we talk about public, but it's not necessarily our only effort, now exploring it in pediatric trials as well, intellectual property protection, litigation, REMS-related matters. Anything you put on that list that has Xyrem next to it, you can bet is a top priority for us. Don't take any of my comments as anything other than this is very important to us. I think we've been pretty consistent with our Investor Relations strategy over time in terms of when we lay out timelines for things. We like to hit the timelines we lay out. That tends to mean we're not quite as aggressive sometimes that saying before we've even seen data exactly what future timelines will be. I think that's the right strategy for our company, and we'll stick with that. So as soon as we get through this initial collection of human data and have something more to say, we'll be happy to do that. But our job is to engineer the best result for our shareholders, and sometimes a lot of public disclosure is helpful in that regard and sometimes it's not.

Next, we have Gary Nachman with Goldman Sachs.

Bruce, sorry to beat a dead horse here on the central pharmacy, but were they understaffed? Is that why they couldn't handle the call volume? And what are you doing exactly to correct that? I wanted to understand that better. Any repercussions from the 483 letter that you mentioned with respect to patients getting access to Xyrem? And then on the launch of Defitelio, just how quickly should you get those approvals in the rest of the EU? What should our expectation be there?

So on the central pharmacy, it's kind of a tricky question to answer. It sounds like a straightforward question: were they understaffed? I don't think they were understaffed based on what they were expecting and we were expecting. I think the real question is how fast do you react when the situation changes. And the call volume going up very quickly, in retrospect, I think they would say as well as we would say, they did not react to that fast enough and realize that, that was a problem that would require additional resourcing and a fast flex. So back to the earlier question, I can't remember who asked it, maybe it was David, but are there learnings for the future? Absolutely. And part of the learnings are both: you got to have more flex in your system to start with; and second, when you see something different from that, you need to react very quickly. So lots of learnings from this experience. On the 483, I would say no impact on patient access. This is really how we process on the back end adverse event reporting. And remember, I specifically mentioned this included Xyrem as of course we got 483 specific to Xyrem in the past. We wanted to highlight that for all of you because depending on how FDA looks at it, could be considered repeat observations. We know sometimes that triggers warning letters. But I'll point out that a lot of what was identified here, and we give some data in our 10-Q that we'll file, but it was a very low percentage of cases, a lot of that did not relate to Xyrem at all. So this is something we take very seriously, something we have to improve. The goal is 0 late reporting across all products, whether or not partner companies are involved in that data collection and dissemination. That's what we need to get to. We're not quite all of the way there, which means we've got a little work to do. But to your question, I don't think there's an impact on patient access. And then on the rolling launch of Defitelio in Europe, just a reminder that the product is available throughout Europe on a named-patient basis. And therefore, in terms of our rollout across markets, we're very focused on optimizing patient access through our pricing and reimbursement submissions and are going to focus on getting the best possible answer rather than the fastest answer because we know patients have access to the drug today.

Next is Ken Cacciatore with Cowen and Company.

I just wanted to ask on the Defitelio. I'm trying to understand how you fully exploit that opportunity without owning the U.S. rights. It's a very interesting group that now has those rights. Wondering what kind of conversations you're having with them. And how do you kind of justify or push the spending for other indications without really having control of the product? And then I had a follow-up.

Okay. Ken, good question, and worth -- definitely worth spending a moment on. So as a reminder to everyone listening, commercial rights in the U.S. market for VOD are owned by Sigma-Tau, our partner. We are certainly having conversations with them. They are our partner. They were with us during the FDA interaction. In terms of how we prioritize spending on additional development opportunities, remember, we own 100% of the economics outside the Sigma-Tau territories, and we own a good chunk of the economics in the Sigma-Tau territories. Remember, we get about $0.38 of every sales dollar of defibrotide in the Americas. So we do have a big economic piece of that already. Development costs that we incur are actually shared with Sigma-Tau. So I don't think there's a mismatch there in terms of our -- whether this makes sense as a good investment for us. We absolutely think it checks the boxes both of being a product we really want to get to severe VOD patients in the U.S. as soon as possible, and something that will produce an excellent return for our shareholders. In terms of conversations with Sigma-Tau beyond that, I'm going to have to decline to comment on that.

Okay. And then I hate to go back to the Xyrem issue, but just not entirely clear why there is an increase in call volume. Is there any issue with the payers? It's just after listening to you, I'm still not entirely clear what this call volume increase was really related to.

Yes, so let me provide some clarity, if I could. So first thing is that it was not a payer-specific issue. So this call volume is really driven by the fact that we have the Affordable Care Act coming in. We had just longer periods of time going back and forth with physicians and the fact that you're asking a few less people maybe to make more calls. And like I said, this is a very small change in terms of the overall number of days that we're talking about, but there are implications in terms of the refill rates and timing. So it's really just it's sort of a numbers game and just driven by the timing of how long it took in this case as opposed to any major changes in the landscape, especially as it relates to payers.

And the other thing I would just add is we're comparing here 2014 to 2013, and we happen to have some glitches in the first quarter of '14 that were unusual. It's also true we did a particularly good job of handling this in the first quarter of last year. So we were in the opposite situation last year from where we are this year. If you -- any of you remember the first quarter call last year, we were talking about how it was surprising that we hadn't seen the same dip or the same pattern we had seen in several years prior to that. So something we handled exceptionally well last year that through, again, a confluence of factors, was not handled as well this year.

Next question comes through from Jonathan Eckard with Citi.

But one is on the Italian reimbursement. Just real quick, is this the final step for reimbursement in that country? Or is there another parallel reimbursement process that eventually will be implemented when it's complete? And I guess along those lines, with regards to the U.K., do you or would you -- when would you know or expect to hear if there's going to be a NICE assessment around the drug?

As far as the Italian 648 program, that is the reimbursement to help patients get access to the drug initially, and we expect final pricing and reimbursement in the second half of this year. And then, Russ, do you know the...

We do not expect a special assessment from NICE.

Okay. Perfect. Did you hear that?

Yes.

Next comes through from Douglas Tsao with Barclays.

So the topic du jour is really on this call volume issue. Russ, I get in your response to Ken's question the issues around ACA and sort of lack of clarity in coverage. You did make a point, you said there is timed back and forth with physicians. If you could just perhaps walk us through exactly what you mean by that mechanically, I think that would provide some clarity.

Yes, so we did find that there are instances where it was required to get a second call for confirmation from a physician, which is just a new step edit it that you typically see put in place. So that did require more time and as a result, that second call led to some delays, which added up to the overall change in timing.

And so just as a quick follow-up, so I mean -- because I know you've been saying that you've sort of been seeing prior -- an increase in your prior auths, which is not surprising and understandable given the price of the product. Is that what we're seeing now, just simply sort of more steps being put in place, not necessarily restrictions but steps put in place by managed care, which did sort of clog the system, so to speak.

Yes, so here's the way I think about it. So there were some additional steps edits that we typically see. This is no different than what we've seen in previous times. I think the most important thing to think about is what is your overall level of reimbursement. We're not seeing any change there whatsoever.

Yes. So one -- again, referring back to the pattern we see year-after-year, we always see a little bit more of this in the first quarter than other quarters, typically driven by plan changes, not specific to Xyrem, but plan changes you see rolled out on an annual basis. Often, the plan years for many of the enrollees are January 1 through December 31. And so we got that this year plus a couple of additional factors. But we would always expect more of that, a new processing in the first quarter versus the other quarters.

Okay. Great. No, no, that's -- your answer is very helpful.

Next question comes through from Daniel Brims with Brean Capital.

As to the usage of defibrotide in the EU, do you have any insight as to how much is being used for acute and how much is used prophylactically?

So Daniel, great question. I wish we had that data. We can ask the question and get anecdotal evidence, but I don't think we have an accurate way of knowing on a patient-by-patient basis what's happening there.

Yes, and again, what we can comment on though is we're seeing trends to 1 in 3 patients earlier. But whether that turns into real just severe VOD treatment or prophylaxis is a little hard to vet out.

Okay. And then for the path forward in the U.S., you're looking at that's going to be strictly acute, or are you also looking for a prophylactic way forward in the -- for the U.S.?

So sort of both is the answer. When we're talking about the potential for a near-term submission in the U.S., we're definitely talking about treatment. But we have said we're interested in doing additional clinical work around prophylaxis as well. But just to be clear, when we talk about the potential to submit an NDA without the need for data from additional clinical trials, in that case, we're talking about treatment of severe VOD.

Okay. And I guess the prophylactic, you tried tying that in with any graft versus host studies that you might be doing moving forward?

I haven't specifically commented on whether we'd addressed those together or separately. We'll come back to you in the future on that.

And our next question comes through from John Newman with Canaccord.

Just wondered if you could shed some light on where are you pricing defibrotide right now in Europe? And also, if you are able to secure approval for the product in the U.S., how would you approach the current relationship with Sigma-Tau?

So John, repeat the second part of the question again for me?

If you're able to secure approval for the product in the United States, would there be any changes to the relationship with Sigma-Tau?

Yes, so let me take that one first, and then maybe I'll have Kathy or Matt comment specifically on the pricing we've got for Defitelio in the markets where we know that already. So we have an arrangement. By we, we inherited a relationship Gentium already had with Sigma-Tau. Under that, the rights of the parties and the economics of the parties are specified. I don't know what to say in terms of any change on approval and launch. At that point, they'd assume commercial responsibility. We'd be supplying product to them, and we'd be receiving 38% of their sales under the agreement we have.

Okay. And as far as on pricing, so far in the countries where we do have approval, the price is EUR 426 per vial. And as you know, adults would get approximately 8 vials per day and the time to treatment is usually -- the number of days of treatment is usually 21 days or until the disease is resolved. And then for pediatrics, it's probably more around like 3 vials a day. So I hope that gives you a good feel.

And obviously, it varies depending on the size of the adult or the size of the child. And that's sort of a list price. That doesn't necessarily mean that we get every penny of that, but that's the list price.

We have a follow-up coming from Douglas Tsao with Barclays.

Just on the spending side, just curious if we should expect the SG&A and the R&D lines to sort of continue at this rate through the course of the year? I mean, obviously you've given us full year guidance numbers. Or will there be any sort of seasonality that we should be aware of?

Yes, thanks, Doug. Its Matt. Yes, typically, we see higher SG&A in the first half and in particular, the first quarter. You tend to front load certain sales and marketing expenses. You might have other contract renewals that have step-ups or audit fees that come in the first period. So you typically do see higher SG&A in the first part of the year. I think for the year, you'd -- if you look at our guidance, it'll be calibrated to look a lot closer to the 2013 number. In the same -- and with respect to R&D, I think, again there, 5% to 6% if you were to calculate it on a margin basis is what our $55 million to $65 million guidance would translate into. So we do expect spending at or around this level. And I'd remind you, we have a broader overall clinical development portfolio with several of those programs moving in to later stage development. So while that will, again, be consistent with first quarter for the rest of this year in general, next year into 2015 and 2016, we do expect some modest increases on a percentage basis and more significant increase on a dollar basis as those programs move further into clinical development.

And would you expect that to be -- Matt, that's really helpful, and obviously the pipeline is sort of maturing in a pretty significant way with potentially a couple of Phase III studies. I mean, when you say increase as a percentage of sales, I mean, should we be thinking going in from the 5% to 6% range to a 7% to 8%, or could it be above that?

Yes, and we haven't commented. We obviously do continue to provide annual guidance one year forward. But just to put it in perspective, we've talked about the JZP-110 development program representing roughly $100 million worth of expense over the course of 2015 and 2016, which is when those expenditures would occur. And with programs like 416, pediatric narcolepsy, potentially 386 and other things we may do with respect to defibrotide, I think if you look at that, you should expect some modest increase on a percentage basis.

And next we have Difei Yang with R.F. Lafferty. Difei Yang - R.F. Lafferty & Co., Inc., Research Division: Just a quick one, I'm just curious if you have observed upward trend on the out-of-pocket expenses for patients on Xyrem?

So we always see that at the beginning of the year, you'll see the overall patient expenditure go up. Payers make adjustments. So you do see that on deductibles historically. But in terms of the overall out of pockets for us, no, we haven't observed that at all.

Next is Marc Goodman with UBS.

Bruce, can you give us some metrics that occurred with Indianapolis and Charlotte that are going to result in higher revenues, that give us some confidence that going into the other 8 markets makes a lot of sense? And why was there no change in the SG&A guidance if you're going into all these new markets? Was that already baked in from the beginning? Or is this just mean low end moves to the high end, or would you cut spending on something else? And then second question is just on the U.S. conversations on defi with the FDA. You sound more optimistic here and obviously, the history here was some previous guys at FDA, I guess who have moved on, previous guys agreed to the study that Gentium had done, and then new people had come in and didn't really sign off on this whole single ARM historical control thing. And so I guess the question is like, are we now having this new group of FDA who actually agree that what they've done is enough? You actually sounded pretty optimistic there. So how optimistic should we be that we've got something here?

Yes, Marc, thanks for the questions. Let me hand it over to Russ to comment a little bit on how we're thinking about the data we're seeing on the disease awareness efforts. I'll take the second part of that now, which is to say that in terms of what does this lead to in the way of revenues over time. Increased diagnosis of narcolepsy, we believe, would lead to increased treatment of narcolepsy. For some patients, that treatment is going to include Xyrem. So we're confident that a better diagnosis of this disease is good for patients and ultimately, ought to also result in more use of Xyrem. But I'd also like to remind all of you that in general, people don't walk out of their first appointment where they're told they might have narcolepsy with a prescription for Xyrem. So we're making an investment that we're confident can have an impact on diagnosis. Over time, we'll see what that translates into in terms of our business. But Russ, why don't you talk about some of the data we see?

Yes, and so as Bruce mentioned, the objective of this program was to improve the diagnosis rate of narcolepsy. And so if I just took at key metrics, whether that'd be PSGs, MSLTs, I do see those going up in a statistically significant way versus the control. So that's one key metric. But maybe even more importantly, what we're seeing is people actually requesting information on narcolepsy, scheduling visits with their physician and actually going into -- and make those appointments happen. So for us, the key metrics that we wanted to see in the pilots were realized. I will put into perspective, this does not mean that we're going on this national campaign. We're talking about 8 markets that represents less than 20% of the total national reach. We're going into areas where we think it actually is the most cost-effective to do it and where we know that there's really great narcolepsy centers. So it's a very focused effort at this point, and we're actually pretty encouraged with the metrics that we're seeing. And to Bruce's point, this is a long-term investment because very few physicians actually start with Xyrem, but over time, they ultimately get there.

And Matt, why don't you take the question about how this impacts our SG&A guidance?

Sure. Yes, we just wanted to provide a little bit more granularity with respect to timing, which is why we wanted to refer to the $5 million we're spending in the second and third quarter on the narcolepsy awareness program when advertising rates are more economical. So we think it's a prudent time to be making the investment. But we did contemplate this, as well as many other initiatives we have around Xyrem as part of our initial guidance. So it doesn't mean it's a replacement of other costs, and we are comfortable, again, reiterating our SG&A guidance at the $315 million to $325 million level.

And then Jeff, if you're still on the phone, let me ask you to comment on the interactions with FDA around defibrotide.

Sure. So we recently had a Type 1 meeting with the FDA to ask them questions regarding some of the things that you'd raised and to get clarity on whether there was a path forward and specifically, FDA's point of view on some of these issues. As a result of that meeting, we believe that we've resolved some of the issues, but more importantly, have a clearer view on what the FDA wants to get for a successful submission. So the optimism that you're hearing was based on the fact that we have more clarity on a potential path that was agreed upon with the FDA. There are still a number of issues that need to be resolved before that can be finalized. As we've noted, following some additional meetings we plan to have with FDA, we would then come forward with final proposal for a submission strategy.

And do you think all that will get done this year?

Yes, I do think that we would certainly have the meetings and strategies established this year. And if we were able to go forward with a submission, the very earliest that would be would be end of year.

So our last question then comes from Patti Bank with DISCERN Securities.

So 2 questions. First, Bruce, on the dispute resolution, you mentioned -- I thought that you expect to hear from FDA in the second quarter? Can you just walk me through the possible scenarios there and if it did go against you, what the process from there would be? And then I have a second question.

Yes, so Patti, I'm not sure we know what all the possible scenarios are, but we certainly know there are scenarios that range from -- we completely agree with you that we completely disagree with you. If it's a rejection of our position we took, depending on who it comes from, there are opportunities to appeal that to higher levels within the agency and we'll just have to see how that plays out. There are also some cases where companies choose to go beyond FDA if they really feel there's a strong basis for not accepting where FDA has ended up. But we're going to start by seeing what FDA comes back with in the not-too-distant future.

Is there any time frame around appeal process, or is it nothing written in stone?

Yes, it's not written in stone, Patti. There are different ways that can go, and there are some variability around that.

And then just my second question is -- I just had a kind of far-fetched question. But is the call volume central pharmacy issue, is there any readthrough there for how the FDA could potentially think about a shared central pharmacy, in terms of if you're having problems with call volume keeping up, that if you added generic, that could just get more difficult?

Yes, I don't know -- it's an interesting question. I'm not quite sure how to answer it, except we're really talking about a single-shared system that would be developed with the buy-in of all parties involved, including us. And we'd clearly want to take all of our learnings over 11 or 12 years into account in designing a system that we know works for patients and accomplishes the things we think are important to accomplish with the restricted distribution system. So I guess the short answer is yes, and we take that into account in how we think about it, but that's only one of a couple ways this could all play out.

Okay. Operator, I'm going to finish up the call here. Thank you, all, again for joining us today. We're planning to attend the UBS and the Goldman Sachs healthcare conferences in the second quarter, and we look forward to seeing many of you at those conferences. Operator, this ends the call.

Great. So everyone, thanks for your time and your participation. You may disconnect, and enjoy the rest of your week.