Welcome to the BioMarin's Fourth Quarter and Full Year 2019 Financial Results Conference Call. Hosting the conference call today from BioMarin is Traci McCarty, Vice President of Investor Relations. Please go ahead, Tracy..

Thank you, Sarah, and welcome, everyone, to remind you today this nonconfidential presentation contains forward-looking statements about the business prospects of BioMarin pharmaceutical Inc.

including expectations regarding BioMarin's financial performance, commercial products and potential future products in different areas of therapeutic research and development.

Results may differ materially depending on the progress of BioMarin's product programs, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical market and developments by competitors and those factors detailed in BioMarin's filings with the Securities and Exchange Commission, such as 10-Q, 10-K and 8-K report.

On the call from BioMarin management today are J.J. Bienaime, Chairman and Chief Executive Officer; Jeff Ajer, Executive Vice President and Chief Commercial Officer; Robert Baffi, President, Global Manufacturing and Technical Operations; Hank Fuchs, President, Worldwide Research and Development; and Brian Mueller, Acting Chief Financial Officer.

We intend to keep this call to 1 hour, so please reach out to me if we don't get to your questions. Now I'd like to turn the call over to BioMarin's Chairman and CEO, J.J. Biename..

Thank you, Traci. Good afternoon, and thank you for joining us on today's call. As you saw in our press release, we delivered record results for the full year 2019, demonstrating our continued operational excellence.

In parallel, our productive R&D and gene advanced to the next wave of products expected to contribute significantly to top line growth in the coming years. We begin the new decade with an established base business that is foundational to our financial strength. We expect to turn profitable on a GAAP basis in 2020.

For the first time in the history of the company, our revenue growth and improvement in profitability is also increasing our operating cash flows as our total cash and investment grew for the second straight quarter in Q4 of last year.

On the development and commercialization side of the business and investing pipeline focused on larger rare indications, 3 potential blockbusters on the horizons are launched. Palynziq is already delivering strong results, and these results are expected to drive better growth for our stakeholders in the next few years.

Starting with valrox for severe hemophilia A as reported last week, we received a prior review of our BLA from the FDA with a PDUFA action date of August 21 of this year, and no advisory committee being scheduled by the FDA at this time.

For a little perspective, in the last 12 months, we've made the criteria necessary to similar applications for expedited review in the U.S. and Europe, we submitted and were granted acceptance of both applications.

We completed an enrollment in our pivotal Phase III study, and we produced material from our GMP facility to prepare for the commercial launch later this year. We actually already have inventory to treat about 500 patients with valrox this year.

This exceptional execution across the organization underscores BioMarin's commitment to our key strategic priority, significant and sustainable long-term top and bottom line growth. We expect valrox will be an important contributor, and in a moment, Jeff will expand on some of our assumptions as we prepare for a potential launch later this year..

Thank you, JJ. Of course, the acceptance of the BLA is a significant milestone for the commercial organization as we prepare for a potential launch later this year. So I will quickly review the results before sharing our thinking on the valrox value proposition.

The fourth quarter marked a strong finish to a year where all brands contributed to total BioMarin revenues of $1.7 billion, a 14% increase over 2018 total revenues. A notable milestone was achieved with Vimizim becoming the first BioMarin brand to reach and surpass $500 million in annual sales.

Combined growth from our 2 newest brands Palynziq and Brineura was a material factor in this solid performance. Ongoing instability in certain markets, including Turkey, Iran and Argentina presented challenges throughout the year, but I'm very pleased with the overall results delivered by my team in the quarter and full year. .

Thanks, Jeff. I'd like to start by echoing Jeff sentiment about the sense of excitement at BioMarin as we start this new decade. With the potential approval of valrox on the horizon later this year. From preclinical assets through applications under review, the breadth of our development pipeline has never been as diverse or de-risked.

With valrox in roughly 4 years, we have gone from the first administration in humans to having a marketing applications under review on an expedited basis in both the United States and Europe. The efficiency of the valrox development programs is an achievement in and of itself.

The potential for valrox to completely change the treatment paradigm for hemophilia is an even greater feat. We want to thank the hemophilia community for providing BioMarin the opportunity and support to successfully develop valrox, a major part of the support comes from the dedication and commitment of key opinion leaders in the field.

Earlier in the year, we are honored to see valrox recognized for the second time in the New England Journal of Medicine with the publication of a multiyear follow-up of our Phase II program.

To remind you of the data, 3 years after infusion, the median number of annualized treated bleeding events was reduced from 16 while patients were on 2 to 3x weekly prophylaxis to 0. And accordingly, the median use of exogenous factor VIII was reduced from 138.5 infusions to 0 infusions. Leading an all target joints in this cohort resolved.

Given these data and in reference to Jeff's previous remarks on experiencing cost effectiveness and a reasonably short period of time, we now have supportive evidence of such a possibility.

These impressive data were not only the basis of the publication of New England Journal of Medicine but also were the basis of a recent independent academic research paper modeling the benefit that gene therapy may offer as an alternative to prophylactic exogenous factor VIII infusions.

The findings projected that valrox would be the dominant treatment choice, being both cost-saving and producing superior patient health outcomes with at least 2.4 years of durable response. This is based on potential reduction in factor VIII use, direct medical costs, lifetime bleeds and accumulated joint damage. .

Thank you, Hank. Please refer to today's press release summarizing our financial results for full details on the fourth quarter and full year 2019. Since Jeff touched on many of the top line results from the commercial business, I will focus on the bottom line result, operating expenses and our 2020 guidance.

As usual, all results will be available in our upcoming Form 10-K, which we are on track to file over the next couple of days. The endpoint just comments about our revenue momentum, we're pleased to announce total revenue guidance for 2020 of between $1.95 billion to $2.05 billion.

If we are able to achieve $2 billion in revenue in 2020 that would represent 17% growth over 2019. In terms of the bottom line, for the full year 2019, we provided guidance of a GAAP net loss between $45 million to $65 million. And have reported a better than guidance, GAAP net loss of $24 million for the year.

This improvement in GAAP net loss in 2019 over 2018, particularly in the second half of the year, driven by our growing revenues and operating leverage gives us comfort to guiding to GAAP net income on a full year basis for the first time in company history.

For the full year 2020, we expect GAAP net income of between $20 million to $80 million, depending on the contribution from valrox. In our press release, we also noted that our guidance does not reflect a potential tax benefit that we may recognize in 2020. I will elaborate on that in a moment. Turning to non-GAAP income.

We delivered $167 million for the full year 2019 and $46 million in the fourth quarter of 2019, driven by strong top line results across the commercial portfolio. Non-GAAP income for the full year 2019 was over 80% higher than non-GAAP income for the full year 2018 and sets us up for further non-GAAP profitability growth in 2020.

For the full year 2020, we anticipate non-GAAP income of between $260 million and $310 million. The midpoint of which is growth of more than $100 million and over 70% increase over 2019. This anticipated growth in non-GAAP income is substantial, with the midpoint of our 2020 guidance being 3x our GAAP net income from 2 years ago in 2018.

Moving to operating expenses both R&D and SG&A expenses in the fourth quarter of '19, roughly tracked with recent trends and within our 2019 guidance ranges. R&D expenses were flat year-over-year at $173 million and for the full year 2019, were $715 million.

In the fourth quarter, R&D expenses reflected continued enrollment of additional patients in the valrox global Phase III GENEr8-1 study, manufacturing of BMN 307, our PKU gene therapy product ahead of clinical trials this year and the 0- to 5-year-old study with vosoritide for achondroplasia.

For the full year 2020, we expect R&D expenses of between $675 million to $725 million, representing steady-state R&D spending and balancing the completion of the valrox and vosoritide, large-scale Phase III studies with the start of the BMN 307 PKU gene therapy clinical program, preclinical studies of BMN 331 for HAE and the completion of the vosoritide Phase II study in 0- to 5-year old.

SG&A expenses for the quarter and full year 2019 were $188 million and $681 million, respectively. And were higher than 2018, reflecting the continued expansion of our sales and marketing capabilities for the launch of Palynziq in Europe and ongoing preparations for valrox and vosoritide approvals in March.

For the full year 2020, we expect SG&A expenses of between $780 million and $830 million in preparation for the global launch of valrox and ongoing commercialization of Palynziq in Europe. In terms of cash and cash equivalents and investments as of December 31, 2019, we have $1.17 billion as compared to $1.32 billion on December 31, 2018.

Our revenue growth and improvement in profitability is also translating to our operating cash flows as our cash and investments have increased at the end of 2019 for the second straight quarter. Now back to the potential tax transaction that I mentioned earlier.

As noted in our press release, full year 2020 GAAP net income guidance of $20 million to $80 million does not reflect the potential impact associated with intra-entity intangible asset transfers between BioMarin entities that may occur in the second half of 2020.

If these transactions occur, we estimate that the tax effect could be a onetime noncash income tax benefit of greater than $500 million.

You may have seen similar tax gains recognized by some of our peers in the fourth quarter of 2019, and we wanted to make sure you are both aware of the potential transaction and the financial reporting, which, again, is noncash GAAP income tax benefit with no anticipated impact on our operations or cash flows in 2020.

In closing, 2020 is the year that we expect BioMarin to become GAAP profitable based on the expectation that total revenues will be $2 billion roughly for the year. Over the next 18 months, we also expect to accelerate in the next phase of higher revenue and profitability growth through the potential approval and launches of valrox and vosoritide.

Thank you for your support, and we will now open up the call to your questions..

. Our first question comes from the line of Phil Nadeau from Cowen & Company..

Congrats on the progress. Just a two part question on valrox. First, we've heard from some physicians that there's a pool of early adopters out there who want to try gene therapy close to the time of the launch, but it's hard to quantify how many of those patients are out there.

Do you have any data, either from your own market research or your clinical studies as to how big that population could be? And then the second part of the question is just valrox isn't called out in your 2020 revenue guidance, does your guidance include any contribution from it?.

Yes. I'll start with me. Phil, JJ. So in terms of 2 of early adopters, I mean, there is definitely very significant interest in the drug -- I mean, maybe the best way to characterize it in the U.S., we've done a lot -- we do a lot of educational programs on gene therapy, in general. Gene therapy for hemophilia A.

So we have some educational programs website, whereby the patients can opt-in to receive so they can provide us with some personal information to opt in to receive information on valrox. And as of couple of days ago, I think we had already 400 patients in the U.S. alone, that show interest in receiving information on valrox.

I presume these patient are -- I mean, it's unlikely that all of them will actually want to move forward. But I think a large number of them will. And then all of them. It's unlikely that all of them will be eligible for therapy, but they're definitely interest in it.

And also, there's a market research as we have communicated in the past that show that hemophilia patients are very interested in the drug. Second question is valrox -- yes, including in the guidance. Valrox is included in the guidance in terms of top line and, of course, bottom line.

The issue with valrox this year in terms of -- that's why we don't want to give you valrox guidance this year. Actually, we really do it when we were in the launch year for any product because it's highly dependent upon the timing of the approval, PDUFA date is late August.

But you never know, it happen And if it happens in late August, then it must be much easier to generate some significant revenues, than if it happens in October or November. And this is a bit -- as of today, a bit beyond our control. Same for Europe. If we stay on the accelerated assessment pathway, we should get approval in the summer.

But it could be later presented. Even after approval -- I mean, we could ship the product pretty quickly, but we -- then the release of the paperwork just even in the U.S. to get the patients started on therapy, reimbursed. And then remember, we're going to need to get the patients to do the AAV5 antibody test.

Actually, some of them -- we align them up to do it as soon as possible after launch. So this seems like a little difficult to give you a tight valrox-only guidance for this year, but we'll do it for next year.

So Jeff, anything to add?.

Well stated, J.J., nothing to add on that..

Your next question comes from the line of Salveen Richter from Goldman Sachs..

This is Andrea on for Salveen. Maybe just one question for Jeff.

Can you also provide additional color on the registry that's been formed to promote your patient outreach? And help us understand how eligible patients are being identified to potentially come on to valrox upon the launch later this year?.

So J.J. mentioned an opt-in mechanism. So this is not a formal registry per se, these are promotional -- nonbranded promotional efforts that we conduct to -- relative to gene therapy education in general.

To introduce BioMarin to the community, and there is a mechanism for patients to opt-in for further contact from BioMarin and other information as it becomes available. So that's really an unofficial mechanism, and we don't really have anything Hank to note at this point about expectations of a more formal registry..

Other than we'll do a post-approval registry if that's required from a regulatory perspective, although obviously, documenting the long-term outcomes for patients treated with valrox is going to be a prime interest in the medical community over time. Look like that data..

So -- but I guess, as I said earlier, we're going to gear up to -- for these decisions that have shown interest in -- opted in our program, where you have to get these patients tested with the AAV5 antibody test as soon as possible after approval to generate the first revenues..

Your next question comes from the line of Cory Kasimov from JPMorgan..

I've got two as well. I guess, the first one on vosoritide.

I'm just curious what the gating factors would be to submitting the BLA outside of your meeting with regulators? Is there anything left to do on the CMC front or things like that? And then secondly, on valrox, when you're having those reimbursement discussions on the product, it sounds like you've been having a lot of them, how much are payers waiting on that data from your 4-year update to further inform the potential durability of the product?.

Thanks, Cory. I'll start with the first one on gating factors of vosoritide..

Well, why don't you start and maybe Robert can also....

Yes, yes. So gating factors of vosoritide, including consideration of CMC. So as we've said before, that -- and it was nicely demonstrated by the 2018 advisory committee that the FDA held.

There really are 4 principal components to the vosoritide development program, randomized, double-blind, placebo-controlled pivotal trial, p-value of 10 to the minus 13, check, check, check.

205 study, long-term data, treating patients with vosoritide for 4.5 years, demonstrating growth velocity that is sustainably increased over pretreatment baseline levels in spite of declining growth velocity in untreated patients.

A contemporary natural history study that we showed you 4.5 years of comparison at R&D day, demonstrating that compared to patients who were not treated with vosoritide age and gender-matched patients gained at least 9 centimeter more, while being treated with vosoritide than they would have gained if they were not treated, and an ongoing study in patients under 5.

So we're check, check, check as you say, the next gating step is to have the meeting. As you may know from the advisory committee, there were some question about the length of the placebo-controlled study. We believe we have strong arguments to make about why this package checks all the boxes.

And Robert, do you want to comment on any CMC issues we need to address between now and the submission?.

Yes. So thank you for the question, Cory. Certainly, we have been tracking to the clinical development time line. And in fact, we did complete the process qualification campaigns in 2019, collected the data from those campaigns.

Well into the process of writing up the documentation for the BLA, and are tracking along with Hank and his team to a filing date later on this year, and our -- all systems go in terms of the CMC activities.

Currently, anticipated from a regulatory review perspective, having met with the agency several times during the program that outline our CMC strategy..

Then you had a question on payers -- want to talk about that?.

Yes, happy to do that. Great point, great question, Cory.

The commercial audiences, including payers, in general, I would characterize the sentiment of durability looking something like this, an expectation of continued durability based on the data demonstrated so far and based on kind of the biologic mechanism of action here, with a healthy respect of the risk of loss of durability at some point in a future window.

And as I mentioned in my remarks, I think that translates into a desire to try to manage that risk, which is something that we can potentially do with outcomes-based agreements. And I might characterize, that's a very different sentiment than not believing in durability until we see that data reported on.

Of course, having 4-year data mid this year will be a very helpful data point, and we look forward to having that..

Let me tell you. So it's not -- we don't -- just people, Jeff and myself, actually, we mentioned a lot of payers already here. There is -- never heard a payer say, well, if it works at 3, but let's say, we don't have anything at 4. We don't -- we're not going to -- there is no threshold. That's not the way they function.

A minimum efficacy that they need to have to pay for the product. What we're really looking at very closely, it's factory usage. And as we have -- I think Hank mentioned, with the most recent New England Journal of Medicine application.

So we basically almost eliminated entirely, factor VIII usage 3 after treatment, and we're looking forward to showing some big control at the 4-year update..

Your next question comes from the line of Chris Raymond from Piper Sandler..

I've got just a couple of questions, too. So I guess, guys, I know you kind of answered the question a little bit when Phil asked it, but if I can pull maybe a little deeper. Just on valrox's role in the guidance. Just by my math, if you add up all the components and even take into account Aldurazyme royalties.

There's about $125 million or so gap midpoint to midpoint. So I'm not sure if you're going to answer this, but I think....

Chris, it's in the guidance. And obviously, if we have it -- if we have some -- how do I show you? It'll be easier to meet the guidance, then maybe not..

Got it. Okay. So that's -- okay. And then maybe just a broader question on the pricing, J.J., specifically. So I think we all appreciate the cost avoidance, some sure payers as well and not just in factor, but other stuff that it offers.

But -- and just kind of talk a little bit about -- this is a relatively politically charged time with respect to drug prices. I think you've already attracted the attention of at least one presidential candidate on this. Just talk J.J.

a little bit about how this is factoring into your pricing calculus, if at all?.

So -- I mean, so the political factors, of course, we'll enter into our final decision. So that we have a little time before deciding, we'll see where we stand on whether we have to press the drug sometime December -- around December. But I think already the cost offset still is a pretty significant story for the payers.

They know how much these patients cost them, Jeff gave you some metrics. We have a study from general equi economics that was recently published, that does show the dramatic potential reduction in savings, thanks to valrox. Whatever price -- I mean, of course, there is a limit to how much you can price it.

But regarding what's anticipated, the savings, apparent to the health care system in the U.S., are going to be pretty high. So I think the top prices might need to be indicated about the market that we are entering into and the cost of treating hemophilia, in general.

Also I started doing an analysis, we should be available sometime this summer, which would be another variable as to what we can do here. And I think, of course, the headlines are the headlines, but at the same time, we'll see how we communicate our price.

We will try to highlight the price per year of documented efficacy, which whatever price we decide, I'm going to tell you it's going to be much lower than many other therapies that are approved today. So that's definitely the variable. But -- and also, I just want to highlight, so we don't sell a service.

So we're not going to sell service and what's the price. Remember, we're going to sell vials at the end of the day. And actually, the product is going to be dosed based on weight. So price will be variable from patient to patient, depending on their weight for one.

And also, there is something -- is that related to the fact that a lot -- or probably the majority of the patients that needs in the U.S., will be treated in 340B hospitals, whereby there will be a mandatory discount that will be applied. It remains to be seen whether it's going to be 17% to 23%, between 17% and 23%.

The general mandatory discounts is 23%. But factor we placed on actually recently HEMLIBRA got some kind of exemptions, and it's actually only 17% for hemophilia A. We hope to get the same exemption and have a 17% discount.

So let me tell you fact that we're still going to need different number of vials, different weights, different discounts, we'll provide a list this. And you've shown that you are very good in math. I'm sure you'll figure out, Chris..

And your next question comes from the line of Robyn Karnauskas from SunTrust Robinson..

I guess I have another valrox question, of course. So when you're thinking -- I guess, two quick ones.

Just to be clear, so the 4-year data, if you continue to show reduction in bleeds, will that affect the price point? Are you -- is the price roughly been decided already? Or is there any more moving parts? And then second question, so you noted, there's 400 people you've identified so far that really want it right out of the gate.

What are you identifying in your market research that points to what people want to see or what other patients want to see before getting the gene therapy? What trends should we be looking for to -- besides the -- just want to get it right out of the gate?.

I'll start with the first question and let Jeff answer, I mean, the second one and maybe also part of the third.

So the 4 -- we have 3 years, we have already documented 3 years of efficacy, of course, 4 years will be additional data that will enter into the picture, maybe to actually calculate the cost offset more than anything else or documented cost offset.

This is going to be another variable, as I say, it's a variable in the continuum of the reimbursement discussion. It's not we have to pass a certain hurdle. But it will be there. And also, the cost of that just calculated based on the cost of HEMLIBRA. HEMLIBRA and the governing factor VIII prophylactic in the U.S.

is about the same price right now, but at WAC it's about $700,000 to $750,000 a year. And -- but there are many other offsets and values in valrox, patients are going to save the need to go to get intravenous infusions or the equipment that the supply that they need for that.

This is based on our own data, I know, they still have significant bleeding episodes. This is for the emergency rooms, need for surgery. Actually, it's being estimated, I think, in some papers that were recently published that the cost of treating of bleeding episodes in the U.S. is $50,000 per bleeding episodes.

So it always centers into the pictures, and these are metrics that the payers know about, and we'll take into account in negotiating a price with you, so -- with us, sorry. Jeff, you want -- you go perspective on the 4 years and then talk about what kind of people, patients want to see whatever..

Thanks, J.J. I think you've stated it for the 4-year data and price. Maybe in terms of kind of early adopters. We've noted this kind of opt-in mechanism, which is a really, really helpful way of connecting early with patients and caregivers that want to receive more information. And as J.J.

said, we'll have an opportunity, we hope, right after launch to help facilitate, for example, AAV5 sort of positivity testing, which would be one dimension of eligibility criteria.

So our expectation of valrox at launch, is that a minority of hemophilia A patients would be eligible for treatment with valrox based on dimensions or variables such as age, whether or not they're an adult, degree of severity of hemophilia A and others.

So it's not exactly -- I wouldn't want to set the expectation that all of those patients are going to be jumping in the first month and be treated.

In terms of identifying early patients that target at launch, you won't be surprised to hear that we've been conducting market research to identify both with patients that are identifying as early adopters and what their profiles look like, and also physicians that are eager to treat and what they view as an ideal early candidate for treatment.

And because we're operating in a highly competitive environment, I probably wouldn't have anything more specific to say on that subject for now, except to say that we're obviously doing the work..

Your next question comes from the line of Jeff Meacham from Bank of America..

It's Aspen on for Jeff. Just a couple of quick ones on valrox and then one on guidance.

So first on the AdCom decision, is this more of the FDA just not having schedule one yet? Or have they explicitly kind of expressed that they don't think it'll be necessary? And then beyond the companion diagnostic, any other plans to help make diagnosis and treatment as smooth as possible? And sorry, one last one.

On Vimizim guidance, it looks like the midpoint is implying a bit of a slowdown in growth than what we've seen over the past couple of years.

Can you help us understand the dynamics going into the guidance there?.

So AdCom, not necessary, not schedule later. And the reason we're saying it's not necessary is because what they wrote to us is that this time, we don't believe that an AdCom would be necessary. That's pretty definitive for them. And all the discussions that we've had with them, they've never signaled any interest in AdCom.

And there really are -- as we've talked about before, at our pre-BLA meeting where they had a lot of opportunity to ask questions about the clinical efficacy, which would be typically the place that an AdCom would come in.

They said, we don't have any issues to discuss with you on the clinical efficacy because we had agreed on the efficacy criteria before the study was completed and reported on, and you've met all those criteria. So we have nothing to ask an advisory committee since you jumped over our high bar.

And as far as identifying patients, the Canadian diagnostic is unique in the sense that it identifies patients who are AAV5 positive. Now maybe later, we'll be able to demonstrate how to treat AAV5 positive patients. But in the first instance, we think pre-existing immunity to the capsid could inform clinical outcome.

So that's why we're launching the companion diagnostic. As far as other diagnostics to identify potentially eligible patients, it's really not necessary because hemophilia A is such a severe condition.

And the easy way to tell if you have severe hemophilia A is to measure your blood clotting factor in your plasma routine -- very routine lab test done diagnostically -- all of our adult patients already know that they have severe hemophilia. This is not one of these diagnoses that sneaks up on you or requires any kind of specialization to make.

Now severe hemophilia A is one of the most devastating medical conditions there are..

Yes. This is Brian, Aspen. Thanks for the question. Regarding your dividend guidance question, you're right. So the midpoint of the range, it represents about 7.5% growth in Vimizim revenues. We view that as still pretty strong. This brand is in its seventh year of launch, so it is a mature product.

But with that being said, and I can let Jeff color in with any details. We are still finding patients around the world. So still growing..

Yes. Thanks, Brian. Maybe just a little bit of color from the kind of sales tranches here. So the dynamics on Vimizim is we're essentially in market now in all of the primary and secondary and most of the tertiary markets we're going to get into.

So opening up new markets with substantial pools of patients, probably not the source of growth going forward. We continue to identify patients and get them on to therapy at a pretty good pace, as Bryan just noted. So that's kind of a built-in growth driver.

And like with all of our enzymes the patients that get started early on treatment, they tend to perform really well on treatment and stay compliant and durable as patients over time. We are at that point in the life cycle, where we're hitting some price renegotiations in certain markets and -- so that's another one of the little headwinds.

But our expectation is that Vimizim will continue to grow in 2020 and into the future as well..

Your next question comes from the line of Martin Auster from Crédit Suisse..

This is Mark on for Marty. One for valrox, it's on valrox again. So J.J., I know you had previously mentioned that 300 patients had lined to be in the valrox Phase III trial. But unfortunately, the trial was enrolling about 130 patients.

So I was hoping to better understand this 300 number? Was this based on reported interest that was communicated to you? Or was it based on patients actually filling out preliminary paperwork to join the trial? And then secondly....

Sorry, signed informed consent. This was real..

And then in addition, I guess, how much of this excess demand was from patients in the U.S.

versus Europe or rest of the world?.

Global, wouldn't be able to break it out for you sitting here. But there's no -- from the trial that we put in the field, there's no evidence of geographic preference in terms of update.

Our strategy on site selection -- we knew -- Jeff and I have been talking about this for a lot of years, and we knew that as novel is gene therapy is going to be, we're going to have to cultivate centers of excellence for dose administration for monitoring of ALTs for steroid management.

And so we wanted to create a cadre of physicians who have a lot of experience, and we also wanted to do that on a global basis because the condition is itself global and the commercial opportunity is global. So we didn't overpopulate in any particularly key region.

And I think therefore, the representation that we're getting back from this really is a global representation. It's not heavily informed by a particular market or its particular uncertainties..

Your next question comes from the line of Joseph Schwartz from SVB Leerink. My apologies. Your next question will now come from the line of Matthew Harrison from Morgan Stanley..

Everyone, this is Kostas on for Matthew. I have two questions.

My first is, how should we think about potential challenges to valrox revenues in the fourth quarter of 2020?.

Sorry -- a potential what, sorry?.

Challenges..

I mean, the main challenge is the timing of the approval..

And not that, that's particularly a challenge. It's just that uncertainty that the....

Main variable. The timing of the approval..

Maybe just a little bit of color on that.

So revenues are going to be sensitive to timing of approval because the approval sets in motion, these other things that need to be done before a patient can be treated and revenue recognized, for example, we're going to have to have labeled product released in a warehouse ready to ship, and that could take a short period of time.

We're going to have to get reimbursement approvals for patients that want to start therapy. Patients who want to start therapy are going to have to do a 0 positivity test that could take a couple of weeks from start to finish. So there's a number of mechanical things going on that will take a little bit of time.

And that tied with the timing of an approval makes the revenues in Q4 kind of a sensitive or challenging thing to forecast..

And your next question comes from....

We just have one more comment here..

The timing of approval thing is coming. We've got now, I just want to make sure that people are not hearing that we have concerns about the approval of this. When Palynziq was submitted, the FDA told us, expect a major amendment. So we were communicating that the PDUFA date was likely to be expected to be longer. We're not conveying that here.

We have a PDUFA date of August 21, and my theme is working towards an August 21, U.S. action date. And we're reasonably confident that, that's what's going to....

That's a good point. And also, and the commercial team in U.S. and Europe is getting ready for it earlier. We are going to launch -- early August launch, basically..

And your next question comes from the line of Mohit Bansal from Citi..

Great. Congrats on all the progress. Maybe a couple from my side. How should we expect the use of steroids to bed incorporate in the label? Do you think the FDA guidance would be necessary here for the practicing physicians? And the next one is basically, do you have any plans to make valrox available in younger patients like 12 to 18 years old.

Why?.

I didn't hear the second question..

What do we think about steroids on the....

Can you repeat your second question, please?.

Can you repeat the second part?.

Yes, please. Yes.

So do you have any plans to make valrox available for younger boys, 12 to 18-year old? And what steps will you take?.

Okay. So on steroids, very early to talk about the label. It's pretty premature. But what I can tell you is we've got 2 experiences with steroids that have been now well described, the Phase I/II study with prophylactic steroids and a total of 7 patients treated the high dose.

And on-demand steroid use in the interim analysis that's coming to the FDA for review for approval. So we have some of each. And if it's not in the label, we hope that medical information can be provided for prescribers.

I think what you're going to find out there are -- first of all, it's going to take a really long time to establish if there is such a thing as a better steroid regimen because the thing that we obviously care about is duration of effect.

And now that we're out past 3 years, it's going to take longer than 3 years to establish durability and comparisons of one regimen to another regimen. So it's going to take a long time before optimal steroid regimen is actually known. Therefore, in the meantime, giving physicians a choice, I think, is a very prudent option for us.

And we have some of each. We have some prophylactic steroid use and we have some on-demand steroid use. So we think we're well positioned with our steroid experience.

And as far as our plans for pediatric investigation, the process is that we've agreed with the pediatric committee of the CHMP of the European Medicines Agency that will get to an action decision before defining the next steps of our pediatric development program. So we're obviously very interested in getting any younger and younger patients.

Obviously, you also know there's a little bit of headwind around gene dilution at what age, can you actually start toning on valrox and count on reliable, durability.

So we're still doing some preclinical work that we want to finish up, have follow-up conversations after approval with health authorities and then delineate more concretely our plan for children..

Your next question comes from the line of Kennen MacKay from RBC Capital Markets..

First off, congrats to the whole team on the FDA acceptance of the valrox BLA and this hopefully landmark approval. Maybe in relation to that, the SG&A guide came in a little bit above our thinking. I'm guessing that's probably due to the team's plans for the valrox launch, but maybe for J.J.

or Brian or Jeff, maybe you could talk about some of the additions that are behind that annual year-over-year growth? And then specific for Jeff, can you maybe talk about the commercial network that you're building out for valrox? And give us a sense of how many MSLs and sales reps are going to be behind this hematology sales force?.

So Brian is going to start on the financials, and then Jeff will comment on the commercial preparation..

Yes. Thanks, J.J. This is Brian. So regarding the SG&A guidance, again, $780 million to $830 million for full year 2020. We are keeping SG&A flat as a percentage of sales, consistent with 2019, which we thought was a good outcome given we are funding -- or starting to fund the 3 potential launches.

Still launching Palynziq in Europe, preparing for a robust valrox launch globally and then early market preparations for vosoritide as well. So -- although it is growing year-over-year, a lot going on. And of course, we're not realizing all the sales on those products yet.

So over time, we'll expect SG&A as a percentage of sales to decrease, and our margins will improve. But it's just hard in these launch years..

Commercial?.

Yes. So with that as a backdrop, the commercial preparation for launch-readiness for valrox are well underway. We've been building out the framework of the commercial team starting over the last couple of years in both the United States and Europe, including with some really great work that has been done early on.

And we'll continue through launch from our medical affairs organization inside of Hank's R&D organization. In terms of the build-out of the team, we're in 90-plus percent put together right now for the U.S. launch.

The European launch, we're handling a little bit different because of the sequencing of markets and the necessity to go through formal price and reimbursement processes in Europe, which can take plus or minus a year.

So the layering of the country teams in Europe, we're starting out right now with brand marketing teams and market access teams in Europe as well as MSLs and medical affairs. We have sales managers in place in the major European markets. We'll delve out the actual sales teams a little bit slower as we get closer to reimbursement approvals there.

And you'll understand, Kennen, that as we are operating in a highly competitive environment here. I probably wouldn't want to comment specifically on the size of our teams except to note that in the hemophilia world, based largely on the concentration of care in the United States and Europe in hemophilia treatment centers.

We don't need a huge commercial team and that is not what we've constructed. It is certainly adequately sized to address the market and where patients are treated in both the United States and as we go forward in Europe..

And but -- I mean, it's going to be a dedicated sales force, different from our -- unless someone started and 90%-plus of them have significant experience in the hemophilia market selling products that would be -- that are currently on the market..

Your next question comes from the line of Paul Matteis from Stifel..

This is Nate on for Paul. Maybe just one on the valrox filing.

Is the FDA going to see the entire data set of patients who have received valrox? Or will it just be that interim cohort?.

We talked about a data cut off with them. That's actually the same data call off as the data that you've seen. So it will include safety data on a few more patients that have been dosed at the interim analysis dose cohort.

But for the most part, the applications benefit risk will be based on the 22 patients that are part of the interim analysis with full efficacy data for 26 weeks, the protocol-based interim efficacy analysis with full day out in 26 weeks.

And the 3-year data that was updated from the Phase I/II study, and just a little bit of safety data from a few extra patients that were dosed as part of the full 301 study..

Got it. That's helpful. And then one more. I think I might have missed this in Cory's question, but can you talk about how you might incorporate this 0 to 5-year-old data for the vosoritide filing? I think you had mentioned that the conversation with the regulators might focus on the scope of the application.

So I was just wondering if you can explicitly -- if you're planning on explicitly including those data?.

Yes. Well, obviously, we have the pre-NDA submission meeting of the MAA pre-submission meetings for the rector and the co-rector to get really a little bit more concrete about this.

But our thinking is that -- and in fact, our thinking was heavily informed by the FDA's advisory committee during the open public session, basically, the advisory committee said because of safety considerations in children under 5 years of age, it will be more fast out to get the drug through registration-enabling work in children over 5 years of age before you have data under 5 years of age.

And therefore, FDA, you shouldn't hold up the application waiting for data on children under 5 years of age. But you should also expect sponsors to have some measure of safety data on children under 5 years of age before you take in the application, and that's exactly where we are. We will -- we have an ongoing study, it's enrolling.

We have safety data on a number of children who are under 5 years of age. We won't -- we don't intend to hold up the application waiting for that trial. That will be another probably 2 years before those data are available for an application. And the feedback from the community is get this to us sooner than later.

We don't want to wait for the 0 to 5-year-old data. Safety data is good enough at this point..

Thank you. Ladies and gentlemen, we have now reached our time limit for today. I would now like to turn the conference back over to our Chairman and CEO, J.J. Biename. Please go ahead..

Thank you. So in conclusion, we have developed a clear and achievable strategy that positions powering for the long-term success. We have 2 potential blockbuster products on valrox and vosoritide.

And our continued expansion of our PKU franchise with global positive penetration and PKU gene therapy on the horizon along with gene therapy for HAE, vosoritide for dominantly inherited short stature, above cash reserves, wholly owned manufacturing facilities around the world, global commercial footprint.

We believe that all of this positions well for dramatic and sustainable growth and profitability. And the critical growth drivers for long terms are in place that we believe will deliver significant results for our stakeholders.

So in conclusion, we are pleased with our achievements in 2019, and we are full of anticipation for what lies ahead this year and beyond. So thank you for your continued support, and we look forward to seeing you or talking to you soon..

This concludes today's conference call. Thank you for your participation. You may now disconnect..