BioMarin Pharmaceutical Inc. (BMRN) Earnings Call Transcript & Summary

All right. Hi, everybody. Good afternoon, or good morning, and thanks for joining the next session in our 10th Annual second time virtual JPMorgan Biotech Napa Valley Forum. It's my pleasure now to host a discussion with BioMarin Pharmaceutical. As you can see here, we have J.J. Bienaime, the CEO; Hank Fuchs, President of Worldwide R&D; as well as Brian Mueller, the CFO. So thank you all very much for joining us. We, of course, wish we were doing this in person at the Solage, but this will have to do for now, and look forward to being in person next year. Remind our listeners that you do have the ability to contribute to this discussion by using that little blue button in the portal. And you can send me questions that we'll work in throughout this conversation. Before we get started, though, let me just turn things over to J.J. for a little quick intro, and then we'll move on to the Q&A. So J.J.?

Thank you for having us, Cory, and thank you all for your interest in BioMarin. So next year, we hope to be joining you in Napa for this meeting. A few highlights before we get to your questions. We recently announced strong results in the fourth quarter and full year 2020 and despite the challenges that were brought by the global COVID-19 pandemic. Excluding combined contributions, BioMarin revenues grew 13% in 2020 as compared to the full year 2019 revenues. And the company generated $85 million of positive operating cash flow for the full year 2020, underscoring our resilience in a challenging environment and the significant unmet needs that our medicine address. So in 2021, we have a number of important regulatory events ahead of what we expect will drive substantial value over the coming quarters. With vosoritide for the treatment of -- treatment with achondroplasia, we are targeting a CHMP opinion this June, followed by the European Commission decision in late summer, leading to a potential commercial launch in the fall. And in the U.S., our target PDUFA action date is August 20 of this year, August 2021. But our decision to supplement the review with the 2-year Phase III data may result in a major amendment and push the PDUFA action date 3 months to November. Today, we are happy to report, and that's new information, that the FDA has now scheduled a preapproval inspection for our vosoritide manufacturing facility to occur in the coming weeks, significantly ahead of the August PDUFA dates. So we're actively preparing for launch of vosoritide in the U.S. and in Europe. With ROCTAVIAN gene therapy for the treatment of severe hemophilia A, we recently announced that the FDA granted us Regenerative Medicine Advanced Therapy, or RMAT, designation. This designation will provide FDA more options for how to leverage data post-approval, which could be important for early generation gene therapy products, such as ROCTAVIAN, where learning is still ongoing at the time of initial approval. So we are on track to dialogue with the FDA to explore the potential submission of the BLA based on the available 1-year results that could be supplemented with 2 year results during the review. And we are hopeful that the RMAT designation can facilitate this path forward. In Europe, we are also tracking to plan as we prepare for the resubmission of the MAA in the second quarter of this year. Assuming we remain on anticipated timelines in Europe, this could potentially lead to a [ positive ] CHMP opinion in the first half of next year with potential European launch in the third quarter of next year. As a reminder, we believe there are 3x as many severe hemophilia A patients in Europe as compared to North America. Finally, in our earlier stage pipeline, we have 5 programs moving forward, including BMN 307, the gene therapy product for PKU. And I will say that based on encouraging Phe lowering and safety observed in the Phase I/II study with BMN 307 with a low dose 2e13 vg/kg, we are moving to the next higher dose at 60^13, which is the ROCTAVIAN dose in the Phase III trial. And we will share an update on BMN 307 once we have selected the dose for registration-enabling studies, which is likely in the second half of this year. So to summarize, demand for BioMarin's medicine drove second -- strong results in 2020 and are expected to grow 9% this year, excluding contributions from Kuvan and despite some impact from COVID-19 that has carried over from 2020. We are well positioned for substantial growth in 2021 and beyond and significant growth beginning in 2022 with potential contributions from vosoritide and ROCTAVIAN, assuming approvals of this product. So I will be turning back to you now, Cory, for questions.

Great. Thanks, J.J. So not surprisingly, I want to start with ROCTAVIAN or Valrox. And maybe if you could just go a little bit more into the latest thinking around the regulatory path and time lines for both the U.S. and Europe. It sounded like you mentioned with the U.S. and the FDA, things are on track to kind of make this decision in terms of submitting based on Phase I and supplementing with Phase II. What more has happened, I guess, on this front since your fourth quarter call? Is this kind of -- this commentaries are going back to what we learned in, I guess, it was late February?

Yes. Henry, If you want to take that one?

Yes. I think, J.J., [ some held ] fairly consistent with where that report was 2, 3 weeks ago. You're referring to [ anchor out ] nothing material -- nothing materially significant has happened. We're in procedural phases with Europe, and we're in discussion phases -- early discussion phases with the FDA as regards to the full 1-year data set and with the intention that, as J.J. said, target European submission this June and try to get a jump-start on the FDA submission by filing before the 2-year data are in hand. Just as a reminder, we've said pretty consistently that the FDA wants to see the 2-year data before Valrox is approved in the United States. So it's just really a question of where does that 2-year data cycle hit them in a review cycle.

Okay. And then this idea to file on 1-year data and supplement with 2, is this something that is being triggered more by the FDA itself, and they're saying this is the easiest way for us to approach this? Is it more from the panel, the independent panel you convened, of experts? Or is it more from your just -- your desire and what you think would be best for the program?

I think about it is given the agency options in terms of how they manage their workload and their schedule and the kinds of questions that they might ask of the data. I personally think that the more time they have to review the overall package, the better off everybody will be. With the CRL and the type 2 response, you have 6 months -- they have 6 months under review clock. So it's a little brisker than an original review for them. So I think about it as the earlier start, the more -- the earlier and potentially more likely is that we'll finish. But it's balanced, I think, on their side by workload.

Okay. And I guess in terms of -- when you think about the final deciding factor in doing this, is it being able to collect as much of the additional information that would go into the application relative to what you already submitted to them? So for example, you wait and get the 5-year update for the high dose, 4-year update for the low dose, and use that as a basis and file? Or is it something different that I'm not thinking about?

Well, I think there's that. I think there's -- and then how to package that, in what form do they want to see that? Do they just want to see Factor VIII tables from clean audited data? Do they want to see health-related quality of life, safety adverse events? There's a range there. I think the steroid analyses are going to be -- I think in broad brush strokes, the story we've told is a pretty big picture story, 7 patients treated prophylactically in Phase I/II at the same dose. But then you have 17 patients that were treated with, let's call it, light on-demand and then the remaining patients treated with heavier on-demand steroids, where either prophylactic or low on-demand steroids produced a better result than necessarily the heavy on-demand steroid use. I think they'll want to get into that in quite a bit of detail analytically. This is -- part of it is a question that, how much do they want to look at that and how do they want to look at it, that sort of thing. As I've been told, there's a lot of wood to chop.

Okay. So J.J. mentioned the RMAT designation in the opening comments. How important is this in the context of the regulatory volatility we've seen with this asset to date? When did you apply for it?

There was a whole lot of questions.

They're all good.

We applied for it about 2 months ago. Where does it fit into the overall strategy? We went and WHO initiated it. They encouraged us fairly strongly about it. And I think that, that's the groove that they're thinking about how to think about this question of durability, which is still accumulating at the time of the initial license here. J.J. would mention that it gives them additional regulatory flexibility while -- to approve products while learning is still ongoing. And so the learning that's still ongoing and is like the outcome in the same group of patients as it was originally treated and, therefore, durability without saying durability per se. And I think they think about this a little bit differently than like the traditional breakthrough accelerated path because, there, the confirmatory trial is often not in the exact same population on the exacting dosage regimen, not the exact same end points, variations on those themes aspiring to more information about the clinical relevance of the primary findings that led to an accelerated approval. Here, the clinical findings are unequivocal as regards the ABR. And they're likely to be unequivocal ABR in year 2, and they're likely to be unequivocal in year 3, and that's where your midyear update is relevant. But I think that to enable access on the one side and continued follow-up of the longest duration of patients, RMAT kind of creates this umbrella that says we can have an outstanding question at the time of approval while we're still accumulating data of relevance for the population. So that's how I think -- they think -- that's what I pick up of what they think from -- of the RMAT designation family. I think they've approved one thing, fully approved, one thing is an RMAT. I don't think there've been any accelerated approvals. So there's not a lot of history yet with RMAT. So some of this comes from sort of guidance from more senior strategic regulatory folks, and I don't mean our outside advisers. I mean senior regulatory folks in current health authority position.

Okay. So when you think about the level of discussions you were having during your initial review for Valrox and where you are today post the CRL, now with Phase III data on hand, how have things changed in terms of the productivity of your dialogue with the agency, just the frequency of interactions with them? I mean it sounds encouraging that they're -- that they suggested you apply for the RMAT designation. Just how would you characterize it kind of broad strokes?

Broad strokes, I would say that their doctors, not like a lot of other doctors that we work with, they carry a lot of information around and don't necessarily get it out on paper at some of the most critical times in our life cycles. That's gotten a little bit better since the, call it, the second half of review, roughly approximately and which things kind of went silent. We thought that was all COVID and inspection-related delays, and they had this kind of uncertainty to sound at the late cycle meeting, then they went completely silent. And it's been a little bit more effort on our part to get conversation going with them, but we've had good conversations with them. And I think we've gotten much more unpacked out of their head in terms of what they're really concerned about, and I think that's at the review division level. At senior management level, we have a much more open dialogue, much more regular, much more fast, much more easy dialogue. It's unfortunately much more narrow dialogue in the sense that it's basically me and Peter. But I think we're working together well and have a collaborative partnership and a lot of -- developing a lot of respect and trust for each other. And like I said, there's a lot of wood to chop. You got -- the things -- we, at our level, come to risk-benefit decisions on the basis of a few really key points like Annualized Bleed Rate Factor VIII trajectories synthesizing historical information from other trials or our own trials. And that's just a lot -- the finer in detail you get, the harder it is to be absolutely convergent in the conclusions of all those points. And that's been -- that's the challenge of rare disease drug development, as you know, is that the FDA is a dissembling review process. And when you don't have a ton of patients to dissemble or a ton of duration of follow-up, they start to generate more and more questions about where does this go. The good news about all of that is we do have 134 patients who we can treat with our Phase III material, and they have a dramatic effect on clinical outcomes and really not much in the way of safety concerns, at least in the first half or so of the year. And we're at least in the period that the people had the most concern about that's during that steroid phase. So all the important adverse events that occurred have been resolved. And so on balance, we have tremendous treatment benefit, safety signals that we know how to look for and manage. And we think it's just a matter of time before the scales tip.

Right. Okay. All right. So then on the European front, I mean, you've kind of stuck to this June MAA resubmission for some time. And what are the gating factors there? And have things been progressing on track for a while now?

Yes. It's like procedural discussion, procedural discussion, content discussion, procedural discussion, procedural discussion, content discussion, sort of where I may be halfway through all of that stuff. And all the lights are blinking green for us. A big part with Europe is, again, procedural timetables. These -- it's interesting, I think, in the time of COVID, there's been -- I've been a lot more alert to this as a consideration for sure in Europe, amidst Brexit and relocating into Amsterdam. But also, in general, people -- there's a lot more cell and gene therapy interest overall. Those are much more complicated reviews. So I feel like where we are, it's less about the content. We've done a fairly careful analysis of the prior review. We believe that we have most of the issues that have been raised. We have concrete data for or reasonable good answers to. And so we're in the process.

Okay. But this is like nothing has shifted, right, in terms of timing there. COVID hasn't had an impact in terms of not opening as quickly over there. Everything is on track?

Everything is on track.

Okay. And then -- perfect. And then one of the near-term data sets we expect to get is that, that 5-year update for the go-forward dose as well as the 4-year update for the lower dose, the Phase I/II, can you talk a little bit about the significance of these updates in the context of, one, like how it supports the BLA filing strategy but also kind of the future payer reimbursement negotiations and patient acceptance when they see this sort of magical 5-year mark?

Yes. When we left last year's annual updates, I looked at everybody and said, gosh, I hope this could be the last one. I got reassured, it's going to be the last one. Here we are. So it keeps going. I think the kernel of this is that what you see is that the Phase III material, which would be the material that we intend to commercialize, launched somewhere between the 4 and the 6e dose. And tracking 2 years to their initial launch, the first 17 patients treated with IIb commercialized dose are just a little bit -- they're lower than where the same patients were at the same time that the original patients were at the same time point in the 6e group and higher than the 4e group new original study. So the relevance of what's coming ahead is there's kind of like a little bit of a tunnel there in terms of Factor VIII trajectory. And if we sit inside that tunnel, then I think what the prognosis about our data is that we should expect good durability in the third year after transduction of our IIb commercialized material as we have observed so far through 2 years after. And then I think it starts to feel like, okay, we got 5 years with the 6e dose, 4 years with the 4e dose, 3 years with 301 dose and it's intermediate. So durability is going to be somewhere between those 2. If we have a very low ABR in the 4e group, then I think we're kind of in the bull's eye of the target. And I think the implication of that for payers is they're probably not as fastidious about words on product labels as maybe the FDA is, which is, I think, where the FDA is concerned about projecting durability or for payers, and J.J. can comment on this more, much more clinical outcomes over much longer periods of time. And there, we appear to be very favorable as well.

Yes. I mean, what the payers look at is bleeding episodes and Factor VIII consumption because this is what costs them money. So -- and I would say even before we got the CRL last summer, most of the payers we had talked to, they were already ready to go and planning on covering payments for ROCTAVIAN based on the data we had at that time. So anything when we have this new update is 5 years at 6e, 4 years at 3 -- at 4e, sorry. I mean we believe, based on available information, it's likely to show durability of efficacy here in terms of bleeding control and Factor VIII consumption reduction. So it's going to be even better for the payers.

All right. And when we think about this data and we think about it, I guess, first, in terms of Factor VIII activity and how that conveys the potential for protection, how do we even think about sort of the lower bounds of expression? And what that -- it seems like this is a discussion that's coming up again. Like how low you go before you lose that bleeding protection? And how informative this data could be, especially when you think about the lower dose group?

Well, can start with a clinical anecdote from one of our clinical investigator colleagues who was part of the Factor IX gene therapy, say, 5 years ago. Patient was transduced, had relatively undetectable expression of Factor IX level, severe hemophilia b patients who had been on prophylactic therapy and experiencing some recurring bleeding as well on prophylactic therapy. But after gene transfer and not having any measurable Factor IX, this patient hasn't had a bleed like in 5 years. And so it makes the point that what we know about the relationship between factor level from prior, if you call -- if you will, in the wild studies where you're studying people who have naturally occurring mutations in the Factor VIII gene and bleeding phenotype may not represent as well the phenotypes after gene transfer with [ transductive ] particles. So the nut of that is we don't really know how low you go where there's breakthrough bleeding. Now we've seen treated bleeds for ROCTAVIAN out in the later years in 2 patients, both with very, very low Factor VIII levels and trauma and pre-existing target joints. And we've seen bleeding -- we've seen traumatic bleeding, and we've also seen patients who report that they have a bleed. And then the next day, their doctor asks them about it, and they say it's all resolved. And that clearly, based on their history, wasn't actually a target joint bleed but that scored as a target joint bleed. So we think that the majority of -- we've covered the majority of spontaneous-treated bleeds and down to very, very low factor levels, quantitatively, establishing that as a whole different order of magnitude challenge. And even the FDA has said to us, that establishing where the threshold floor is for a gene therapy product, it's going to take a lot more time longitudinal follow-up, a large -- much larger number of patients. So I think the fact that we can't answer that question, as time goes by more precisely and quantitatively, it's actually to the good for what ROCTAVIAN is all about. Just -- it's funny because I went to a meeting and they were talking about every patient who bled in our trial or something like that, and so I took 30 minutes to go through this. Like I asked the question, "Well, how long did this have taken if we talked about every patient's lead prior to gene transfer?" Like we'd still be here like a year later. So I mean it's just like -- this is what like these high percentage reductions in bleeding fraction are.

Okay. And obviously, so we have this data that we're looking forward to by the middle of the year. Should -- when do you anticipate presenting data from the 1-year look at your Phase III study? Is that something that's coming here in the near term as well? Or will you wait to get to your data for that?

Yes. The thrombosis hemostasis study is relatively smaller on the. So they don't have a plethora of main places we'd make and go. And you know that we've done -- we followed ISTH and WFH over the years, and it's a matter of which one of those scientific conferences and where, without getting too committed to what specifically.

Okay. And a lot of people try to look and compare and contrast the data you have from Phase I/II and the 1-year data for Pivotal 3. Clearly, there are changes -- there are differences between the 2. Like how do you think about those 2 studies and the results in terms of how much they corroborate each other versus conflict with each other?

Well, I think that the bigger picture piece of this is there is greater collaboration, for example, in the end of '17 at year 2 with the 301 study compared to the end of 6 and 7 from the prior study with 4e and 6e13. The trajectory of how you get there is a little bit different. And I think that if -- the best description is that the Phase II material at 6e13 launched the highest, but it also had the highest fall from the end of year 1 to end of year 2. 4e13 launched the lowest of these 3 groups of patients. It also had the lowest amount of fall from year 1 to year 2. And the material from the Phase III trial launched in between and had the most in between magnitude of all of the 3 data sets. In so far as the to be commercialized material is the -- in between one, the one we have the shortest follow-up, we are optimistic that it will follow a trajectory that's somewhere between the 4 and the 6e. And that's what I was calling that kind of a tunnel between those 2. And especially as you get out in the later years, they're more comparable than dissimilar, at least so far, looking at the end of 17, 2-year Phase III group. The things that could explain the difference is we've talked about fairly extensively, and they really boil down to change in the manufacturing process and change in the corticosteroid regimen. We now believe that it's not just a matter of giving more steroids or being more attentive to stuff when it happens because you can give them twice as much steroids on demand and have no meaningful dent in their week 52 Factor VIII expression. So we're down to -- it's either prophylactic steroids or on-demand steroids. It explains that initial higher velocity or something about the material that we've not measured. All the measured stuff doesn't tell us that there's an inconsistency in the process that could explain the difference between Phase II and Phase III. But there's always a possibility of unmeasured. Now the -- wrapping all that up, it's a fairly neat package in the sense that 17 patients have done now 2 years past transduction with ABR that's really quite acceptable, bodes well for the 134 patient update that will happen next year and bodes well for future prognosis of bleeding control in year 2, year 3, year 4 for this whole population that moves through. And that's why I say really, it's more of a matter of time because we're getting farther and farther out from -- further and further up from transduction. We're into that stable sort of either settling or gentle decline down phase.

Okay. I want to work in an investor question, says if a sponsor developed a drug solely for the purpose of a 1-year holiday from prophylactic Factor VIII with the same supporting data as Valrox, wouldn't the FDA approve that drug? Why can't Valrox get an approval label like that and leave further durability as a post-marketing question?

Well, further durability is a post-marketing question. And If ROCTAVIAN -- the premise of the question on the front end was if ROCTAVIAN gets approved with what package now?

Well, they're just a sponsor developing the drug solely for the purpose of a 1-year holiday from prophylactic Factor VIII with the same supply?

We're not going to get approved. Yes, we're not going to get approved for the 1-year holiday. I think it will be interesting to see what approval package would be required from a 2-year study with ABR as a primary end point and what size population. Now Pfizer and Sangamo are behind us. But they're reporting, I think they're playing as a 60-something patient study at a 1-year time point. And so I can't -- I don't see how they could be kind of very near to us with that package. They would have to have way more homogeneity of response than we do. And so far, if anything, they have worse variability than we do. So I think that there's going to be a lot of weight on the scales in terms of the packages you have to bring, even for follow-up approvals.

Okay. One more question on Valrox, for now at least. We'll see if we get more in the portal on this. But do you think the delay here for Valrox or ROCTAVIAN has kind of any sort of material impact on the intermediate to longer-term commercial potential for the product, assuming, of course, it's ultimately approved?

No. I mean based on our marketing research, we absolutely don't believe this is going to happen whatsoever. And as Hank said, we believe, actually now, it looks like the Roche-Spark product is putting further and further behind. It's unclear what is their strategy. I mean one remaining is -- so it's Sangamo-Pfizer. But as Hank said, their most recent update showed a faster decline in Factor VIII levels in the 6 months to 1 year and beyond that we have seen given with our Phase III trial. And all the data they have shown so far, by the way, is not on the commercial scale product. And also, as Hank say, they are even -- as per our analysis so far, based on the data reported, they have worst payability that we have. So it's pretty unclear as to what they're going to be offering. On top of it, based on the factors that are using the AAV vector and then using, are they going to have more patients that will be -- to have preexisting antibodies to their vector than to ours, so all this combined, we don't believe that the delay we've been facing with ROCTAVIAN, the material impact on our future revenues for ROCTAVIAN, and we are still very optimistic also based on marketing research and payer research about the potential of the product. And by the way, also something we probably going to update you guys sometime this year is we have some [ quantitative ] data, which we believe is going to be very exciting, that also should help for launching the product. Actually, as compared to having to launch the product last summer, if we launch it this year or early '22, we're going to have a much more solid package to support the value of ROCTAVIAN.

Okay, is that quality of life data from the pilot study? Or is this from starting to emerge from Phase III?

Phase III.

Okay. Great. All right. Look, let's transition -- we got 15 minutes, transition over to vosoritide and some other questions and bigger-picture questions in the portal as well. I guess, first of all, Hank, key takeaways from your recent ENDO presentation. Anything you'd highlight is incremental to what we already knew about this program in terms of data that continues to come out for it?

Just incremental robustness of different analysis. I mean, I think the numbers were ever so slightly different in our press release most recently from the earlier one, reflecting just sort of different investigator takes on which analytic framework is the most appropriate one. But it just shows you how robust -- because it's in the third decimal that everything is moving around. I think the reception of the presentation was nice. I think that's an important piece of this, which is now -- this information is no longer in just in any press release. It's now in the scientific community being taken up and digested by them. And I think it's amazing. I -- it seems like every update we get on competitive intelligence, there's somebody else that's coming into the field. So it really feels like achondroplasia is a condition that people are starting to recognize as a condition of an importance to treat it. So maybe that, to me, is the most noticeable change, that there's a lot of density now people have interest [ to spend ] in achondroplasia and vosoritide in particular.

Okay. And then with regard to your ongoing regulatory review, when do you expect communication from the agency and with regard to whether or not the PDUFA has extended 3 months for a major amendment?

Well, we're in fairly regular communication with them. It's not a milestone. Well, there are a few milestones in the PDUFA pathway to registration that are mainly between the company and the agency. And there's not any real play in public milestone because they said no AdCom until the PDUFA action date. And so there's nothing that we can hang our hat on for you to say by such and such a date, we'll know they do or they don't. And the plain factors. So what matters is that they can pull the trigger whenever they feel like it. And there's a lot of internal procedural things that govern when and how and why they make major amendments. So all we've done, as we've said, like this -- to you, this is a big enough chunk of information that we're alerting you that they may pull the trigger on this at any time. And when we just reiterate it, we don't reiterate it on the basis of hearing something new. We just reiterated it from attached to the original decision to submit the 2-year data. But I think you've seen everything more or less that there is to see about this data supplement in the form of the most recent ENDO presentation, for sure, or the original press release at the beginning and at the end of last year when we announced it. And that's substantially what they're going to see and it's just whether a question of, again, how much -- how much do they want to dig into it, how much time do they want to take with it and, also, how much time do they need from other stuff that's going on.

Did you submit this data to the EMA as well?

Yes.

Okay. Obviously, different review and the whole process there. Okay. I guess -- so your inspection is coming up, you said in the next several weeks on the U.S. side. I mean what do you see as the biggest risk to approval in the U.S. for vosoritide?

It's just the adequacy of the 2-year data to support -- and the adequacy of the combination of the 1-year pivotal placebo-controlled trial, together with the long-term follow-up in the absence of randomized, placebo-controlled clinical trials, either on functionality or longer-term placebo-controlled trials. They said they wanted a 2-year study. Now we've given them the equivalent of their 2-year study, and so it's just a question of whether they choose to invent further durability questions. Do they want to wait to see the under 5 data in some kind of way? I think now we're starting to get much more remote in terms of possibility of risk. But in the sense I'm paid to think of any possible risk. And I have a rich imagination, but it's not completely rich.

Well, I guess a question I have, Hank, is the -- I can see, and it's very easy to see why investor outlook for this review would be skewed by what happened with Valrox, and they look at the 2 as being related. But when you think about it -- and the way I've tried to think about this and look at a lot of orphan disease reviews we've had in the past. Remember, we had these discussions around Vimizim, when it was going through.

Yes.

It's not always a perfect data package, but the totality of it in the context of the unmet medical need and nothing being approved here, you look at natural history data, you look at your pilot data going up 5 years, the Phase III, now the extension data, I mean, do you -- is there something from this package that you would think is missing other than the fact that it's not the 2-year randomized data going back to that panel?

I mean in an ideal world, I think they would like to see 2 trials and 2 different age groups each with clinically relevant end points of 2 years of duration. And I think they got alerted to the possibility that the registration decision would be made on the basis of the greater than 5-year-olds because of safety considerations of you can't really start randomized trials in under 5s until you have a lot more confidence about the safety in children over 5. And so the headlights shown on the 2 different age population, I think the 2 different trial -- 2 trials from each population, that issue light was shown on fairly carefully. A p-value of 10 to the minus 13 does wonders for that issue. And then the only remaining issue is the duration of randomization, and that's the 2 years versus 1 year. We think we have pretty good arguments about. All the things that you said, Cory, absolutely if you put on one side of the scale -- FDA, this is one of the things they say, just make it easy for us in the review. Just do longer and more, longer and more, just make it easy for us. And we said, okay, we'll give you longer, and we'll give you more. We're just going to give it to you a different way than that way because the feedback we had gotten from our investigators was 2 years of placebo is a long time for a child and a long time for a family to put off waiting for benefit. So we got to the same place, we believe, it's by a different way. All the -- by the different way, I mean, all the things, the strong positive things that you said about the program. And we think that, again, once the sort of the way that this is all put in front of people it will come to ripen.

And also, I mean, recently, we got priority review from the FDA. This is a recent event, which obviously occurred after they made some comments about referring up to 2 years of data. So I think on the regulatory front, this is positive. And then the other thing is that we also have data, clear data that we are submitting to the regulatory authorities, showing that vosoritide does not precipitate early [ closer ] on the growth pace. Consequently, it's very likely that the effect, the positive effect, the benefit of vosoritide for us will be maintained for several years. So that's pretty exciting, too. And I would say compared to Vimizim, we actually have a much larger data set here and longer data set that we had with Vimizim once we get Vimizim approved.

Right. Okay. So taking a step back, there's, clearly not just for BioMarin point of view, but from an industry point of view, a lot of investor concern these days on what they perceive to be happening with the FDA. They've been -- it's not just you that's been surprised. And you're in a unique position relative to most companies and that you have kind of 2 products kind of sort of under review at the same time or having these discussions ongoing by 2 different groups. How concerned are you with what you're seeing at a...

Very.

Very. On what basis? I mean, they...

Well, they're commissioner-less, they're -- like they're a little bit [indiscernible] compared to the Gottlieb days. Dr. Woodcock is under siege as the acting Commissioner because of the opioid crisis. And it's just the pattern, as you just described it. And it's not just us and it's not just one review division. It's a lot of review divisions. And they're all using fancy words like durability, but it's basically come back later because nobody wants to take a risk right now. And so -- and to take a risk is -- you have to be sort of scientific and good. And -- but the FDA is really good at this institutional policy of bureaucracy, and I don't mean that's bad. I just mean that's where their strength is. And then the absence of either strong affirmative leadership or [ depth-full ] scientific caliber, it becomes hard for them to move into that balanced space where the bureaucracy of the monolithic is balanced by good science. And they're a little out of kilter right now. And part of that is resource-driven, and we took up -- we'll talk more about this at some point, but we played a more significant role in PDUFA negotiations in the past. And I was pleased to see a headline, cell and gene therapy, for example, come out winners because I think that's where a lot of the backlog is in terms of scientific caliber. And to some extent, like you said, we've always been dealing with this. But when we were dealing with divisions that were much more fast out with rare diseases, they recognize when you assemble the data in the rare disease population, not going to have the same effect as we assemble the data in a 50,000 patient cardiovascular disease trial. And so they're more facile with it. So I think the combination of all these things, leadership void, together with underresourced, together with an instinctive conservative bend at the lower levels and all contributes to just come back later. And the good news, like I said, is we've got over 100 patients in 2 rare disease clinical trials with definitive clinical outcome -- outcomes that the agency themselves have taken very -- have taken positive actions on drug approvals for us. So it's just -- that's why I keep coming to a belief of just a matter of time. And if it's a matter of time for us, it's a matter of time for everybody. And as J.J. said, the package that we're accumulating for people now is just stronger and stronger and stronger.

Do you believe the appointment of a new Commissioner will go a long way towards giving people -- giving FDA staff as the comfort level to kind of go up more in them than they have then?

It will. But the question is going to be, which side of the step. Will it be the bureaucratic or will it be the enlightened and innovative? It depends on which -- and I think the pro-innovation administration's posture strikes me anyway is, I'm not going to kill the goose that lays the gold Medicare. And if you're in not at, we say the American pharmaceutical industry saved the planet last year in case anybody hadn't noticed.

Right. Right. You think that'd get us something. The last few minute, we'll work in another portal question, a bigger picture one. Why isn't now the right time to do some bigger or more transformational M&A to move into the next chapter, both commercially and with more pipeline?

So yes. I mean it's not clear to us that why we would need to do that right now because transformational, generally, you have to raise -- you going to need to raise a lot of cash that risk your shareholders to go after a transaction that hopefully will generate more revenues down the road, especially if it's a product that's derisked, you're going to have to pay a lot of money. I mean in the past 6 weeks or so, valuations have taken a little bit of a hit, but it is still pretty high, especially for biotech companies that don't have any product revenues. So -- and then we still believe very strongly that we're going to get vosoritide approved over the next 18 months in U.S. and Europe. So why take a big risk on a transformational deal here? We don't believe that's necessary. And then on top of it, we have a growing pipeline coming up after those 2 products that is very exciting, too. And we are going to do an R&D Day in the second half of this year to highlight this pipeline. We haven't set a date yet, but that's coming.

Okay. One quick question on Palynziq before we wrap up here. Just in terms of PKU clinics opening back up, are you seeing any kind of improving trends as vaccinations roll out?

Brian, do you want to...

Yes. Yes, thanks, Cory. I can take that one. So -- yes, so we're optimistic about the -- about Palynziq, PKU clinics opening up here in the next few months with the vaccination success in the U.S. We've not observed significant changes from the conditions at the end of last year, early this year here in Q1 thus far. So as expected, when we gave our guidance, we mentioned that we assume that conditions would not worsen in terms of the COVID impact in our commercial business. We're not experiencing that, but we're still waiting for the turnaround.

Okay. All right. Inside of our last minute here, the question to sum it all up. If you had to pick just one, what's your favorite Napa wine, and you can go taste it in person next year?

I'm doing the Caymus reserve, Caymus reserve.

[ Fresh wine ]. Sorry. Brian?

It's been a while since we've been up there. I like V. Sattui, that family winery, and St. Helena, it's one of my favorites.

And J.J.?

Screaming Eagle, I knew that was coming.

Well, having a good year [indiscernible] in person next year, hopefully, with a couple of products. So thank you very much.

Thank you.

Thanks very much. [indiscernible]

Yes, yes.