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

Hi. My name is Kennen MacKay. I'm one of the biotechnology analysts here at RBC, and it's my great pleasure to kick off our last session of the morning with BioMarin Pharmaceuticals. From BioMarin, we have Brian Mueller, Executive Vice President and Chief Financial Officer; as well as Hank Fuchs, President of Worldwide Research & Development. With that, I turn it over to you.

You're keeping me on my toes this morning with a little bit of news out of the -- a lot of bit of news out of the Valrox program. Maybe you can talk a little bit about that and just give sort of a brief background of where we are.

Sure thing. Good morning. Thank you, Kennen, for the introduction, and good morning, good afternoon, everybody. It's a pleasure for me to kick off today because today is about new ROCTAVIAN news. And of course, nothing makes me happier than talking about good clinical data. And today, we do have some good clinical data to report. In fact, we're pleased to share -- to have shared some of the 5-year update from our Phase II study with ROCTAVIAN early this morning. The consistent and durable treatment benefit demonstrated through year 5 in the 6e13 new vector genomes per kilo cohort and through year 4 in the 4e13 vector genome per kilo cohort. Treatment with ROCTAVIAN is a major step forward for the field and for people with hemophilia A interested in a treatment option with gene therapy. All participants in both cohorts remained off Factor VIII prophylactic therapy and have been off corticosteroids since year 1 to now an additional 3 and 4 years after steroid withdrawal -- cessation. The mean annualized bleeding rate through year 5 in the 6e13 cohort with -- treated with ROCTAVIAN was 0.7, an ABR reduction of 95% prior -- compared to prior to gene therapy -- prior to gene therapy and while patients were on best available standard of care prophylactic therapy. The reduction in Factor VIII usage through year 5 in the 6e13 vector genome cohort was 96% compared to pre-infusion levels. And again, all subjects were on prophylactic Factor VIII treatment prior to being transferred. The mean annualized bleeding rate in the year 4 cohort -- in year 4 in the 4e13 cohort was 1.7, with a mean cumulative ABR reduction through those 4 years of 92% and a Factor VIII usage reduction of 95% through 4 years compared to pre-infusion levels on standard of care Factor VIII prophylaxis. Of relevance, Factor VIII activity levels declined commensurate with the most recent year's observations and continue to remain in a range to provide hemostatic efficacy. Needless to say, we are encouraged by the durability of effect observed in the Phase II study at years 5 and 4, respectively. And when we talk about effect, again, let me remind you that we're comparing patients who had been on prophylactic factor replacement therapy and still experiencing breakthrough bleeds, given gene therapy and then have their prophylactic therapy withdrawn. So the fact that they're doing as well or better than they were before is really encouraging from a clinical perspective. We look forward to sharing more data during an oral presentation at the upcoming International Society of Thrombosis and Haemostasis Virtual Congress, July 17 to 21. Importantly, regulatory plans are on track with the Market Authorization Application submission planned for the end of June in -- for Europe and the BLA submission to the FDA in the second quarter of 2022. Briefly on VOXZOGO for the treatment of children with achondroplasia, our largest opportunity to date with roughly 20,000 children eligible for treatment. With potential European approval in the third quarter, assuming a positive CHMP decision next month, followed by the November 20 PDUFA action date in the U.S., the commercial team is eager for the potential launch of VOXZOGO and bringing the new therapy for patients with achondroplasia. We also have a lot going on in the early and research organization, and we hope to share with you a lot of new data at our R&D later this year. So with that, Kennen, I'll kick it off to you.

Perfect. No, thank you very much. Maybe just sort of first on ROCTAVIAN. Obviously, still thinking about that 1-year data with the EMA and that earlier submission there. That was sort of the plan. But I guess, has the FDA's request for 2-year data evolved into any other conversations with the EMA around requirements for longer durability there or additional data there?

No. The EMA is certainly aware of the FDA's actions clear back until this year. And we had a pretty clear dialogue with them in presubmission meetings that are part of the routine practice. And they are aware, clearly, the -- in the first cycle of submission, we were still enrolling patients. Now at this point, we have the whole cohort identified, treated, et cetera, and they're in follow-up. So the EMA has clear-eyed vision of both the -- this 5-year update that we're talking about today and also the availability of the 2-year update. And they were very clear that they didn't require those data for the initiation of submission and review. Now of course, during review, questions will arise, and we'll provide additional data as per request, but they were -- the EMA was fairly clear-eyed about where the FDA stood, and we're willing to accept a submission of -- that was based on the 1-year data.

Got it. Okay. And maybe I'm just speaking to the data today. Obviously, Factor VIII -- exact Factor VIII levels at 5 years or mean median left out. You have to say something for the conference coming up here, completely understand that. But just to be totally clear, no additional treatments -- excuse me, no additional patients had needed rescue therapy in year 5 here versus prior. Is that sort of the right way to think about this and no patients then ever needed to drop off, go -- I shouldn't say drop off, but needed to go back on prophylactic factor treatment?

Right. So there is some residual additional need for factor replacement therapy in patients.

For emergency [indiscernible]. Yes.

But that level is now 90-something percent reduced compared to prior to treatment. But I think the important point is the second point that you made, which is that all patients remain off of prophylactic therapy. In other words, the transgene is still delivering enough power that they're able to maintain these low bleeding rates that keeps them off of that chronic 2 to 3x per week -- really, more than 2 to 3x per week recurrent infusions with the peaks and the troughs and the unpredictability during the day and having to plan around the infusions. So this is what's so attractive about gene therapy to patients. Obviously, the longer, the better. And today, we celebrate arriving at the 5-year milestone. But really, the benefit of treatment is really quite substantial in enabling patients to live a much more normal life off of infusional therapy.

Got it. Okay. And maybe just thinking about the 5-year data when we do get that presentation at ISTH. Thinking about sort of durability or where the focus has been for physicians, what do you think is sort of the most critical end point there? What should we be paying the most attention to in that 5-year data?

Well, I think the another thing that's most overt and tangible to people is their bleeding frequency, and secondarily, how much activity they can undertake now that they have that more continuous protection compared to the peaks and the troughs and then how to plan their lives around that. So I think that element of benefit is a really key driver of consideration for people. Now clearly, people would like to know -- I mean everybody, obviously, would like this to last forever. And in recognition of the declining Factor VIII values that we talked about, I think this becomes -- it starts to help clarify the importance, the criticality, really, of things like understanding what controls expression long term; are there specific patients who have better or worse outcomes long term; are there ways to awaken the transgene, if it's dormant in there; are there ways to improve the vector to provide a more durable effect. So hopes still remain for a one and done. But today, it looks like Factor VIII expression is declining. What patients should be thinking about is now with available evidence suggests many years. And of course, we'll have to go through all the language of this with the regulators in terms of how this ends up getting conveyed to patients. But I think the therapeutic concept really is to be as prophylaxis-free and as bleed-free as possible for as long as you can. And these data are encouraging now out to clinical benefit. Mainly, our main focus is clinical benefit and well-being out to 5 and 4 years, respectively.

Got it. Maybe then switching gears to ROCTAVIAN -- or I'm sorry, switching gears from ROCTAVIAN to vosoritide. I'd love to just run through a little bit sort of the conversations that you've been having with the patient community, physicians, and then also just to understand that the regulatory process is there a little bit better after you'd updated the EMA and FDA with some of that longer durability data. But going back to the beginning of that, what is sort of the focus of the patient community and the physician community these days in the updated vosoritide data?

Yes. I think the focus is eagerness in awaiting the availability of the product. Unfortunately, there's no medical therapy available for patients with -- for children with achondroplasia. And there's -- obviously, every day that goes by, there's an accumulation of deficit and a promulgation of risk for later in life poor outcomes. So there's a fair amount of eagerness in the community for availability of the product. The -- I think the updates that we've provided recently at medical congress has continued to reassure the community about the treatment benefit. I think the crossover of the former placebo patients onto drug was, on the one hand, expected. On the other hand, it's always gratifying to see that treatment benefit and another 60-something patients joining the ongoing clinical experience. I think people are increasingly gratified by the evidence of durability, both the 2-year data from the original pivotal trial, but also now out many years past the initiation of treatment for some patients, I think, 6 years in some cases. And so just fortifying and more solid basis of clinical evidence support. And I think also, there have been a lot of publications recently to characterize better the condition of achondroplasia in medical terms in terms of surgical frequency. I think I saw statistically something like every -- I think it's like 100-patient days on average per 100 patients. Every patient has like one hospitalization per year between -- from 0 to 4. It's astonishing actually how robust these kids are in terms of what they have to deal with. And so I think that's also represented, that then is what triggers the hope for VOXZOGO sooner and the hope that, that impact that we've seen so far in clinical trials will translate into the whole community who chooses to take VOXZOGO. So a lot of excitement in the community.

If I can add maybe a couple other things on the community, especially when you look back and compare or contrast VOXZOGO with our prior product launches, is the overall size of the patient population and the early diagnosis that comes with achondroplasia. So as Hank mentioned, roughly 20,000 eligible patients in the world. We believe there's approximately 11,000 patients in Europe. That's roughly 3x the U.S. patient population. So to have the European regulatory decision lined up first is great to have that being the much larger market. And then, again, comparing it to the lysosomal storage disease therapy launches, where most of our commercial and launch efforts were identifying patients and helping physicians diagnose MPS. Achondroplasia is often diagnosed very early, if not in utero. So that, we feel, is a good tailwind for the launch.

Got it. Absolutely. And thinking about the Phase II data, one of the conversations that we've had, and it seems really interesting about that data was the potential for treatment of these patients throughout the entirety of their growth curve, for these patients actually reach sort of the lower limit of normal height. And I guess, just thinking about the data that we've seen so far from the Phase III study in terms of sort of being able to extract like that data and sort of make that claim. Is that something that's still sort of standing up? Or where are we on that?

And Kennen, if you could just maybe clarify your question a little bit more about -- you're asking about how the Phase III data read on long-term durability?

Yes. Yes. Just versus the Phase II, it looked sort of relatively interchangeable, but I just wanted to get your perspective on sort of where we are for the potential for, again, vosoritide to maybe help some of these patients reach the lower limit of normal height, again, if they get sort of throughout the entire growth curve.

Yes. Yes. I think -- so if you start at 10 and your growth plates are aged 10, and your growth plates maintain open for another, say, 6 years, you're going to get 9 or 10 centimeters of treatment benefit, 4 inches or so. And that's going to be important for some people. But I think that where you're kind of pointing to is that the -- you've already lost a lot of stature by age 10. And so we have studies, for example, initially -- initiating therapy in children who are under 5. So far, the safety of that looks good. We know a little bit about PK and pharmacodynamic effects. And so we have an ongoing blinded trial. Look, the general wisdom in the genetic conditions is that since you're born with it, the earlier you initiate, the correct the therapy, the better off you are. And so I think it's hard to extrapolate numerically from the results of the pivotal trial, which the average age of the patient population was 8 years, to what happens if everybody starts at age 5 or 4 or 3 or 2 or 1. That will take a little while to accumulate. But clearly, the earlier you start, the less worse you off -- you are at the beginning, and therefore, the greater potentially you have the preservation of benefit.

Yes. Got it. And then maybe just sort of moving to the regulatory process that -- the processes that are going on with vosoritide, obviously had added that updated durability -- have provided that updated durability to the FDA, which should constitute at the major amendment pushing out of the PDUFA. But it didn't seem like that had occurred in Europe. We're still thinking about the same time line. I would just love to understand sort of where that submission package is with the CHMP.

The -- we had talked about that with the EMA, the rapporteur and co-rapporteur during the process. These things are known and they're well aware of the timing of availability of the data. And they have these milestone points where they initiate an initial assessment report. And then there's this sort of we respond and we do another assessment report. So we had timed it so that the data were available at one of those assessment reports. That was -- there was never a major issue for them in the second year's worth of data. And so they folded that data into their review, and that's been several months now. And our issuances continue to be on track. Continue to be on track, I think, reflect that they received the data and that more things remain on track.

Got it. And the -- yes, just adding on for the CHMP. It seems like those initial questions, one of those clock stops was sort of in December. I've seen that in the minutes. And then obviously, there's sort of a 3-month stop there where you can respond to questions and provide more data into sort of day 180. And so has that -- has day 180 sort of come and gone and we're currently in that clock stop? Or sort of are we beyond that now?

We're tracking to -- when we say we're tracking to an opinion, I think that's like the official day of that is 210 in the cycles. I think that's right. You got the [ length ] of this, Kennen. And so you can imagine that, let's see, what are we like, 45 days away from that, something like that, maybe even less, something like that. My math is thinking right now. But we're in the tail end of the submission process at this point. We're past the -- we'd be in the majors price territory if the track changed materially.

Okay. Got it. No, I -- yes, we'll keep watching there. And I guess, as it relates to sort of the regulatory focuses, both with the FDA as well as the EMA, as it relates to the submission package, where really has been the focus of the agencies?

The FDA and the EMA have been slightly different with each other. I think the EMA's focus has been on this genetic issue that we just talked about, which is when's the right time to start and what data do you have available to support starting earlier. And they want to do the right thing scientifically and medically. And I think that all I can say about that is that they're thinking real hard about the question that you asked themselves. And I think that's where they've been spending most of their time. The FDA is, I think, a little bit concerned about that question -- not concerned, but thinking about what's the right answer as far as that goes. And I think they're also thinking on the other end of the spectrum, which is what's the evidence around durability. And so you can imagine that the vosoritide is going to be most powerful when you're growing fastest in the early years, but you don't really know that yet. And so I think you're all just trying to figure out like when's the -- what's the relationship between age and outcome. Now of course, that will take a lot of years to really formally establish. And I think for the most part people are left with, if you're born with the condition, the earlier, the better. So I think logic tells you to try to support where you can. This is what the FDA's Advisory Committee told them in the 2018 Advisory Committee. They said, you should -- this is literally what they -- you should anticipate that at the moment of your first consideration of the availability of this intervention, you're going to have a lot of data on children older than 5, and you're going to have a lot of science and medicine that says to you, you should probably start earlier if it's safe. And here we are 3 years later in exactly that position. And so I think in general, I think that's the main wrestling match that people are having.

Got it. And the Phase III trial had enrolled patients aged 5 through 18. So is that kind of what we should be thinking about as a potential label population? Or could it be just because this is a new therapy, could it be even sort of more restrictive? Usually, if you've got patients that young, sort of below 10, it almost requires a different trial. Obviously, this was a pediatric trial, so it is a little different. But...

Well, that -- yes. I mean the -- this goes back a ways now. The development -- this is why the AdCom gave the response that they did. The -- in general, in children, children can be deemed reliable reporters as of age 5 and beyond, and they're unreliable as reporters. So they're -- one of the key pediatric ethical considerations is to have sufficient safety data in children who can report adverse events before you start treating children who report. So you're going to be stuck in a situation where you're going to have more data on the children who can report their symptoms than on the group that you'd ideally like to be, who don't know what's going on quite yet. And so that's where we are. That's why we have 2 years' worth of data on the pivotal population. And we're coming up on the 1-year mark early next year for the under 5 population. So what we have are a lot of safety data, obviously. It's still -- it's blinded trial. But we have some additional information on sentinels that helps inform the discussion. But these are all -- we're in the middle of a lot of these discussions, and it's premature to report out on which way the wind is going to blow. But in general, I think the general theme is we want to get ourselves satisfied that it's going to last. And if it does decline in effect over time, when -- what's the data that supports the earliest that you can start seeing get the most benefit.

Got it. And maybe then one -- Brian, I don't want to let you go without putting the focus on you, but maybe for both of you, just thinking of this launch, Hank, you've mentioned theoretically this wanting to get patients on as early as possible, get being treated for as long as possible. Just thinking about this, should we be thinking more about sort of an incident launch and if it will be maybe a few years of sort of the younger end of this spectrum of patients or really more of that prevalent population, kind of a pediatric population between 5 and 18?

You start. You go.

Yes. No. I'll let Hank comment on it. This touches on your label question. But again, if we're -- when you look at the prevalence out there, this being a much larger market for a BioMarin product launch than we've experienced in the past, and again, Europe with being roughly 3x larger than the U.S. And to your earlier question about the anticipation and excitement in both the patient and medical health care professional community, we feel like the dynamics are there for a robust launch. And one way to think about it is the different jurisdictions. So in the U.S., we tend to see -- because of the pricing and reimbursement dynamics, we tend to see a faster and earlier revenue curve and ramp. And in Europe, although we get sort of this regional approval from the -- or Marketing Authorization from the EMEA, the pricing and reimbursement negotiations happen at the market-by-market level. So you tend to see a slower and lower launch curve, but because of the patient population and the size of that market, it tends to be the engine of growth. And we've seen this with the enzyme replacement therapies. We're still adding patients for Vimizim and Naglazyme, which has been on the market for almost 16 years. So with this size of patient population, I think the prevalence is one thing to be excited about, but these are therapies potentially over 18 years until the growth plates close. So we'll see incidence growth over time as well. Hank, you want to...

I think you said that better than I said or could have said that. I mean, like from the medical point of view, I think there's a reason to believe that it's more likely that you're going to start on the therapy if you're 5 years old than if you're on -- if you're 17 years old. But on the other hand, what Brian is saying is also true, that at a macro level, the prevalent market is still very large. And the lumpiness of the trajectory of the launch is going to be driven more by regional considerations like reimbursement or whatnot. But two different ways, I think, coming to the same place.

Got it. Okay. And maybe then just circling back on vosoritide and sort of the process with the CHMP. Hank, I'm sorry for digging into this so much. The agenda for this current meeting that's going on now actually had just been posted. And I had hoped to see the day 180 question or response there. I didn't see it. But is it still possible that, that decision could then come in the June meeting? Or could that sort of be then a June-July dynamic? Or day 180 or around day 2 time?

Yes. And I apologize, Kennen, I'm not up to today's or even yesterday's vosoritide, CHMP agenda postings, although it's funny because this does come up from time to time exactly like this and our rate -- we have a great EU regulatory team, and they are on top of this because they know these questions come my way, right? And as procedurally oriented as the EMA is, occasionally, they'll have these things where they're late or the agenda doesn't reflect accurately. So I can't speak to today's or yesterday's agendas postings. What I can tell you is all the lines you're pointing to in action by June 25. And the recent -- we have a lot of sort of inside communication with them. And like I said, we're guiding towards June.

Perfect. No, that sounds good for me. I know we're certainly holding our breath. I know the patient community is as well. And I'm very excited to see this come across the finish line here. I know it's been a long time.

Yes. Yes. Yes.

Well, with that, I want to thank...

[indiscernible] sorry?

No, I was going to say we're bumping up against the end of our time here. So I just wanted to thank you for the excitement with the Valrox news this morning, and thank you both for joining today. It's been a real treat. And as I mentioned, incredibly excited about vosoritide.

Well, thank you, Kennen.

Thanks, Kennen, for having us. Thanks.

Thanks, everybody.

Thank you, Brian. Thank you, Hank. Take care.

Yes.

Good night.