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

Okay. Good morning, everyone. From the virtual JPMorgan Healthcare Conference. My name is Cory Kasimov, I'm the senior large-cap biotech analyst, and it's my pleasure to introduce our next company, BioMarin. As you can see on your screens here, we have quite the contingent. So in addition to J.J. Bienaime, the Chairman and CEO; Hank Fuchs, President of Worldwide Research and development; Jeff Ajer, Executive Vice President and Chief Commercial Officer; Greg Guyer, Executive Vice President and Chief Technical Officer; Brian Mueller, EVP and Chief Financial Officer; and Lon Cardon, SVP and Chief Scientific Strategy Officer. So they'll all be here for Q&A in addition to some of the slides towards the end. [Operator Instructions] So with that, J.J., thank you for being here today. Let me hand things off to you.

Thank you, Cory. Good morning or good afternoon, everybody. So please move to the next slide. Just want to remind you that this presentation will contain forward-looking statements and the results may differ materially depending on the progress of BioMarin programs. So please refer to risk factors that are detailed in BioMarin's filings with the Security and Exchange Commission, such as 10-Q, 10-K and 8-K reports. Next slide. So we have built a global fully integrated company over the last 15 years, and these are some of the components that provide the foundation for future growth. First, we have financial stability and robust long-term prospects. We have a durable and scalable commercial portfolio, sustainable, growing pipelines of products under development. And also, we have revenues from new products, ROCTAVIAN and vosoritide that are expected to grow margins and profitability very significantly over the next 5 years. We have a commercial portfolio that's supporting a pipeline of next-generation products. So our legacy products, the ultra-rare disease products are supporting expansion into the pipeline of larger indications. We have new transformative therapies that offer blockbuster potential. We have an integrated established plug-and-play manufacturing and commercial footprint. On the -- also, we also approval our drug development expertise and capabilities to facilitate future approvals. We have an efficient R&D engine, establishing biologics and gene therapy. On average, our products take 5 years from Phase I initiation to approval, and we have worldwide rights to all our products. We had 7 out of 8 programs commercialized since 2005 with an 87% success rate. Next slide. So what is BioMarin's parts in the large -- is the leverage that we enjoy from having all of the components in place to discover, develop, commercialize and manufacture and supply and launch the most complicated therapies in the world. Starting to the left -- top left of the slide, we have a high science, innovative approach to drug discovery, with a rapidly expanding gene therapy platform. 5 of our 6 currently marketed products were developed in-house and 4 are -- with 4 pipeline products that we have now in the clinic or entering the clinic were discovered in-house. On the development side, we have a highly efficient and effective R&D machine with strong regulatory capabilities. Again, 5 years on average from IND filing to approval, 87% success rate of pivotal studies. And we also have on the manufacturing side, best-in-class commercial manufacturing capabilities, wholly owned GMP biologics facilities, first and largest geotherapy manufacturing facility in the world. On the commercial side, we are serving over 75 international markets, and we have end-to-end commercial capability, including patient identification, access, availability, reimbursing sales. Next slide, please. So our city-based business enables important investments in the R&D that will provide future growth of the company. And our commercial footprint is spread across the world to allow us access to key markets for all our products. And we've had steady revenue growth over the past 10 years, actually, fueled by the introduction of new products. And again, in 2020, we're anticipating around $1.9 billion of revenues. Just want to highlight on the right side of the slide that the U.S. -- compared to many other large biopharma companies, the U.S. is less than half of our revenues. And I think sometimes not enough attention is paid to the market opportunities outside the U.S. Next slide, please. Now we're on slide 6. So we have made the transition to larger rare diseases, such as phenylketonuria, or PKU, and now moving into hemophilia A and achondroplasia and all are very different indications and different technology platforms that are larger rare disease indications. And you can see on the slide here that the number of patients in different areas of the world with the different indications are pretty significant here. Next slide, please. Just to highlight that with Palynziq, we are just barely scratched the surface of the marketing opportunity. We have treated slightly over 1,000 patients now, but there are many, many on the right side of the slides. In terms of adult PKU patients, they are over 30,000 patients in the world. So we see that major room from expansion. You see on the left side of the slide, the growth of Palynziq, its introduction in the third quarter of 1918 -- 2018, sorry, so it's growing pretty fast. And it was slowed down on all bits with the pandemic, but I think things should accelerate starting in the second quarter of this year, hopefully, as more and more people get vaccinated for COVID-19. Next slide. So the news of -- actually, it was the news of yesterday, but news of today, too, is related to our Phase III trial for Valrox gene therapy for hemophilia A. So we -- so we've demonstrated that in the largest gene therapy trial ever implemented over 1 year, that the study met all primary and secondary end point and has demonstrated superior efficacy to prior Factor VIII prophylaxis. This is a -- this is actually the largest -- the first time that any randomized trial in gene therapy showed superiority over standard of care. We also have shown significantly reduced mean annualized bidding rate by 84% in 1 year, from 4.8 APRs at baseline to 0.8 in 112 patients with a highly significant P value. We also showed that we are super to Factor VIII replacement therapy with a 99% reduction in mean annualized Factor VIII infusion rates. So very, very significant p-value. And just -- and also highlighted that the Factor VIII expression level with chromogenic assay at 1 year was a mean of 42.89 IU per deciliter. So also interestingly in the subset of patients that were dosed more than 2 years ago, 17 of them, we showed a slower rate of decline in Factor VIII expression compared to prior study and then the mean annualized bidding rates over the first 2 years in those patients was 0.9 as compared to, again, over 4.8 in the baseline. Next slide, please. So just for making it easier to understand the different ends in the reporting of the results. So the study enrolled 132 patients. So these are all the patients that received Valrox. Then they were within the 132, 112 rollover subjects, we completed approximately 6 months of noninternational baseline observational study prior to being treated with Valrox. And then there is also within the 132, a subset of 17 patients in a modified intent-to-treat to receive Valrox at least 2 years prior to the November 2019 data cut. Next slide. So we were thrilled that over 80% of the subjects in our Phase III study were bleed-free after 5 weeks. And again, here, we're not comparing our product to placebo. But this is not a Phase III trial against placebo. We are comparing our results through the standard of care baseline. So again, the -- also the percent of subjects that highlighted on the bottom right of the slide that were free of Factor VIII infusions went from 0% because all of these patients were on at least probably twice a week Factor VIII infusions to 67% of them being free of any infusion at 1-year trial. Next slide, please. So this slide, we have this slide, we have on the left, the Phase II trial, in the middle of the phase -- sorry, the Phase III trial at Phase II trial with patients at a high dose 60 to 30 and on the right the patients have the low dose, 40 to 30. And then within each study, you have on the left column before treatment, and on the right column, after treatment of Valrox. So if we look on the left year, again, in the Phase III trial, the ABR baseline was 4.8. It went down to 0.8, 1 year after treatment. In the Phase II trial, it was in a high dose, it was 16 patients at baseline, went up to 1.3. And then in the low dose Phase 2 at 12.2% and down to 0.9%. And it's same here for the infusion rate with [indiscernible] Factor VIII. So you can see that our results in our Phase III were very consistent with our Phase I/II studies. And just to remind you that the Phase I/II study, the low dose we reported last year, last summer, that had 3-year after treatment, the ABR was around 0.5, if I'm not mistaken. And for the high dose, it was about the same. So the point is that here, we have data that is at least as good, if not better, than the low dose Phase II trial, and consequently, we believe that the durability that was observed in the Phase II trial is probably rehabilitated with this trial, and it's likely be that the efficacy of the Phase III product will last at least 3 to 4 years, and we believe more on that. Next slide, please. So this is a -- the -- on the y-axis, the mean Factor VIII expression level at 1 year, I mean over the first 52 weeks, sorry. And then you can see that there is a peak expression around 6 months, weeks 21 to 24. Then you see that the high expressors are actually for a little while above normal range come down, and you see a flattening of the reduction in the Factor VIII levels. And if you go to the next slide, this is the slide that highlights the results for these 17 patients that were treated more than 2 years before, you see here the Factor VIII levels between treatment and week 104, which is basically 2 years. You see again that the high expresses are coming down and -- but you see a flattening of the reduction of Factor VIII levels over time. So I think we still have a lot to learn about transient factor expression and the relationship between transient factor expression and bleeding control. And I think we still have a lot to learn, and we should be careful about making predictions about future relationships between the 2. Actually, a little anecdote that's interesting is that one hemophilia investigator that has been in our trial and also has been in the hemophilia B gene therapy trial told us that there was a patient who was treated with factor line gene therapy and was deemed a treatment failure because he had almost undetectable Factor IX levels. So -- but however, this patient has not received any Factor IX injections or bled in the past 5 years, while the patient has almost undetectable Factor IX [indiscernible] level. So I think before making conclusions about the future of gene therapies, one has to realize that we still have to learn about the relationship. Next slide. So in terms of safety, ROCTAVIAN is well tolerated. The most common side effects were infusion reactions, ALT elevations and steroid-related side effects, which most resolve and actually all of them resolved during the study. Next slide. So in conclusion here for Valrox, our next step is that we anticipate submitting the MAA in Europe next quarter. And we also are planning on meeting with the FDA as soon as possible to review this data and then determine what would be the next regulatory step. Let's move on to next step, to the next slide, next slide, vosoritide for Achondroplasia So here, this is new information today. So a few weeks ago, we shared the 2-year data from our Phase III study with vosoritide, but the data again on this study is news today, many of you were interested in the efficacy results from those children that were switched from placebo after a year of placebo, and we are pleased to say that their growth trajectory, their AGV, which is the y-axis here, was the same as a treatment arm once they receive vosoritide. As you can see on this slide, it went from an AGV of 3.99 when they were under placebo to 5.68 when they were switched to the drug 1 year after treatment. So this is another piece of evidence for vosoritide's efficacy. Next slide. I think I -- sorry, I look at -- I skip that slide. If we go back to Slide 17, just a reminder that Achondroplasia is the most common form of human dwarfism and that in addition to short stature, serious medical manifestations, including Foramen magnum compression, sleep apnea, bowed legs, permanent sway of the lower back, spinal stenosis and obesity. The market opportunity is, in the BioMarin territories around the world, excluding India, China and Africa, around 22,000 patients under the age of 18 that have Achondroplasia. Next slide, please. That was a slide, the slide 18 that I just covered. So let's move to Slide 19. So I want to remind you again that when we give the update, the 2-year update in December last month, we demonstrated 3.52 centimeters of growth in the treated arm on the Phase III as compared to the untreated children, which is consistent with the growth seen in the year 1, which was 1.6 centimeter. So these patients are diagnosed before birth so assuming that the ongoing under 5 years of age study keeps showing safety. Patients -- mostly patients would likely be treated for about 15 years or so. So us over 2x the 3.5 centimeters that was observed here -- sorry, 7x the people in 2 centimeters was observed. So potentially, the benefits here of treatment would be close to 1 foot for these patients, assuming a linear growth, a linear impact of treatment, which actually is conservative since patients under 5 are growing faster than patients over 5. So what's the next step here. So we file in the U.S. and Europe. We anticipate a CHMP opinion in the second half of this year. And the PDUFA action date in the U.S. is August 20 of this year. So it's a potential global launch in Q4 of this year. Next slide, please. Just want to highlight also that vosoritide is a great example of our strategy to expand indications beyond the original indications with high-quality targeted programs that leverage genetics and biology to maximize the potential of a given therapy. So as you can see on the slide, we have multiple potential genetic growth disorders that we could potentially pursue. A number of which we're currently exploring such as GSS, which is being study in collaboration between BioMarin and Children's General. So I just also want to highlight that we do have a long-acting formulation that's under development and which is covered by recently issued U.S. patents. So we're very excited about that. And the long-term expansion within GSS, genetically short stature indications, is up to 275,000 patients. Next slide. So we're on slide 21, if you're following on your computer here. So in summary, our base business on the left here has enabled BioMarin to build a global, fully integrated company with sales expected in the 1.5 -- $1.8 billion range for 2020. This base enables the development. This is the middle of the slide here of our next-generation pipeline that addresses much larger indications, such as achondroplasia, hemophilia A and PKU. And on the right side of the slide, beyond these larger near-term opportunities, we are tapping into multiple new modalities that will feed our earlier-stage development engine. And I would like to invite Dr. Lon Cardon here, Senior Vice President and Chief Strategy Officer; to give you some more information about the early stage pipelines over the next few minutes. Lon?

Thank you, J.J. Looking to the right-hand side of Slide 21. If you think back historically, BioMarin, as we've grown sort of a larger sustainable business, we've tended not to discuss our early-stage pipeline in much detail. But we wanted to end this presentation with taking just a few minutes to update you on where we are and what has actually been a very busy and productive 2020. Now as J.J. noted, several years ago, we began a pipeline pivot into larger rare indications. And we've really spent the latter half of 2019 and all of 2020 growing the next generation, the new pipeline. So on Slide 22, I'd like to tell you what kind of -- what we're looking for and what kind of indications and properties that we are after as we grow this new pipeline, and in particular, we look for 4 key features in every program. Even though we're getting larger, we remain absolutely committed to utilizing the understanding -- mechanistic understanding of genetics, and we insist on a genetic understanding in everything we're looking for, even though we're going larger. We’re not looking for targets implicated by inference here whatsoever. We're still in the rare disease indications. Secondly, we look at diseases where there remains an important clinical need. We're not looking at me toos. We're looking for -- when we have genetic understanding, we get big, large -- we get very large effect sizes, which sometimes allows us the ambition to even go for normalization. So these are big effect sizes, and that enables us to continue our sweet spot, which is what we're really good at in trials of rare diseases. And finally, where possible, we aim for the proximal biomarkers like we have with Factor VIII or Phenylalanine, which can greatly simplify the trials and the rapid evaluation of efficacy. So that's what we're looking for as we build our pipeline, and you should see those attributes in most everything we bring forward, and I'm going to share some information with you in just a moment about those. On the right-hand side is more of the value proposition, which comes into play on how we're really building things from a portfolio perspective and how we can leverage our investments and our core capabilities. So when we choose assets with those properties on the left, the 4 attributes on the left and the 3 axis on the right, we call that 4 plus 3. When we choose assets, we try to fit them into one of 3 categories. The first one is where possible, let's build a franchise, just like we're doing on PKU and where we really cover the overall space of the disease with whatever modality is required. Secondly, is the disease expansion. Now this is a really exciting area that I think we are leading in at BioMarin, which is completely fueled by genetics. That is a lot of the discoveries of genetics over the past decade really are showing that most of the genes have multiple mutations, and they actually are relevant for broader or other indications than just the primary lesion that brings us to the Mendelian genetics indications. That's exactly what we're doing with CNP, as J.J. just described, is broadening this. And we've got quite a lot of these in our portfolio going forward. And as you can see, naturally, with the exciting Valrox data that we described today, we've got a large investment in gene therapy. So that's Slide 22. Now on Slide 23, which is really the last slide I want to show, but it's got quite a lot of information. Really, where have we landed then in 2020? We've hinted at a few things that have gone on -- that we've had going on over the year. But we've had a lot more than we have revealed to date. And in fact, we've doubled our preclinical pipeline in the past year, partly by BD and partly by -- business development that is and partly by organic growth. And from the business development side, we announced 2 deals that we're really excited about with DINAQOR and Deep Genomics, but we actually did 6. And of those 6 deals, we collectively brought in 10 new preclinical assets just from the external side. These are spread amongst different modalities and different disease areas, including metabolic, cardiac, neurological neuromuscular skeletal dysplasias and some opportunistic ones. But they're much larger indications and they fit those attributes I described a moment ago, the 4 plus 3. So just very quickly, running you through the type of portfolio that we have. You can see we haven't sat still in 2020. In the middle of this wheel or the pie chart, you can see that we have -- we've landed by ambition of mix of about 40% to 50% gene therapy programs. And about the other half, a mix of biologics, oligonucleotide programs and small molecules. Now just very quickly to walk you through a few of these. On the top left, if you can see the very top left, as I mentioned and J.J. mentioned before, we see great potential in vosoritide and expanding vosoritide, again, driven purely by the biology and the genetics here. It's really fascinating, and we're excited about moving this forward in a number of indications. To the right, on the gene therapy side, you may recall, we did the DINAQOR deal for hypertrophic cardiomyopathy. We're really excited about that program and others in that area. And we're also advancing a number of additional programs, some of which are in-licensed and some organic. Going down to the bottom right, we have revamped and retargeted our oligo program for Duchenne's muscular dystrophy, and we have some really exciting preclinical data that we think fills a niche in this very competitive area. We're also particularly excited about the Deep Genomics and other oligonucleotide programs that we've slightly discussed and announced with the Deep Genomics approach, which merges artificial intelligence and all that goes for a really unique and interesting and exciting approach for haploinsufficiency disorders. And we think that will be really powerful. We have multiple programs in that area. And finally, on the bottom left, we don't have a massive set of activities in small molecules, but we do take the opportunities when they arise. And in fact, in 2020, we quietly filed an IND for a very interesting molecule that we think can take that expansion model and leverage our approach from rare diseases into subsets of broader indications, in this case, chronic renal disease. So we are still very active in the small molecule space and take that in those opportunities as they arise. And that -- the BMN 255 was driven by genetics discoveries for both mechanism and for identifying individuals for treatment. We have several other small molecules, looking really exciting for those -- for similar indications. So this is a snapshot of the early-stage pipeline. I realize that there's not a lot of detail here and not really possible in a meeting of this size. We will be having an R&D day in the near future at some point, and we'll be covering these programs in more detail at that time. Thank you for your attention, and back to you, Cory.

All right. Great. Thank you guys very much. I think the rest of the team is going to be coming in now, and we'll get started with the Q&A. And I'll remind everyone while we do this for -- we have about 15 minutes or so here to ask questions. You can submit questions that I can read to management via the ask a question feature in the portal. We have some in there now. I'm going to get started, though, probably for Hank to start. A lot of people are scratching their heads over the market reaction today on the heels of the update last night. And while much of what we've heard from investors has been positive, one cautious thing I have heard is an argument about mean versus median and that the median matters more and it's lower. So Hank, can you speak to this dynamic and your take on that stance that I've heard some taking so far this morning?

Yes. Thanks, Cory. The mean is higher than the median, although that phenomenon is getting narrower as time goes by. And it's -- when that happens, that's driven because high expressors are losing more vector quantitatively than middle or low expressers. Actually, in the grand scheme of things, that phenomenon is probably a good thing because we had like 9 people who were over 150 IU per deciliters, and they came down so that there are no safety concerns from over expression. The fact that the median is as stable as it is means that the bottom half of the population is stable like a rock. And so what you see in the amalgam of the NF 17 population, is -- and it's on Slide 13, is basically a flattening of the median over time. And in fact, in the last 6 months of observation, we only lost one point of factor expression off the median. And the reason I say that's a good thing is because while going from 100% of factor expression to 50% factor expression, maybe there's a clinical sequela associated with that. That's far better than going from 5% factor expression to 2% factor expression or 2% factor expression to 0% factor expression. So stability of the median is, in fact, encouraging. J.J.'s comments about, well, where do you have to be to control bleeding is a -- we're still evolving the data set about that because we frankly don't have a lot of people who have low factor levels and a lot of bleeding. So we don't really have great data on how high you have to be. But the fact is that through 2 years with these levels, you have extremely good hemostatic efficacy, an ABR of about 0.8 through 2 years. And the prognosis is very good because when you look at similar patients with similar factor levels in our earlier studies, for example, the 4E group out to 3 years, exited with a very low ABR in that third year. And so we think we're well above the threshold for the hemostatic efficacy for the vast majority of the patients in the population and that the degradation of factor expression that is occurring in more of an inconsequential way and preservation of factor expression is being more substantially demonstrated in the population.

Okay. And a couple of audience questions. I'll get to one of them right now. While the updated Phase III data shows durability for Octavian that is comparable to the Phase I/II, the variability between patients appears quite wide. How are you thinking about this data potentially affecting physicians' willingness to adopt gene therapy? And do you think the data to date is convincing enough to satisfy the EU regulators with respect to approval?

Lot of questions in there. The range of expected factor expression in the current data set, it's similar to the range of factor expression in the earlier data sets. So I don't think there's any evidence that there's anything that's more variable. And in fact, if anything, it's probably a little less variable now that we've gotten at a higher end. So for example, one of the concerns was, well, how many patients will never even get off the ground. And it was 3 out of the first 16 patients in the interim analysis treatment set, and I think there was some concern, for example, at the Food and Drug Administration that, Jesus, as you go from 16 patients to 120 patients, much larger sample size. That number could get a lot worse. And in fact, it didn't. And our initial, if you will, failure to launch rate is quite low. Lower than it was in the interim analysis population. So I think that's really good. I think another concern of variability was, what's going to be the magnitude of, if you will, crumping and past the 26 weeks because at the interim analysis point, there was not very much data in the application from 26 to 52 weeks. That's a time when transduction is somewhat vulnerable and you want to pay attention to the steroids, and it turns out that the failure rate from 26 to 52 weeks was essentially negligible as well. And then finally, another concern that was present in the data in terms of variability is all of this is going to go away when you take away the steroids, and importantly, fewer than 10% of patients in the Phase III trial in the very large data set are still on steroids from the NF 17 population you see there is a little bit of decrement from week 48 -- from about week 52 to about week 64, which was similar to what was seen in the earlier trial though of a much smaller magnitude. And I think that's a key point of emphasis, much smaller magnitude of vector loss after the withdrawal of steroids. And then from about week 64 on, you see it looks flat. And I think that bodes -- that answers the -- that addresses the third question of consideration. And is there an element of variability that's due to steroids such that when you take the steroids away, you're going to see vector loss. And so I think we're greatly reassured that we didn't see that. For all of those reasons, we feel that the issues of the complete response letter were addressed. We want to -- we also want to remind, at the same time that the agency in the U.S. says -- wants a higher sample size at 2 years. And so we'll get into some discussion with them about these data. And -- but on the other hand, the European Medicines Agency was a little bit more interested in the 1-year data version, and that's why we're remaining confident about near-term EMA submission and have a little bit more of a conservative wait-and-see approach from the FDA, not so much different from the FDA about how our data are looking but more driven from their concern to have a robust sample size at 2 years.

Okay. Can you talk about what you think is driving the slower rate of decline in Factor VIII expression in the Phase III top line results within the non-rollover subgroup compared to the Phase I/II results over 2 years?

Say again? The very front end of that compare the non...

The slower rate of decline in Factor VIII expression.

Compared to the -- well, compared to the prior trial?

Yes.

Yes. Well, we did -- we used prophylactic steroids in the prior trial. And I don't know if there's a cause and effect to that result. But the fact is that the phase -- the expression level at week 52 in the prior trial was a bit higher. It was like 63% at week 52, then we achieved in this population that week 52. And so I think when vector -- what we've learned is, is that the higher vector expression is, the more it's going to fall shortly after it reaches that peak. And I think what goes on in the cell is, is that you can put a lot of vector into a cell, and you can even get sort of transient stabilization of that expression but there -- the cell has a sort of a finite capacity for durable expression. And so what you're seeing in the early period is if you put a lot of vector in, you stabilize it really well, with corticosteroids, you can get 52 weeks' worth of good vector expression. But it's a fragile level of expression in the sense that when you take the steroids away, it comes down a little bit. It came down a lot in the prior Phase I/II trial, which is what concerned the FDA, it didn't come down nearly quite as much in the Phase III trial. It didn't go as high in the first instance, and it didn't fall as much in the second instance.

Does that give you more confidence in terms of the potential for durability here, even though the Phase I/II is showing good durability after 4 years?

Yes. I think these fluxes in the Phase I trial, it went from, I think it was like 63% to 26%, something like that from year 1 to year 2. That's a lot of flux. And I think that probably represents something like a fair amount of cell turnover. And I think the smaller decrement in gene expression in the more recent trial probably represents a better sort of approach a result for the liver in terms of holding on to vector for a longer period of time. And again, I just -- I think it's -- we give you the table to look at. So you can look at numbers at discrete time points, but we also show the visual of the factor expression in the NF 17 population. I think it's -- there's a little bit of bouncing around. There's a little day-to-day variability between patients. But I think it's really important to look at the chart on Slide 13, especially in the outer time points. It really does convey a more confident and flat picture.

Okay. And we only have a few minutes left. So I want to make sure I get in at least a couple of vosoritide questions, too. It seems kind of unusual for the FDA to call out the discrepancy between what you submitted and what they'd ideally like to see in your initial package. Now that you have this 2-year extension data as well as the new information we got today on what the crossover patients did. How comfortable are you as you head into these regulatory reviews over the course of 2021?

Very comfortable. I mean, the -- first of all, the European regulators weren't nearly as preoccupied with the issue of the 2-year, they were much more comfortable and facile with the natural history control information that we were providing. And the issue of the FDA is inserting that 2-year statement into their filing letter. It was very different than what happened to us with Valrox. With Valrox, they didn't even bring up the subject until the complete response letter was issued literally. Here, we've been talking to them about this for a little while. And it's not uncommon for the agency to set an enormously high bar and just keep repeating that bar through -- all the way through to the end of the application, we had this exact same issue with Vimizim years ago. They kept on repeating. They wanted a responder analysis as the primary endpoint. And then they realize that the evidence was sufficient on its own. I think the 2-year data that we've seen give us an extremely high amount of confidence. And I think the other thing that gives us a lot of confidence about the agency's willingness is that when -- is that they really put us through the pressure cooker at the pre-NDA meeting about our natural history control data. And I think we did really well there. And you could have said maybe it's going to -- it would have been a Hail Mary expectation to get them to sort of quiet down about the 2-year data until they're in review. I can say that we're in review, and we don't usually typically give details about how the review is going. But they haven't turned over any cards that were unprepared for haven't seen already. And so we're pretty confident about the progress of the review and that the issue that the agency addressed is going to -- the issue the agency raise is going to be extremely well addressed in the application.

Okay. And when do we expect to get updates from your younger patient cohorts that you're evaluating with vosoritide?

Yes. So last patient in the very youngest group is imminent in the next couple of weeks. And so it's a 1-yearlong study. So a year from now, they'll have the last patient out roughly. And so look forward to seeing the unblinding of those 3 cohorts. Just to remind you, we enrolled the trial in successive cohorts by age. And so we were -- we chucked the under 5 into 3 different groups, 2 to 5, et cetera. And the point of that is that we want to put -- look, we're presently planning to look at the amalgam of all 3 of those cohorts to look at the change of -- on growth velocity. Again, a reminder, that is a second placebo-controlled trial.

And you're not -- you're going to wait for all the cohorts of those data, right? You're not going to do it on a cohort-by-cohort base?

Yes, that was the original plan and until and unless there's another reason, that was the original scientific plan.

Okay. Well, I wish we could go on. I have a lot more questions for you, but unfortunately, we're out of time. So we're going to have to stop it there. And thank you guys very much for taking the time to talk with us today. Appreciate it.

Sure thing, Cory.

Thank you for having us.

Thanks.