BioMarin Pharmaceutical Inc.

Good day and thank you for standing by. Welcome to the Biomarin First Quarter 2022 Financial Assault Conference Call. Hosting the conference call today from Biomarin is Tracy McCarty, Group Vice President of Investor Relations. Please go ahead, Tracy.

Thank you, Ashley. Thank you, everyone, for joining us today. To remind you, this non-confidential presentation contains forward-looking statements about the business prospects of Biomarin Pharmaceutical, Inc., including expectations regarding Biomarin's financial performance, commercial products, and potential future products in different areas of therapeutic research and development. Results may differ materially depending on the progress of Biomarin's product programs, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical market, and developments by competitors. And those factors detailed in Biomarin's filing with the Securities and Exchange Commission, such as 10Q, 10K, and 8K reports. On the call today from Biomart Management are JJ Bien-Aimé, Chairman and Chief Executive Officer, Jeff Ager, Executive Vice President, Chief Commercial Officer, Hank Fuchs, President, Worldwide Research and Development, Greg Geyer, Executive Vice President, Chief Technical Officer, and Brian Mueller, Executive Vice President and Chief Financial Officer. I will now turn the call over to our Chairman and CEO, JJ Bien-Aimé.

Thank you, Tracy. Good afternoon, everyone. Thank you for joining us today. So we begin 2022, of course, for significant growth and the transition to sustainable gap profitability. Interest in Voxogo from families seeking a treatment option that addresses the underlying cause of echocardiopatia has been very positive, as underscored by today's increase in 40-year 2022 Voxogo guidance to between $100 million and $125 million. We also will affirm previously released financial guidance for all other metrics included in our full year 2022 guidance. So we generated 519 million record revenues in the first quarter, representing 11% growth year over year, excluding CUBAN. This marks the start of Biomarine's return to significant double-digit growth. Actually, the revenues for products marketed by Biomarine were up 15% including Kuvax. So really after a strong start to double-digit revenue growth, hopefully over the next few years. So these results highlight the strength of our base business and the significant opportunity that lies ahead with Voxergo. It is important to note that $13 million of the $20 million total for the first quarter for Voxergo sales We are from outside the United States, emphasizing the breadth of our global footprint and commercial capabilities and the importance of the ex-U.S. markets. This will be advantageous as we prepare for the potential European launch of our Procter & Gamble in the second half of this year, ahead of a potential U.S. approval. With the financial outlook and robust global launch of VoxOvo tracking to plan, We look forward to the next important regulatory steps with roctilia and gene therapy over the coming months. For people with severe hemophilia, seeking hemophilia A, seeking B control, that is superior to test therapy or prophylaxis, we think roctilia presents an excellent treatment option based on the results that we observe in our phase 2 and phase 3 studies. We believe this data provides supportive evidence of efficacy as part of the marketing authorization application currently under review in Europe and planned for inclusion in our PLA plan for resubmission in late June. We were also pleased to share the news today that we have completed the genomic analysis of the salivary gland mass from the participants in our Phase II rock david study, which was treated over five years ago. The findings from the completed analysis did not identify evidence that vector integration contributed to the salivary gland mass. This is great news for patients and the safety profile of Octavians and actually for the entire AVG and therapy field. And we'll say a few more words on this in a moment. As we look forward to the remainder of 2022, we are on our way to achieving the goals set forth at the start of the year. turning the corner to sustainable gap profitability, ramping up our largest pediatric opportunity to date with VoxOvo, and progressing routinely in applications with health authorities in Europe and the United States, and also advancing the broadest earnings change pathway in our history. We will continue to build on this financial, commercial, and regulatory momentum in 2022 and beyond as we make the transition to an earnings growth story. So thank you for your continued support, and I will now turn the call over to Jeff to discuss the commercial business update. Jeff.

Thank you, JJ. I'm very pleased with our performance in the first quarter of 2022, recording $519 million in total revenues. The $20 million BOTSOGO contributions in the first quarter drove increased BOTSOGO 2022 full-year guidance to between $100 million and $125 million. and will be an important component of our 2022 growth story. Now, turning to specifics of the VoxOgo launch, we are pleased to share that as of March 31 this year, an estimated 284 children were being treated with commercial VoxOgo. This includes 201 children in countries outside of the United States and 83 children within the United States. An estimated additional 53 children were in process in the United States as of April 15. At the end of the first quarter, bus sales were spread across 15 active markets, including sales in new markets not previously reported in Saudi Arabia, Slovenia, Czech Republic, United Arab Emirates, and Italy. We continue to be very pleased with uptake in the EMEA region which has been driven by a combination of growth in Germany and collectively from individually smaller markets. Upcoming and outside of the EU, we expect potential approvals in Japan and Australia later in the year. The opportunity in Japan is expected to be significant, and we expect revenue contributions to begin there later this year. Turning to launch dynamics in the United States, We have seen prescription demand pick up quickly. We have been able to rapidly convert patient referrals to patient starts. In the quarter, we experienced prescriptions from geneticists and pediatric endocrinologists as expected. We also see more payer coverage policies published, which are largely consistent with our label or our clinical trials criteria and are aligned to our expectations. In summary, we're very pleased with the pace of uptake during this ramp year for Voxogo. Launching in the EMEA regions ahead of the United States was a first for BioMoran and underscored the ability of our experienced commercial teams to tap into large market opportunities regardless of location. This is of particular importance as we look toward a potential Roctavian launch in the coming months should the CHMP opinion and European decision be supportive. Turning now to our enzyme replacement therapy brands, Vimazine and Maglazyme both achieved record quarterly results in Q1 of 2022. Consistent with our experience last year for both brands, we fulfilled large orders during the first quarter from such markets as Turkey, Brazil, Egypt, Russia, and Saudi Arabia. This demand is gratifying and good for our business and we expect will cause the first half of 2022 to have some concentration of our annual revenues similar to our experience last year relative to the second half of 2022. As JJ mentioned, we reaffirm our annual guidance for Naglazyme and Bimsum revenues. 33% growth year over year and revenue of $36 million in the first quarter was driven by 18% growth in new patients starting therapy. Moving now to Palantique. Net product revenues grew 2% in the first quarter as compared to the first quarter of 2021 and were impacted by a variety of factors. In the U.S., seasonality of healthcare coverage, similar to what was experienced with Kuven in the past, resulted in a Q1 dip in Palantzec revenues as compared to the fourth quarter of 2021. And while we expect this dynamic in the U.S. to recover for the remainder of 2022, impact from ongoing PKU clinic limitations has full-year Palantzec revenues trending to the lower end of the guidance range for the full year. Continuing with the PKU franchise, KuVan contributed $59 million in revenues in the first quarter of 2022, down 16% as compared to Q1 2021. Since the loss of U.S. market exclusivity in October of 2020, we experienced a further step down in the U.S. in the first quarter. As KuVan nears the end of its life cycle, as we would expect, we are gratified to be able to retain the market share and the resulting revenues we are experiencing. Based on market conditions, we expect four-year CUBAN revenues in 2022 to trend closer to the lower end of the previously provided four-year guidance range in 2022. Lastly, with the CHMP opinion on Roctavian expected in the near future, launch readiness activities continue to progress The team is on board and well prepared to launch, assuming regulatory approvals later this year. We are encouraged that our longer-term data results offer a potentially attractive value proposition and treatment option for those with severe chemophilia A, and we look forward to providing you with more detailed updates at launch. In conclusion, in 2022, we anticipate increased demand for all of our commercial brands with the exception of KuVan, as just described. Our MDS products are expected to contribute significantly to revenue growth this year. We also expect Voxogo to be a meaningful factor in this ramp year, as noted in today's increase in Voxogo revenue guidance. We believe that robust prescription demand represents a foundation for continued growth, including in new markets throughout 2022. Thank you for your attention, and I will now turn the call over to Hank to provide an R&D update.

Hank? Thanks, Jeff. I thank you all for joining us today. The R&D organization had a very busy quarter as well. Our regulatory team has been focused on health authority interactions with the European Medicines Agency on the Roctavian application currently under review and preparations for the June resubmission of our biologics license application in the United States. We have enjoyed a high degree of collaboration with the EMA as we enter the later stages of the review procedure. Thus far, we have been able to satisfy their requests for information. Putting us on track for a potential CHMP midyear is precise scheduling of subject to the EMA. As JJ mentioned, we were pleased to have completed the analysis of the parotid gland tumor that was identified in one of our Phase II study participants as noted in our EHAT presentation this past February. The results are consistent with a benign integration profile for Octavian, as we did not observe Octavian integration associated with growth of the tumor cells. We plan to provide EMAD's data as part of the ongoing review of our marketing authorization application, as well as include the data in the biologic licensing application in the United States in the resubmission in June. Needless to say, we're pleased with the findings as it further supports the safety profile Octavian has demonstrated to date. As leaders in the field of gene therapy, we look forward to sharing the results of the analysis with the scientific community at the upcoming World Federation of Hemophilia 2022 World Congress and the annual American Society of Cell and Gene Therapy meeting in addition. Turning to Batsu, though, we are pleased to share that Dr. Andrew Dauber will present results from his study in genetic short-statural conditions at the Pediatric Endocrine Society meeting this coming Sunday, May 1. As he shared in our last R&D day, The study spanned six different genetic central conditions, so we look forward to learning about the potential of OxoGo to positively impact children with other conditions besides achondroplasia. The next milestone with OxoGo is a data update from our Phase II randomized double-blind placebo-controlled OxoGo study in infants and young children up to five years of age with achondroplasia. The team has had the opportunity to analyze the results since they were unblinded in February, and we expect to share them at a medical meeting in the middle of the year. Finally, turning to the earlier stage pipeline, all of the candidates under development continue to advance. A new update today is that we have begun dosing patients in the Phase I-II Harmony I study using BMN331 or gene therapy for hereditary angioedema. We are encouraged by this new opportunity for HAE patients, as our preclinical data suggests that BMN331 can reduce the frequency and severity of attacks and potentially eliminate chronic therapy for some patients, significantly reducing the treatment burden of HAE and the current standard of care. We're excited to begin this development journey and learn about the potential for BNN331 to restore C1-asterase inhibitor protein in humans based on the encouraging preclinical data observed. The BNN255, which addresses a subset of chronic renal disease, we completed the single-setting dose arm of the Phase 1-2 study and are in a process of analyzing results. Concerning BNN351 for Duchenne muscular dystrophy, we expect to follow the IMD in the first half of the year with the goal of treating the first Duchenne boys in the fourth quarter of this year. Our preclinical studies of BMN349 continue to build our enthusiasm for its potential to dramatically improve liver health in people living with A18B, alpha-1 antitrypsin deficiency, and BMN293, formerly referred to as DINA001, is on track to be our next gene therapy clinical candidate, in this case for the treatment of hypertrophic cardiomyopathy caused by mutations in cardiac myosin binding protein C3. We continue to advance 349 and 293 towards INDs in the second half of 2023. Lastly, on BMN 307 PKU gene therapy, we await the results of non-clinical studies required to remove the current clinical hold. And as we said in January, in February, we believe that this will be a multi-quarter process. So we'll update that program status when available. We look forward to keeping you apprised of our progress across the R&D organizations as we advance our Octavian applications. present data at upcoming medical meetings, and move the earlier stage pipeline products forward. Thanks for your support, and I'll now turn the call over to Brian to update financial results in the quarter.

Brian? Thank you, Hank. Please refer to today's press release summarizing our financial results for full details on the first quarter of 2020. Since Jeff touched on many of the top-line results from the commercial business, I will primarily focus on operating expenses, bottom-line results, and other key financial updates this quarter. As usual, all results will be available in our upcoming Form 10-Q, which we are on track to file over the next few days. As we highlighted in February, we believe that 2022 is an exciting year for BioMarin, as the company anticipates transitioning to sustainable gap profitability driven by the continued strong growth of our base business, plus a significant contribution from VoxOgo in its launch year. We are pleased to be tracking the plan based on the company's first quarter results provided today. Total revenue growth of 11% in the first quarter of 2022, as compared to the first quarter of 2021, excluding KUVAN, sets us up nicely to achieve our full meter GAAP and non-GAAP income goals in 2022. To elaborate upon one important comment from Jeff, while we expect Naglazine and Zimazine orders to be weighted to the first half of 2022, Based on the ordering patterns of select markets, we expect that our total revenues for the full year will be balanced out by growth in our other brands in the second half of the year, and that total bottom-run revenues will be roughly even between the first and second half of 2022. Also, comment on VoxOgo. While we are pleased to observe the early patient uptake trends for VoxOgo globally, which drove our increased expectations for the full year 2022, It's important to note that even though we expect to continue to add new Voxogo patients over the remainder of 2022, the mechanics of daily dosing mean that these new patients on therapy for just a portion of the year will contribute slightly less to full year 2022 revenue. Moving to operating expenses for the first quarter of 2022, both R&D and SG&A expense fell in line with our expectations. R&D expenses for the first year were $161 million. a slight increase as compared to the first quarter of 2021, reflecting increased Roctavian development efforts and increased R&D on our early stage programs. SG&A expenses for the first quarter of 2022 were $195 million, as compared to $174 million for the same period last year, and reflect the global VoxOgo commercial launch efforts since the European and U.S. approvals in the second half of last year, as well as the Roctavian commercial launch preparation costs. Moving to bottom line results for the first quarter. As we shared in February, during the first quarter of 2022, we sold the priority review voucher received with the approval of Voxilgo in the United States. The transaction was recognized as a gain on sale of a non-financial asset on our statement of operations and was the primary driver of Q1 GAAP net income of $120.8 million. While GAAP profitability in 2022 will benefit from the CRV sale, We note that our business plan for the year and the related profitability expectations are not dependent upon the after-tax gain from the PRV sale. With respect to non-GAAP income, Q1 2022 non-GAAP income of $105 million excludes the gain on the sale of the PRV and was relatively flat to 2021 first quarter non-GAAP income of $104 million. and represents a strong start to our expectation of earning between $350 to $390 million of non-GAAP income this year. Turning to total cash and investments, we ended the first quarter of 2022 with $1.5 billion, mostly flat to year-end 2021. While our total cash increased with the proceeds from the sale of the PRV, we also experienced quarterly working capital time and differences during Q1 2022. As we said when we provided 2022 guidance, we do expect positive operating cash flows for the full year. Briefly on the Ukraine crisis, given our global footprint and commercial presence in this region. As we previously shared, the Russian and Ukraine markets represent approximately 2% to 3% of Biomarin's total revenue. And based on what we know today, we expect that to be consistent in 2022. Given the essential nature of our products, which treat underlying conditions for which no alternative pharmaceutical treatments are available, we continue to serve our patients in the region and are working to minimize the treatment disruptions for Ukrainian patients. In fact, we have already fulfilled a significant portion of the expected 2022 supply to Ukraine and Russia. In closing, 2022 is off to a great start, and we are on track to achieve our transition to sustainable profitability with record first quarter revenues driven by a strong global launch of Octobo and solid growth in the base business. Our plan to support both continued product approvals and innovative pipeline growth, while at the same time generating sustainably increasing revenue, profits, and operating cash flows is being realized with an eye towards continued growth further into this decade. Thank you for your attention, and we will now open up the call to your questions. Operator?

Ladies and gentlemen, if you would like to ask a question, please press star, then the number one on your telephone keypad. To withdraw a question, press the pound key. Your first question comes from the line of Salveen Richter of Goldman Sachs. Your line is now open.

Good afternoon. First, congratulations on turning GAP profitable. Two questions for me. For Voxogo, in the U.S., how is outreach and uptake progressing in pediatric on endocrinologists? And then for Octavian, anything you can provide us on how regulatory discussions are playing out in the US. Thank you.

Hi, Salvi, and I'll take the first question. Yep, we're doing really well with outreach to pediatric endocrinologists. It is a new call point, and as we're emerging from the shutdown, Our teams are establishing connections with this new call point in the United States and other markets where we're active, for example, in Germany. And we're seeing prescriptions coming in from a mix of physician specialties, as I noted, but mainly from geneticists and pedandos physicians. as we would expect. So I would say it's going right on track with nothing notable to describe that's kind of surprising or different than we expected.

And on regulatory discussions, again, the bulk of the conversations have been with European Medicines Agency, and we felt pretty good about the connection between the remaining questions they have and the information that we have to provide them, including the recently completed genomic analysis of the salivary gland tumor, which is favorable. In regard to the U.S., we do plan to have even further discussions with the Food and Drug Administration in advance of our resubmission. Presubmission interaction is, in fact, scheduled with Food and Drug Administration. But we've also already had quite a bit of dialogue since the CRL about information they'll want us to provide back to them when we do resubmit. Also feel pretty good about the sufficiency of the data that we have in hand for satisfying the concerns that were raised in the complete response letter. So feeling pretty good about the regulatory situation in both markets.

Got it. Thank you.

Your next question comes from Chris Raymond of Piper Sandler.

Hey. Thanks for taking the question. Just on VoxOgo, maybe just a couple questions on the dynamic there. I think with the number you guys gave, about a third or so of revenue last quarter was in the U.S., and just a little less than a third of patients. I know it's early, but is this maybe indicative of more sort of parity pricing, or is there some sort of patient ad dynamic? And then also just doing the math on the revenue and then the patients, that seems to be a relatively high number for the quarter. Is there any – I think you can add there in terms of the pricing dynamic. And if I can ask a pipeline question. No mention of, I think I heard no mention of BMM 307. Can you just give us a sense of where that program sort of sits? Thank you.

Hi, Chris. I'll start off on the Vontogo question. So you mentioned in confirming the we stated about a third of our revenues from the United States and the balance XUS, which ties up pretty closely to the patient numbers that we're reporting also. In the United States, early in Q1, we did have some specialty pharmacy stocking, which was a one-time event. Not a huge number, but but enough so that there's a resting inventory in our specialty pharmacy network. That's kind of a one, as I say, a one-time event. And by late March, I would say we were seeing reorders of our specialty pharmacy network in the U.S. on a consistent enough basis that you would conclude that there was no further buying down of that inventory and that the SPs were essentially ordering to demand. So that could be a little bit of a bump in Q1 and or tilted towards the U.S. And you followed along our pricing discussion. As usual, we have a robust price, particularly in the U.S. And so far, we're managing a pretty tight price corridor for Baksogo and other markets. Does that cover your question?

If I may add, so actually the launch is going very well in both sides of the Atlantic. And the difference there, I mean, two aspects. The difference you see is because we started selling in Germany actually in October of last year, so a little ahead of the U.S. We really started selling in January. But basically what's happening is that the The revenues are commensurate with the market size. And we have always said that the largest opportunity was outside the U.S., and the numbers are confirming that. Also, the good news here is that, again, I think there were some anxieties as read in some language reports about launching a product first in Europe and before the U.S. That's the first time we knew that. And it shows actually that we can be very successful launching a product in Europe ahead of the U.S., which is likely to happen for Octavius.

Chris, the game plan is we've got to complete some additional preclinical studies that pertain to the findings that have been previously reported to the agency. We were hopeful that based on some early interactions with the agency that we would be able to remove the hold quicker. But unfortunately, with this requirement to conduct additional studies, we probably won't have any updates for you on that until we have the results of those studies. from our states on 307. Okay. Thanks, guys.

Your next question comes from Robin Karnoskis as Truist.

Hi, guys. Thanks for taking my questions. So just a quick one. I guess for the EMEA discussion and the U.S. discussion, given that you're adding this additional salivary gland data, You know, is it possible that we could go into July? I know you're not on the docket. It looks like for April for EMEA and same for the US. Do you think that this could take a little longer if the filing could be middle of the year, like July, August? And then second question is on Voxogo. So it seems like you have the same number of patients in process that you did last quarter. Do you expect this, the addition of patients to be consistent or do you think this is more of a bolus up front? And then maybe you can comment on, and it's a lot, but maybe you can comment on compliance given the early, and it's early, but compliance with daily sub-ketosing.

Thanks. Hi, Robin. I'm Bob. This is Hank. I'll take a shot at the first part of your questions as to the timeline in the European Medicines Agency. You know, we're feeling pretty optimistic that all the information that we said we'll be able to provide in the EMA in the last leg of review. will enable them to make a decision in June. But, you know, it's also a decent amount of information, and the EMA has, based on the questions that they've asked, they've requested a decent chunk of information for them to review in terms of risk management plans, labels, post-tribal commitments, and things like that. So, yeah, it could drip into July, but, you know, we're working to be lined up with them and enable them to come to the positive opinion. Of course, that's the objective of all this. And in regard to the U.S., you're right to ask a question. My team will certainly appreciate the nature of the question, which is that they're carrying a lot of water on the European application at the same time. We're finalizing the U.S. application. So, you know, as with execution things, and it's really down to execution, yeah, short things may take a little longer. We really want to make sure that we'll submit an application that will facilitate an effective review by the U.S., but that target, again, is in June, and we're hopeful of remaining on that track.

And we got a question on VoxOvo. I mean, I let Jeff answer the question of whether it's the police or patients or whether the course is going to be sustainable. I believe it will be, but Jeff can elaborate on the compliance. I think we've lost only one patient. Is that correct? All the patients we saw, we had a We have lost one patient so far. Jeff? So extremely good compliance.

Yeah, thanks, Robin, for the question. It's actually a positive sign of the launch trajectory in the United States, which is the one place in the world that we're able to track patient numbers in process. So the fact that our in-process is holding steady compared to where it was a quarter ago is indicative of you know, getting a steady stream of both of new patients being enrolled and then also having the ability to pretty rapidly work through those patients, get them approved for treatment, get the product shipped out, and first prescription fulfilled. So I view that as a positive. Related to compliance, JJ noted a small number very small number on drop-off so far. We don't have, at this stage, I don't have a quantitative estimate of compliance other than the drop-off figure, which is supportive of a high rate of compliance so far. The other thing that we're doing is we're being very proactive with patients and their families about kind of training for this daily injection, and we've gotten super feedback in both Europe and the United States. So that's been really helpful for families, giving them the confidence to go out and begin the daily injection routine. And I think that bodes well for compliance going forward. Thanks.

We have very good visibility in the U.S. because patients basically first enroll in the program. They signify that they want to be It's a family that they want the kids to be treated with Loxogo. So we have a good visibility for the increase in rates, and we have no sign of disturbance. It is new patients wanting to be treated that it is slowing down. And I think, Jess, you want to mention how long it takes between when a patient is basically signed up and when we start shipping on average in the U.S.? ?

Yeah, so far it's pretty rapid. Our average is 23 days from complete enrollment with a prescription to shipment of that first prescription to a patient. So some variability around that means.

Great, thank you. Your next question comes from Corey Kasimov of JP Morgan.

Hey, good afternoon, guys. Thanks for taking my question, too, for me as well. Both probably for Hank. First, just to follow up on the U.S. Roctavian situation. Is there anything specific that needs to be addressed in that pre-BLA meeting that hasn't been dealt with already? I guess just curious if this is standard operating procedure for a resubmission or if there are issues to still discuss. And then the second thing, I was just wondering, Hank, if you could set the stage ahead of the short stature update this weekend for Voxogo. What would be compelling in your view or an investigator's view when you speak with them? Thank you.

Yeah. You know, I think the interaction with the FDA pre-submission is more of the SOP rather than necessarily particularly new information. You know, I think the agency's stance is likely to be, you know, these are all issues that are going to be resolved during the review. What's important for us to do is to make sure that we have a clear-eyed view of the information that they're looking for. We have all these data. So it's really just a matter of making sure it's in the form and content of what they're looking for. So more on the SOP side. As far as the Dauber presentation, I think the expectation to have is that in the amalgam that sort of across a range of mutations, I think a reminder is that he's indicated that he's accrued patients with six different types of mutations. that there can be an improvement in stature as measured by the AGV in children who have mutations that are different from the achondroplasia FGFR mutation. And he's got a lot of biology as to why he believes that to be the case. But of course, the data itself themselves will be positive for his underlying . So I would focus in on the AGV change from baseline across the different types of mutations that he's included. And I think, you know, a good outcome would be similar or better than, you know, similar to what we've seen in achondroplasia, a great outcome. And it might be mutation-specific. It might be that some mutations are even more responsive to serotypes. So, I think that's the stage to set for the current data.

Great. Thank you.

Your next question comes from Paul Matisse .

Sorry, we couldn't hear.

I think she said Paul Matisse at Stiefel. Thanks a lot for taking the question. Good to talk to you. Just one box to go question on the commercial side. I guess, are you seeing physicians or do you think physicians will do anything to determine whether or not patients are benefiting? Obviously, you can look at growth, natural history, but every patient is different. You kind of can get into hypotheticals. So maybe just comment on how you sort of verify efficacy with this drug and then To the extent you've seen any discontinuation so far, what are the reasons, if you wouldn't mind clarifying? Thank you.

Thanks for your question, Paul. So, in terms of tracking benefit, that's not something that we guide specifically to, but we would certainly expect We would certainly expect physicians to be following along the progress of their patients. There is newly published guidance on the management of achondroplasia, which I think is helpful in providing those prescribers the guidance to do that. And growth velocity and height would be kind of a lowest common denominator that could be expected Some of the US insurers are requiring evidence of benefit for future renewal of prescriptions, for example, which seems reasonable enough. And back to the publication on management guidelines, as you've heard me say before, Really, there was no medical home, particularly in the US, in our system, no medical home for achondroplasia patients. And I think part of the opportunity here is to establish a medical home for kids with achondroplasia up to and including but not limited to the use of VoxOgo as a part of that overall management scheme. And I think that's going to be good for Biomarin and VoxOgo and it's going to be great for the kids with achondroplasia and their families. In terms of discontinuation, We don't really have enough data, as JJ mentioned. I think we have one discontinuation, and I don't have a stated reason for that one.

Okay, thanks. And maybe just one... Sorry, go ahead.

Back to tracking the efficacy, and this is not a scientific way to do it, but just an anecdote, that when we tested the advertising campaign with European healthcare professionals and patients, We actually have a picture of a young girl who has been treated with VoxOvo for, I think, over four years, very close to five now. And she's obviously an achondroplastic patient. And the reactions from the panels of doctors and families of achondroplastic patients were that we should be using really achondroplastic patients for advertising. But that's my only way to answer your questions.

Thank you, JJ. And last, just one quick thing. Any update on the path to full approval? Thanks again.

Not in particular. You know, the good news is that the data that's going to generate the full approval package is going to be if you follow up these patients from the pivotal clinical trial. And as you just heard, you know, the compliance and the program overall is pretty good. Excellent. So we do expect to be able to provide that in a timely fashion. I don't know that we've got it to a specific submission date.

Understood. Thanks again.

Your next question comes from Jenna Wang of Barclays. Thank you for taking my questions.

I have two sets of questions. So the first one is regarding the roctavian salivary gland mass integration analysis. So you saw similar patterns but did you see any unwanted sites that show up in this analysis? And a related question for your 307 TKU program, your analysis also showed integration not tumor-initiating event, but FDA still asked for data that requires several quarters of work. So what makes you confident that similar situation won't happen here to Octavians? And I have quickly on Voxogo question, just wondering what is the price range for the ex-U.S. different countries? And for France, now you have like listing prices at 300,000 U.S. dollars. But since you expect future negotiating price will be lower, how would you book the revenue here?

Yeah. Hi, Janet. So as regards the pattern of integration, there really was nothing particularly noteworthy about the pattern of integration. And I think one of the keys is to compare the pattern of integration between the healthy tissue and the adjacent in the block to the tumor tissue. And as has been previously described for wild type AAV, recombinant vectors have a relatively low propensity of integration. And I think that's That has been foundational in the regulatory perspective. You might remember there was an FDA guidance document on this, and they referred to AEV vectors as having a low propensity for integration. I think one of the great things about what we've found so far is that it appears that the recombinant vector is saving similarly in terms of distribution integration patterns and frequencies and sites of integration. similar to the wild type. That is to say, not binding preferential hotspots of particular relevance. And so, the next part of your question was, the 307, how does that read effectively? I understood the question to be, how does it read on the 270 evaluation, and why not imagine that there could be similar requirements for 270 as there have been for, as there appear to be for 307? I think the short answer to that is, because the 270 vector has cleared its safety studies to the adequate satisfaction of health stories to date. There have been the only sort of suspicious signal that's arisen in the 270 program is what we just talked about, which was the Prada tumor, and there's nothing unique, particularly in the findings in this individual. And so I think having not seen this with neither preclinically the roctavian itself nor with a vector whose construction is very, very similar to roctavian and studied for a longer period of time, even the roctavian study, That similar vector similarly is not oncogenic in preclinical species. So I think all these things taken together bode quite well for the Roktavian overall risk-benefit evaluation, namely that in preclinical studies and in humans, no particularly confirming signal of oncogenic potential in the vector is existing.

And clearly, the FDA seems to products very differently in this respect because Although, you know, 307 is on clinical hold, Rokavin is not on clinical hold. We are enrolling each of these studies as we see.

Nor is PMM331 either also enrolling and, you know, therefore I think that the agency is reacting to this as it's a vector-specific, indication-specific decision.

I had a question on the revenue. In price range, I'll box over in Europe and revenue recognition. Maybe we'll start with Jeff and then Brian.

Okay. Regarding the price range, Gina, the prices that we're anchoring to, we've got the WAC price in the United States, and on our approval call, we guided to our expectation of gross or WAC price to net realizable price for per patient, I think that's a pretty solid estimate. We've got the list price, as you note, in Germany and France, and our expectation is that it's going to take about a year from product introduction to get to kind of negotiated prices for full reimbursement. So that'll happen later this year. And in the meantime, where we're establishing pricing for our name patient sales markets are right in a pretty tight corridor consistent with the US, French, and German pricing. And I'll let Brian cover the discount piece.

Yeah. Thanks, Jeff. Thanks for the question, Gina. This is Brian. There's nothing materially unique to speak about with respect to Voxogo growth to net. Our experience and our expectations are that the overall growth to net will be similar to our other products, as well as our prior launches. You know, not to get into each of the European country by country dynamics, but in some cases, you do start with an initial price, and then there could be a clawback when you get to that final negotiated price if it's lower. But we're required under GAAP to make estimates of those and record those reserves, if you will. So what you're seeing in our reported revenues would be the net net revenue.

Great. Thank you. Very helpful.

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

Hey, guys. Thanks so much for the question. I just had a couple along kind of the same theme as everyone has been asking. Hank, on Octavian, I know it's parsing the language a bit, but is the shift from 2Q to mid-2022 from the CHMP, is that just a normal fluctuation or was, in fact, there an impact to the review clock when you look at the tumor analysis? And then on Voxogo, you know, commercially, I know it's early, but are there some themes in new patient starts in Europe, you know, who weren't in the clinical studies in terms of you know, patient flows or awareness. I'm just trying to get a sense for, you know, what was working there this early in the launch and maybe if that could be similar or different when you look to the U.S. launch. Thank you.

Jeff, on the earlier, you know, there's no concrete piece of information that is underneath the shift. the minor, you know, I was talking about it being June, maybe shifting into the summer. I think the only news here is, or that's not even news, is we've been off, we just came off accelerated assessment. And that was anticipated. But you never know at the beginning of the procedure, or even in the middle of the procedure, is just sort of how their timelines line up and when they want to receive information. And so I think, you know, as much as anything, We're just being a little abundant caution here in terms of projecting timelines because they're not entirely in our control as a result of the fact that we're giving them a pretty big slug of data towards the tail end of the review. They obviously knew it was coming, so that's why we're confident we're going to stay in the procedure and that we're going to have an opinion by the summer, but it also is like we've got to follow their lead in terms of exactly when they're going to take it to an opinion. I think the most important thing is we believe that we have the information that addresses that questions they've issued to us. And based on those questions, we believe that a positive benefit-risk opinion can come, but that happens after they've done their meetings with non-closed-source. So that's what we're working to support.

Talks about locations, European locations.

Yeah. So, Jeff, what I would say about themes is diversity of experience here, which points kind of away from common themes in an important way. Diversity, I would say diversity of age group that we're seeing starting therapy. One example, diversity of prescriber specialty that we're seeing, mainly genetics and pediatric endocrinologists, but also some pediatric orthopedists and pediatricians. showing up here, and also kind of diversity of approach. So in Germany, we're essentially operating under a full price of reimbursement approval, even though we haven't negotiated a final price there. It's kind of how the market behaves. And so we're seeing pretty rapid uptake. In France, in contrast, We're currently operating under a very structured expanded access protocol there. So it's a more kind of structured approach to getting patients started and from a relatively small network of clinics. And in France, as I've noted before, The physicians there are actually starting older patients and working down in age on the logic that they want to take full advantage of the window for treatment with their older kids. That's not really something that we've seen anywhere else. And in the smaller named patient sales markets, I would say the theme there is we're getting one or a couple of patients approved initially under named patient sales approvals, and our opportunity there has been to kind of build off that, get the third, the fourth, in some cases the fifth or the eighth patient treated, and we're working hard to do that. So a lot of diversity actually of experience. Gotcha. Okay. Thanks, guys.

For the next question, we have Phil Needle with Cowen.

Good afternoon. Let me add my congratulations on a productive quarter. Just a couple of follow-ups from us on Voxogo and Ractabian. First, on Voxogo, Jeff, I think on the approval call, you identified one of the challenges of the U.S. launch that a lot of patients were in expert centers. Are the expert centers reporting that patients are inquiring about being treated, or is there a general flux of patients towards the expert centers with the availability of Voxogo? And then second, on Ractavian, Hank, just briefly, what are your expectations for an ADCOM? I know there wasn't one in the first review. Do you think the FDA is likely to hold an ADCOM to review the Ractavian resubmission? Thanks.

So I'll start on the Boxogo experience in the United States. You're right. On the approval call, I noted that longer term, our big task was to establish a referral network and kind of get patients out of the random physician which is not a medical home for achondroplasia, get them referred either to a genetics clinic that's interested in achondroplasia or to a pediatric endocrinologist. And moments ago I mentioned that that's an opportunity to create a treatment home for achondroplasia. And also earlier I said, you know, we've got a pretty steady rate of patients coming in in the United States for referrals and an in-process group. And that's a good signal indicating that we didn't just have a bolus of patients that wore off and is slowing down over time. However, underneath that, I think you're right, a lot of our early patients, were coming from the genetics and skeletal dysplasia clinics expert centers that had achondroplasia patients lined up. So a lot of interest in referrals early on from that channel. And in the last couple of months then we've been able to get that referral network established in the U.S. and start driving patients from a random physician that they're being seen by to pediatric endocrinologists. So that's picking up now and I think that's going to be the longer term driver of growth for the U.S. market.

On the issue of ADCOM, Phil, I don't know that I have, like, meaningfully more information to add to the dialogue since the agency won't really decide the ADCOM until they're in review. I mean, I think if you were asking personally what would he say, it would be something like, well, the agency calls ADCOMs generally for two purposes. One is when they want to approve something and they want to rally the troops around the decision they make, and then the other is when they want to kill something and they want to use the ADCOM to kill it. Feels like, you know, there's not a lot of info that they could show to an adcom to kill it because the efficacy profile is good, the safety profile is good, and so what would you point to to be the motives for killing it? So I guess Hank would say I hope they do call an adcom because I hope that what they are doing is going to be serious about, like, how they regulate gene therapy products and use a fairly robust package of Octavian to establish standards for review.

That's helpful. Thank you.

Your next question is from Matthew Harrison of Morgan Stanley.

Great. Good afternoon. Thanks for taking the question. Jeff, I just wanted to follow up on two things. One, I think you talked about some inventory dynamics that helped VoxOgo this quarter at the specialty pharmacies. Could you or maybe you're willing to just quantify or give us some sense about how much that helped? Secondly, just as you're preparing for Roctavian in Europe, can you give us some sense of how much work has been done so far and how much engagement you've had with each of the countries around or if any engagement around price and just sort of initial commentary there? Thanks.

Okay, thanks, Matt, for the question. So back on Voxogo and the U.S. and kind of a resting specialty pharmacy inventory, you could judge from the mix of revenue ex-U.S. and U.S. and say, well, Bymore is guiding the $7 million of revenue with U.S. I also said that by March, we were seeing orders that indicated to me that specialty pharmacies were not drawing down that resting inventory. We also know specialty pharmacies don't like to hold a lot of inventory, and really they don't have to because we've got really good reorder dynamics for them. So I might guide you a couple to several million dollars of resting inventory in the United States. And then with respect to Rockabian in Europe, One of the things that I think the VoxOgo launch in Europe is doing is validating that where there is a large market opportunity and you have an experienced company with experienced teams that know what they're doing, we can capitalize on that market opportunity and have successful launches in the EU in particular. We're leveraging all of the experience that we've gotten from the past launches As in the United States, we formed specialized teams to prepare for Rocktabian, including seeding our teams with people with significant experience in the hemophilia business. We're essentially ready to go, particularly in the markets where we're expecting first revenues. And you might expect from the current and past experience, That would be in places like France and Germany and Italy first, and in places where we get main patient sales uptake on a relatively rapid basis. So we've got people in those places. Yes, we've been doing price research. We have an active program working with market access, advisors in Europe. We followed that practice, for example, with Voxogo. We're doing the same thing with Rock Damien. I think we're really ready for this launch, and we're excited about it if we get a CHMP positive opinion and an EC approval here.

I may add a few things. So in Germany, at least at launch, we're seeing a price, you know, towards the U.S. Fed's price, we're on $2 million. And we also have done a lot of reimbursable research. There's major interest by German payers about outcome-based agreements. And we will be making those available because now we have great data showing that, you know, the majority of the patients do respond very well to Roktavid and very few of them, you know, lowest single digits are either not responding or go back to after a few years so we can maximize the price at launch by basically offering a guarantee of success to the payers. And that's something that they understand very well and they are very interested in considering that they know how much the species are costing them. So that's kind of the plan.

The next question comes from Joseph Schwartz with SVB Securities.

Hi. A lot of my questions have been answered, so I'll ask some things about your mid-stage pipeline. I guess it's been over a year since the I&D was filed for BMN 255, so I was wondering if you could give us an update on this program. I see you completed the SAD work and are analyzing that. Do you think you'll be advancing to the MAD program? portion and when can we expect to see some data there? Is it possible to see a signal from the med trial even though these are healthy volunteers?

All good questions. You know, the early stages of small molecule development are sort of oftentimes the twistiest part of the road. I think all I can share with you now is what you put in your question, which is we've completed the single ascending dose portion of the study, and we're analyzing the results of that. I think the excitement for 255 is its genetic enablement, namely that we understand there to be a molecular pathway that's key to regulating oxalate excretion. And, you know, there's a lot of oxalate excretion in recurrent stem corners or people with chronic renal disease. So if we really figured out a way to open the tap on oxalate, it should be excretion. It should be, or I should say close the tap. It should be exciting for patients. But stay tuned as we gather data in this particular twisty phase of the dissolving program.

Okay, thank you.

Your next question is from Debjit Chathopadhyay with Guggenheim.

Hey, thank you for letting me in. So just on Voxer, on the commercial loan so far, upper age limit of patients who are currently getting prescribed, and number two, any clarity on the sleep apnea signal noted in the younger subjects in the 0 to 5-year-old study, and finally, are you planning to advance the long-acting version into the clinic? Thanks so much.

I'll start with the question on the age range. As noted earlier, we've seen where we have the data to measure it, quite a lot of diversity in age range, including teenagers being enrolled for treatment, as well as younger kids. So don't have a ceiling on age, but what we know is that kids that have their bone plates closed will not benefit. So we would expect that upper limit to be something plus or minus or 18 years old plus or minus. And I think your second question was related to the zero to five-year-olds.

Yeah. So biggest possible picture on the zero to five-year-old is that in Europe, the first territory we launched, Europeans were compelled by the overall package of data and the Sentinel data that we provided to them during the application review, and I think we talked about that. That means we have a label, so we have a label, and we can sell a product for the two- to five-year-old population. And the United States FDA wanted a little bit more information, and the results of 206 are going to inform that. We've announced the positive trends were observed. And I think in the treatment of these young children, I think the next step, therefore, is to have conversations with Food and Drug Administration about labeling requirements. And we're going to pursue a similar pattern throughout the rest of the world. We believe that data support giving families treatment options for children who are under five years of age with achondroplasia and working with health authorities to provide them the information that they need to come to that decision. And different geographies may come to that decision at different time points based on emerging data. So I'd say stay tuned for further updates from us on both regulatory plans as well as overall plans for addressing that.

And we are in the stage of a review in Japan for our petition that, you know, the funding is for, you know, for zero, I mean, for any patients from birth to exposure. So I don't know if you want to say if you want to, but when the So data will be presented?

Yes, so the data will be presented. I think we said summer on the call or the middle of the year. And then I think you also asked about long acting. And long acting, I think so far, thought about it as not much of an efficacy advantage in most children, not much of a safety advantage. We've talked about all the numbers behind all that. But it is an interesting question as it pertains to the children who are under five. You might know that Ascendus has in their phase two study enrolled some patients who are under five, so there could be some data about the effect of long acting on overall growth. But again, a key reminder about that is how far behind us Ascendus really is in terms of development path, but this is a relatively small phase two study. So I think we have some room to both offer this option on a global basis for young children, because there is nothing else, and time is of the essence, as well as to further iterate our product offerings to continue building strength in the Voxozo brand.

Thank you. Good luck.

Your next question is from Joel Beattie with Baird.

Thanks for taking the questions. The first one is for Voxozo. What's the level of awareness of the drug among patients with acanthoplasia and their families? And then also for 351 for DMD, What will be learned from the initial study starting later this year?

Maybe I'll start with the question about level of awareness. That's something that we would typically be market researching to get a quantitative estimate following launch, and the answer on that one is we haven't yet gone out to market research that question. We will at some point during the year, and we'll have to wait until we do that work to have an estimate. Qualitatively, I would say it looks to be pretty high based on the level of patients that we see coming in for treatment.

And as regards what we'll learn from the initial 351 study, As I said, our goal is to get into the treatment of DMV boys as quickly as we can, hopefully by the end of the year. Now, of course, that's always subject to regulatory review of an IND. But assuming that that's the plan, I think, and that should be the plan, because the essential question really is, what's the relationship between a delivered dose, its safety profile, and the level of dystrophin increase that you can achieve? And you know, based on the biology of the compound that we've developed, we believe that the nature of the chemistry being so similar to what we use with Drizeperson, that we should be able to achieve tissue concentrations, muscular tissue concentrations of our 351 compound that would produce skipping in the range of between 20 and 40%, meaning that the patients would have 20 or 40% of this shortened dystrophin protein which is pretty high relative to what ambulatory patients with a far less severe condition called Becker's muscular dystrophy have. So as quickly as possible, the initial 351 proof of concept study will gear itself towards demonstrating safe improvement of a meaningful quantity of dystrophin protein in muscle. Can't give you a timeline specifically for when those data will be available, as we're just getting started.

Thank you.

Here are next questions from Luca Isi with RBC Capital.

Well, great. Thanks so much for taking my question. Quick one on Valrox. I know you're ruling out AAV as the potential cause of the salivary gland cancer, but can you actually share the integration frequency that you have observed on the surgical piece? I know Unicure mentioned in the past 0.027% of their cell, showing evidence of AAV integrations for their hepatocellular carcinoma case. So just wondering how your number compares to that number. And maybe also related, I think Ask Bio and Bayer reported a case of tonsil cancer in their hemophilia B program. So wondering how you're thinking about a read-through for your program. And then still on Wild Rocks, assuming it does get approved, can you remind us what's the latest thinking on pricing strategy? And feel free to dichotomize the answer between the US and the EU should that make sense. Thanks so much.

I think specifically as regards numbers, coming to the presentations that are coming around the corner at both WFH and ASGC, the way I think about it is that what we've seen so far is consistent with what's been previously described as low propensity for integration. qualitatively anyway that's the brain take into your review of those presentations as regards you know the occurrence of other tumors I mean I do think that over time there are going to be patients developing cancer I mean that's the fact of getting older in life and I think that what we've seen today doesn't really suggest that there's been particularly clustering of tumor types I think also one has to really consider sort of vector at a time That's kind of what we've learned in our 307 journey, as we were talking about earlier, that is to say the agency is proceeding with 331 and 270 enrolling clinical trials. It's only 307 in which this question is kind of raised. So instead of sort of lumping everything together, I think the agency is taking each vector in each clinical situation sort of on its own face for the time being. I think the data that we're talking about today are pretty encouraging as regards to reaffirming what was known all along about AAV, relatively low intensity for integration, relatively low specificity for integration events in particular spots in the genome, and no reason to believe fundamentally that what's been observed with AAV is that, you know, people run around talking about the cancer risk of hepatitis C or hepatitis B. You know, AAV is not the thing that people are running around talking about systemic cancer risks from. So I think that low propensity of integration of corroborations that we're talking about today is really a powerful finding.

We covered already the previous question, the pricing in Europe. I don't think we need to go over that again, but do you want to say a few words about the U.S. pricing, Jeff?

Yeah, so what you've heard JJ say publicly a couple of years ago was probably not less than $2 million at WAC, probably not more than $3 million, but that's the range that the ICER first review that showed Roctavian to be a dominant choice at a presumed price of $2.5 million kind of worked up. We'll announce a final price when we get an approval and launch, but I think generally those ranges look pretty solid to me. Maybe just one other comment on pricing and our ability to capture a premium price. JJ mentioned outcomes-based agreement earlier. That's crucial to our ability to capture value for Rocktabian. Payers, in addition to wanting their patients to do well, to not bleed, to not have to infuse two and a half times a week on average, payers are concerned financially about their risk of non-performance following administration and the risk of durability of effect over time. The data that we have so far would suggest risk of non-performance following administration is very, very low. and the durability data that we've seen both out of the 201 study and the Generate One study, including the 17 patients that we have three years at, is really encouraging about the durability of effect over time. So we think that we can largely take those risks off the table for payers, and that's one of the factors that will allow us to capture at high value initially. Thank you.

This concludes the Q&A session. I will now hand it over to JJ Banime for closing remarks.

Thank you, operator, and thank you all for joining us today. We are, again, pleased to begin 2022 with a record first quarter results. The addition of VoxOgo to our commercial portfolio is definitely an important component of our growth story going forward, and it paves the way for gap profitability, sustainable gap profitability beginning this year. We have successfully transitioned our focus to the development of a commercialization of genetic therapies for larger genetic conditions, and we are hopeful that 2020 will be the year that Rotarian will be approved in the U.S. and Europe, and we look forward to keeping you apprised of our progress over the coming weeks and months. So thank you all for your continued support, and we look forward to seeing you soon.

This concludes today's conference call.