Biomarin Pharmaceutical Inc Q3 FY2022 Earnings Call

Thank you, Ross, and thank you all for joining us today. To remind you, this nonconfidential presentation contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc., including expectations regarding BioMarin's financial performance, commercial products, and potential future products in different areas of therapeutic research and development. Results may differ materially depending on the progress of BioMarin's product programs, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical market, and developments by competitors. And those factors detailed in BioMarin's filings with the Securities and Exchange Commission, such as 10-Q, 10-K, and 8-K reports. On the call from BioMarin's management team today are JJ Bienaime, Chairman and Chief Executive Officer; Jeff Ajer, Executive Vice President, Chief Commercial Officer; Hank Fuchs, President Worldwide Research and Development; Greg Guyer, Executive Vice President and 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 Bienaime.

Thank you, Traci, and good afternoon, everyone. Thank you for joining us today. BioMarin's results in the first nine months of 2022 represent record year-to-date total revenues of more than $1.56 billion. In the third quarter, total revenues grew 24% year-over-year and increased 31% excluding KUVAN. VOXZOGO revenues of $48 million in the third quarter and $102 million year-to-date led to today's increase in full year 2022 VOXZOGO guidance. Planning these impressive results is the continued strong demand from across Europe and the United States for VOXZOGO, a significant increase in overall patients treated, and notable uptake in Japan since launching there in August. With no lower age restriction on VOXZOGO treatment in Japan, we are thrilled to share that one of the first patients treated in the third quarter was a three-week-old patient. Turning to our second and most recently approved product opportunity, ROCTAVIAN, a gene therapy for the treatment of hemophilia A, since receiving European approval in the third quarter, we are now in the final stages of negotiating outcome-based agreements with key payers in Germany. With ROCTAVIAN pricing in Germany, product in our warehouse ready to ship, we expect to treat the first patient there in the fourth quarter, and in additional EU countries beginning in the first quarter of next year. Jeff will provide an update on the European launch in a moment. Briefly on ROCTAVIAN in the United States, the BLA is under review. We were very pleased to have received acceptance of the BLA from the FDA two weeks ago, with a PDUFA date of March 31, 2023. The FDA recently informed us that they plan for an Advisory Committee meeting. As we have said before, we have been preparing for a potential outcome for some time. We believe it is a good opportunity to discuss the demonstrated clinical benefits and established safety profile of ROCTAVIAN from the largest label program ever conducted. As we near the end of 2022, I am struck by what has been accomplished in the last 12 months by BioMarin employees. On top of this list is our transition to profitability and the approval of our two largest product opportunities. While some of the approvals late last year enabled the most successful quarter launch in the history of the company, they underscore our capabilities across research, development, regulatory, commercial, and manufacturing. We intend to extract maximum value from ROCTAVIAN beginning with our European launch this quarter. I want to thank my colleagues for their contributions to achieving these significant milestones, which have solidified our foundation for growth. We will build on this momentum for the remainder of 2022 and beyond, and complete our transition to an earnings growth story, a unique accomplishment in our industry. Thank you for your continued support. I will now turn the call over to Jeff to discuss the commercial business update.

Thank you, JJ. I am very pleased with our performance in the third quarter, resulting in $505 million in total revenues, which represents 24% growth year-over-year, including KUVAN and 31% growth excluding KUVAN. Year-to-date and in the third quarter, all brands marketed by BioMarin, with the exception of KUVAN and PALYNZIQ, demonstrated double-digit revenue growth year-over-year. Starting with VOXZOGO, we are pleased to share that as of September 30, an estimated 713 children were being treated across 29 active markets, including a number of children in Japan. Japan is unique in having high awareness and an established treatment network for achondroplasia based on the existing use of growth hormone, and we expect it to be a material contributor to future growth. As a result of robust VOXZOGO uptake across all commercial markets, we are increasing full year guidance to between $140 million and $170 million. We are thrilled with the reception and interest from families seeking VOXZOGO treatment. With 12 months of experience launching the world's only approved genetically targeted treatment option for achondroplasia, we are on our way to recording the most successful commercial launch in BioMarin's history. The successful global launch of VOXZOGO is an excellent primer for the next product launch of 2022, and Europe. As part of the initial launch, we are in the final stages of negotiating outcomes-based agreements with payers in Germany. These agreements allow us to capture full value for ROCTAVIAN and will allow patients to be treated while we go through the full price and reimbursement process. We are targeting payers that we estimate cover 85% of hemophilia A patients in Germany. We expect to treat our first German patients in Q4 and look forward to sharing progress at our next update. On the ROCTAVIAN EU approval column August 24, we committed to update you on the European list price. On September 15, the first European price was listed in Germany in the amount of EUR 60,781 per vial, which, for an average patient consuming 32 vials, would equate to EUR 1.94 million. It is important to note that our net revenues will include the mandatory rebate currently 7% to the German healthcare system, additional negotiated discounts, and a reserve to estimate our obligations against the outcomes-based agreements, resulting in expected net revenue per patient of less than EUR 1.5 million, net of all discounts and reserves. Relative to our experience with VOXZOGO and previous brands, we believe that this level of net pricing in Germany will be closer to the final net price to be negotiated with GBA for federal reimbursement because instead of using the pre-pricing period in Germany, we are going through robust negotiations as part of initial market access. With our first commercial ROCTAVIAN update and for six quarters, we look forward to providing a number of metrics to help you understand the progress of the launch. These include total quarterly revenue, the number of active markets, milestones of numbers of patients treated, and other commentary related to the launch. Considering that individual patients substantially contribute to revenue, to simplify our external tracking, we plan to provide updates on patient uptake by numeric milestone, which will include the first patient treated, the first 5, 10, and 25 patients treated, and the increments of 25 to follow. Turning now to the U.S., with the ROCTAVIAN BLA under review, we are preparing for a potential launch based on the March 31 PDUFA date. The cost of therapy for the treatment of severe hemophilia A in the United States is high and well understood by payers. Based on this and the potential for ROCTAVIAN to provide significant savings to the healthcare system, we were pleased with the draft evidence report issued on September 13 by the Institute for Clinical and Economic Review, or ICER. At a presumed price of $2.5 million, the report referred to ROCTAVIAN as a dominant treatment relative to emicizumab on cost-effectiveness. ROCTAVIAN was projected to have lower costs and slightly higher quality-adjusted life years. This report by a neutral third party underscores our belief that cost savings to payers will be a significant contributor to ROCTAVIAN uptake and an overall opportunity in the United States. Turning briefly now to our enzyme replacement therapy brands, which collectively achieved record year-to-date results. As noted last quarter, and due to uneven ordering patterns, we do continue to expect a higher concentration of revenues in the first half of the year compared to the second half, with VIMIZIM trending to the lower end of full year guidance and NAGLAZYME trending toward the higher end of full year guidance. BRINEURA achieved 15% growth year-over-year, with revenue of $38 million in the third quarter, driven by 20% growth in commercial patients versus one year ago. Moving now to PALYNZIQ, net product revenues grew 9% to $66 million in the third quarter compared to the third quarter of 2021, with 5% revenue growth year-to-date, while positive trails our overall growth expectations, and what we continue to believe PALYNZIQ can achieve in the longer term. Looking ahead, while PALYNZIQ is expected to continue to grow from year to year, resuming substantial growth rates next year will likely be constrained until our new strategies can gain momentum. This year, while we have not updated full-year PALYNZIQ revenue guidance, we do expect full-year revenue to be at the lower end of the guidance range. Continuing with the PKU franchise, KUVAN contributed $57 million in revenue in the third quarter of 2022, relatively flat compared to the second quarter of this year. As we have stated previously, KUVAN nears the end of its life cycle, with some market exclusivity in the U.S. in October 2020. We are gratified to retain meaningful market share and resulting revenues. Going forward, we anticipate generic competition to enter the European KUVAN market in mid-2023, somewhat sooner than previously expected, and with the assumption that this will further reduce our market share and revenues. In conclusion, we expect to end the year strong and anticipate increased demand for all of our commercial brands, with the exception of KUVAN. We believe that robust prescription demand for VOXZOGO represents a foundation for continued growth, including in new markets for the remainder of the year. The team in Europe is very excited to be launching the world's first gene therapy treatment for hemophilia A with ROCTAVIAN, and we look forward to updating you on launch progress at our next quarterly update. Thank you for your attention. I will now turn the call over to Hank to provide any update.

Thanks, Jeff, and thank you all for joining us today. With ROCTAVIAN approved in Europe and the successful BLA resubmission, we look forward with great anticipation to patients in Europe experiencing the life-altering treatments that follow with the world's first gene therapy product for the treatment of severe hemophilia A. The journey to ROCTAVIAN European approval has been both unpredictable and gratifying, and I want to thank my teammates and colleagues for their tenacious pursuit of the ROCTAVIAN advancement in the face of many headwinds throughout the process. We now turn our focus to the U.S. review and are energized and inspired by what has been achieved in Europe. As JJ mentioned, the FDA recently informed us of their plans to hold an advisory committee meeting to discuss ROCTAVIAN, and although no date has been set for this meeting, this is something that we have been preparing for over the last few months. We believe the ADCOM will provide a good forum to review the demonstrated bleeding control and established safety profile of ROCTAVIAN. We're also encouraged that the FDA has approved 11 original BLAs for cell and gene therapies, five of which had complications and were approved. On a related note, in an effort to manage expectations throughout the review process, we plan to only update those milestones that are material to the ROCTAVIAN journey. For example, we plan to share the data of the advisory committee when available. Thank you for your understanding as we focus our entity on quality communications with the agency, advisory duty preparation, and all other elements of the BLA review process. Turning now to the recently presented findings of the more in-depth whole genomic analysis of the leukemia case discussed in September from a subject in our Phase III study. As presented at the European Society of Cell and Gene Therapy Congress in Scotland, a more in-depth sequencing analysis from the patient sample did not detect any integration of ROCTAVIAN vector DNA in the subject's leukemia cells. Furthermore, we identified a collection of mutations across the patient's genome that are often observed in this form of leukemia. This was the outcome we expected based on prior findings that have been already submitted to the FDA. Now that we've completed our genomic studies in this case, we're filing our correspondence to global authorities again in the coming days. Moving to VOXZOGO during the third quarter, we met with both the FDA and the EMA to collaborate on the path forward for admission to supplemental applications for VOXZOGO to expand the age range for which VOXZOGO has indicated. Based on the feedback that we've received, we're interested in both applications by year-end. Turning to new VOXZOGO indications beyond achondroplasia in 2023, we look forward to reviewing the 52-week dataset for Dr. Dover's investigator-sponsored Phase II study in other conditions. These data will be the combination of the exciting preliminary data presented at the end of the meeting this past May and will form the basis of potential new indications selected and Phase III planning for VOXZOGO and other central conditions. Finally, turning to the earlier stage pipeline, we look forward to activating our IND with BMN 351 for the treatment of Duchenne muscular dystrophy in the first quarter. With BMN 255 addressing a subset of chronic renal disease, we have moved forward with the multiple ascending dose portion of our Phase I/II study with BMN 331 hereditary angioedema in those patients based on the HARMONY study to evaluate this investigational AAV5 gene-mediated gene therapy for people with hereditary angioedema. We have recently progressed through escalation of the 6e+13 vector per kilo dose group, where our nonclinical studies progressed to project therapeutically relevant expression. Our preclinical studies of BMN 349 continue to build our enthusiasm for its potential to dramatically improve liver health in people living with alpha-1 antitrypsin deficiency. We expect to file an IND with BMN 349 in the second half of 2023. BMN 293, formerly referred to as Dyna-001, is on track to be our very next gene therapy clinical candidate, in this case, for the treatment of hypertrophic cardiomyopathy caused by mutations in the myosin-binding protein T3. Our preclinical studies continue to generate exciting evidence for the potential of BMN 293 to improve cardiac hypertrophy and diastolic dysfunction in patients living with hypertrophic cardiomyopathy. We also expect to file the IND for BMN 293 in the second half of 2023. It's been quite a busy time in the R&D organization; it's inspiring to reflect on all that's been accomplished, and I want to thank my team for their unwavering perseverance moving our important medicines through preclinical, clinical, and regulatory review on behalf of the patients we serve. We look forward to keeping you appraised of our progress with ROCTAVIAN in the U.S. and look forward to potential approval in 2023. Thank you for your support. I will now turn the call over to Brian to update financial results for the quarter.

Thank you, Hank. Please refer to today's press release summarizing our financial results for full details on the third quarter of 2022. Since JJ and Jeff spoke to our revenue performance for the quarter and future revenue outlook, I will primarily focus on the remainder of our P&L and other key financial updates for 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 couple of days. Our 2022 key financial objectives of delivering double-digit annual revenue growth, together while achieving our operational goals while controlling expenses, is resulting in solid GAAP profitability through Q3 and significant growth in non-GAAP earnings consistent with our plan for the year. One more comment on total BioMarin revenue is that while most of our commercial brands have been tracking within our expectations this year, the strength of the global VOXZOGO launch, driving our increased practical revenue estimates over the course of 2022, has compensated for the impact of foreign currency exchange rates as well as the restricted growth of PALYNZIQ. These factors have balanced each other, and we're pleased to maintain our total 2022 revenue guidance of $2.06 billion to $2.16 billion. On the impact of foreign currency exchange rates, while we have a robust hedging program that has offered material protection during 2022, the strengthening U.S. dollar impacted our year-to-date revenue growth by approximately 3%. On a constant currency basis, Q3 year-to-date revenue growth was 15%. Lastly, on foreign currency, our disciplined hedging program has a small amount of hedge contracts at favorable exchange rates in place for 2023. However, our non-U.S. dollar-denominated revenue base remains largely exposed to the current environment. While we expect solid patient growth in both the base business and our newly launched product next year, we also expect that the current foreign currency exchange rates will continue to be a headwind against 2023 revenue growth. With respect to operating expenses for the third quarter of 2022, R&D expense came in lower than we expected, mostly due to the timing of certain expenses that moved to the fourth quarter, and SG&A expense fell in line with our expectations. R&D expenses for the third quarter were $158 million, exactly flat with the third quarter of 2021, and SG&A expenses for the third quarter of 2022 were $217 million as compared to $183 million in the same period last year. The largest component of the increase in SG&A expense is related to the global VOXZOGO and European ROCTAVIAN launches, some balance sheet foreign currency remeasurement, as well as expenses related to our recently announced organizational changes. While we expect those organizational changes to bring significant operational and financial benefits in the future, we estimate that one-time charges associated with the changes will be approximately $20 million to $25 million, of which $5 million was recorded in the third quarter. Moving to the bottom line results for the third quarter and nine months of 2022. While we are on track to report GAAP net income for the full year 2022, the company recognized a small loss for the third quarter. The Q3 GAAP net loss was mostly due to the timing of revenue and expenses on a quarterly basis over 2022, plus the one-time costs associated with the corporate reorganization just noted. Despite some unplanned expenses and the negative impact of foreign currency exchange on the full year, it is noteworthy that we're maintaining our 2022 GAAP net income guidance of $105 million to $145 million. Regarding non-GAAP income, Q3 2022 non-GAAP income of $83 million was more than double the $34 million of non-GAAP income in the third quarter of 2021. Likewise, non-GAAP income guidance for the full year 2022 remains unchanged at $350 million to $390 million. Turning to total cash and investments, we ended the third quarter of 2022 with approximately $1.65 billion, which is an increase of over $100 million compared to both year-end 2021 and the second quarter of 2022. While the company continues to experience quarterly timing differences in several cash flow categories, mainly working capital, BioMarin generated $169 million of operating cash during the first nine months of 2022, which is a positive indicator of the progression and maturity of the business in this transformative year. In closing, with just over two months to go in 2022, we look forward to closing out a potentially record-breaking revenue year and solid footing for sustainable and growing profitability into the future. We look forward to providing further insights into our 2023 expectations early next year, which we expect will include substantial revenue growth driven by VOXZOGO and ROCTAVIAN despite the headwinds of foreign currency and continued KUVAN erosion from generic competition. Together with the improvements to our operating model through the reorganization, we expect continued leverage in our business that can support both our growing R&D pipeline and strong top and bottom line financial performance. Thank you for your attention, and we'll now open up the call to your questions.

Our first question comes from Phil Nadeau from Cowen & Company.

Congrats on the progress. Hank, one for you. You mentioned that you've been preparing for the FDA AdCom for ROCTAVIAN for quite some time. We're curious to know what issues you anticipate will be discussed at the meeting, what questions are you preparing to field? And has the FDA in any way indicated what discussion topics they're likely to bring up?

Thanks for the question, Phil. It's really too early to anticipate any of that stuff. They just got a huge file for review and they're just underway. And in any case, as the days go by, and I get asked this question, I'm going to have to defer answering it because so much of the questions are about things to speculate about rather than to know. But we'll tell you what there is to know about when we know about it, as I said in my prepared remarks.

Could you give us any sense of what you're preparing for now, what the key points are?

Yes. We have a significant amount of efficacy data, safety data, well-being data, insights on optimal concomitant steroid strategies, details on optimized patient monitoring, and relevant safety information for the package insert related to our post-approval plans. Therefore, we have been preparing for months because it’s essential not only to document the BLA but also to present the key narrative of the BLA. The AdCom presents a valuable opportunity to review the accumulated information comprehensively. While we can summarize findings in a brief press release, the reality of the review and approval process involves examining extensive data, as we have printed the BLA containing seven tests’ worth of information.

Our next question comes from Salveen Richter from Goldman Sachs.

Two for me here. Just one on ROCTAVIAN and the launch in Europe. Could you talk about how quickly you can get the two key payers, the two key remaining payers in Germany on board? And any guidance as we start to think about the cadence of launch starting in Q4? And then secondly, what are your outcomes regarding your discussions with the FDA on moving VOXZOGO into younger patients?

Salveen, I'll take the first question. So as we've described probably at length over the last six months or so, we have devised, in consultation with German payers, prior to the approval outcomes-based agreements, which basically cover payers' risk of failure to respond or failure to be durable through a multiyear period. We've previously advised that multiyear period, we're targeting 5 to 8 years spending on the payer in Europe. While we go through the federal process of reimbursement with GBA, during the free pricing period in Germany, we've determined that it would be favorable to treat patients early to negotiate outcomes-based agreements with individual payer groups in Germany that we think will look largely like the eventual federal outcomes-based agreements, in terms of the outcomes-based terms and also likely the discounts we negotiate. We think we're close with 2 of the 3 largest payer groups in Germany. We don't have ink on those agreements yet, but we think that we're close. And that will facilitate patients to be tested with our co-diagnostic in Germany and to go through liver function testing to be treated. It's worth noting that we've got some really important things done in Germany. JJ noted that our price was listed on September 15. That was an important step. Our tops organization has done an amazing job. We've got commercial label approved products sitting in a warehouse ready to ship; our commercial and medical teams have been doing site readiness work with the key treatment centers in Germany that we're targeting for first patients to be treated, and we're well on our way for site readiness. At least one site is 100% ready to go at this point. So we're poised and ready. We've got those outcomes-based agreements that need to just get signed up and we'll start moving patients in. So that's what the cadence looks like. I think you've seen some data from maybe another analyst that indicates patients that are in queue with these key treatment centers. We think that's true, and we're looking forward to letting those patients get moving in Q4, get treated.

To the second part of your question on VOXZOGO and regulatory interactions, just a reminder of the three large pharmaceutical markets engaged in VOXZOGO, the ages that we would be seeking for additional expansion are in the United States, with another two in Europe, because we already have the full range of ages approved in Japan. I think the key feedback that we've got and the key avenue to pursue is based on positive trends observed in growth. The safety profile has been characterized in a much larger population at this point now. And the recognition that treatment from birth in genetic conditions is of most immediate relevance, especially something like achondroplasia where you're talking about severe skeletal dysplasia, and it's not a process that's undone. And so getting in early is really important to families, as was illustrated quite nicely by JJ's comments about our first patient in Japan. So we think we have a pretty good strong package, and there's a pretty good basis for health authority acceptance of that package for review.

Our next question comes from Jessica Fye from JPMorgan.

Is it possible to give the VOXZOGO patient number at the end of Q3 broken down by U.S. and Rest of World? And within that strong revenue number you reported, how much of that VOXZOGO revenue represents demand versus maybe some initial products sent to new markets as they come online?

Jessica, I'll field that question. So we actually have not committed to breaking out geographically patient numbers. We committed to launch to provide global patient numbers. Last quarter, we did that as a way of enhancing the color commentary on the U.S. launch, which at that point was six months underway. But the cadence of patient growth is strong across markets, as we've noted.

Demand versus initial stocking.

Yes. So good observation. We've made the same observation. We sell into some important markets where there's distributors and where we think that there could be some forward demand that is put into stocking. Examples of markets that we've had significant orders for that fall into that category include Japan, Brazil, Russia, for example. So we do think there is some forward buying. It's a little difficult based on how dynamic the situation is to adequately characterize how much of those sales are forward buying and how much is responding to patient demand. But we've estimated in the revised guidance range for Q4 that probably looks like continued strong growth in patient numbers and a little bit of stocking of initial inventory. And sorry, I can't be more precise than that.

But again, we have pretty strong growth in the number of patients in Q3 over Q2, and that is going to continue in Q4 and next year.

And our next question comes from Geoff Meacham from Bank of America.

Just a follow-up on ROCTAVIAN. You have provided some insight into payer discussions in Germany, but do you anticipate that the larger countries will have significantly different outcomes-based agreements? I was curious if different payers utilize varied metrics for risk-benefit or cost-benefit evaluations. Additionally, when considering the AAV antibody profile, could you discuss how you characterize that and your expectations for ongoing monitoring as you continue to expand across Europe?

Geoff, I'll take the first part and maybe turn it over to Hank for the AAV5 antibody profile question. So in terms of the outcomes-based agreements, the details of those agreements, which are not really the main point in my view, the details can vary a lot. In terms of the terms, this is simple. So what we're covering in these agreements is a risk of failure to respond, which, by the way, in our clinical studies, we've not experienced a failure to respond to initial therapy. But that's a risk that we can cover. And a return to prophylaxis is the second piece during an agreed-upon time window, and that time window is proving to be variable by country. We're guaranteeing that the product will prevent patients from bleeding and returning to prophylaxis through an agreed-upon window of time, which is variable. The other piece that's variable, we think, is whether or not we get upfront payments or payments over time. Some other markets have fed back to us that they'd like to get in on a pay-over-time model compared to the upfront payment. Maybe I'll just briefly ask Brian to comment on his views on revenue recognition if that occurs.

I think if I heard your question correctly, it related to other peers in Germany, maybe and not just Europe. And in other peers in Germany, we are in a free pricing period right now, but in probably six to nine months from now, there will be a final federal German price and all the peers will be aligned on that price. So this question of the deals we're doing with some payers right now is related to the initial pricing, not the final pricing, which will be the same for all peers in Germany, we say by Q3 of next year.

Okay. Sorry if I misinterpreted your point. The question is, if that your perspective may vary from country to country.

I think we've said maybe in previous calls, for instance, in France, although two or three years ago, it seemed they were interested in just upfront payment and then outcome-based agreements. They feel interested in our agreement, but they want to pay over time instead of upfront. But at the end of the day, financial year, as Brian just going through, doesn't make much of a difference.

Yes, that's right. So while hearing over the last couple of years that systems weren't set up for pay over time and they were interested in pay upfront, as we get deeper into these actual OBA negotiations and exploration, it ends up that some countries in Europe are interested in paying over time. But importantly, under the U.S. GAAP revenue recognition rules, we would still recognize the entire ROCTAVIAN revenue upfront instead of over time. If the payments are over time, we'd be carrying that receivable, so there could be a cash flow element for those pay-over-time ROCTAVIAN customers. But importantly, revenue would be recognized upfront.

There was a question about the AAV antibody program.

You raised a point about ongoing monitoring. Geoff, could you clarify the question you were asking?

Again, please?

Yes, yes. And if not...

Perfect. Yes. Sorry, Hank, I recognize obviously AV testing is for the launch, but I'm just thinking about ongoing diagnostic obligations like Factor VIII, for example.

This is all basically standardized clinical assay commercial lab kind of stuff. As regards to AAV diagnostic testing for the companion diagnostic, and we do have a CE marked product that has conformed to the trials that we conducted, and it's going to be available in a commercial lab with a short turnaround time and a very simple report to study. In addition, we have ongoing work to study the population of patients who are AAV positive by this test to see if they are also amenable to ROCTAVIAN therapy, and that could be a potential label expansion. So time down the road if we can get it to work. But by and large, things like ALT monitoring and Factor VIII monitoring, etc., are really all just lab kinds of things.

Our next question comes from Chris Raymond from Piper Sandler.

A couple of questions. I guess, first on VOXZOGO and the decision to submit for marketing in this younger age group. Just I know you've described a dynamic in the past, Jeff, with the original labeling that favors faster uptake in Europe. Should we be expecting and modeling a similar dynamic with this age group, U.S. versus Europe? Or is there some other nuance?

Thanks for the question, Chris. I think that since we are talking about a label change, that will take effect 1.5 years to 2 years after launch. I would guide towards kind of incremental material, but incremental increase in market opportunity in existing markets. So in European markets, that's largely going to look like gaining access to the 0 to 2-year-old patient population, which is probably a 12% additional market opportunity. By the way, the initial experience in Japan, where we have a diagnostic label, has been pretty positive so far with very young patients. So if you might be considering, hey, are prescribers and parents going to be moving really slow in that age segment, we'll have to find out, but the early returns from Japan would suggest some uptake there. Then in the U.S., the 0 to 5-year-old age segment could expand the available opportunity by like 30%. So that could be a material increase to an existing patient base that's pretty large.

Yes, great. And then maybe a follow-up for Hank on the ROCTAVIAN AdCom, and this is maybe another question you can't answer, but we're being asked by folks. So excuse me, but do you have any indication if the agency is planning to want to hold this AdCom with or without the three-year data?

Don't have any indications.

And our next question comes from Matthew Harrison from Morgan Stanley.

Great. I have two questions. The first is about the dynamics in Europe for ROCTAVIAN. You've mentioned patients in the fourth quarter. Can you provide some insight into how prepared the system is to handle throughput in the fourth quarter compared to how much capacity could be utilized in the first half of '23, especially regarding any patients waiting? The second question relates to some of the pipeline candidates. Hank, could you provide a broad overview of the gene therapies currently in the clinic, specifically regarding dosing and the safety data available?

So safety data broadly on gene therapies in the clinic, not including ROCTAVIAN. I'd say, across all of them, infusion-associated reactions are the most common adverse events. They tend to be generally mild and moderate, or managed. There's a frequency of transaminitis post-dosing for all of them, but nothing particularly severe that has been observed. In general, when we put it into the clinic in humans, it's proved itself to be safe in humans.

Matt, I'll try to address your question about the dynamic European situation and the kind of cadence of patients in Q4 versus H1 2023. The first thing I'd say is really focused on Germany is the first place where we think we can get reimbursement through these outcomes-based agreements that we've talked at length about. We're on the cusp of having those. That's one of the two big last pieces that need to fall in place to treat patients commercially, the second being site readiness, which we're also either there or on the cusp with our target treatment sites. Once those two pieces are in, we start pushing patients through the system. And what I would say is with basically two months left to go in this quarter and the holidays, I'm more interested in proof of concept and ensuring that the system is ready to go and primed in Q4. Once we have that established, I think pushing additional patients through that system is a relatively small lift compared to what we've gotten to already in Germany.

And I would add, because it's a question we've had, because I think investors and analysts are more familiar with the U.S. healthcare market than the European. Once we have an agreement in place, and they should happen pretty soon now, there is zero impediment left regarding reimbursement of ROCTAVIAN. Like in the U.S., even when the product is approved and officially reimbursed, sometimes patients go through a lot of groups in terms of states going to make a necessity, and they try to slow these out. In a single-payer system, once the product is approved and approved for reimbursement, there are no impediments anymore. It’s based on patient demand and healthcare provider demand and our ability to supply it.

And our next question comes from Joseph Schwartz from SVB Securities.

I had a couple of questions about the steroids that may be used with ROCTAVIAN. It seems like the EMA recommended that physicians use them for a couple of months, which is much shorter than what was done in Phase III, where I think it averaged over 8 months and half of patients were still receiving immunosuppression at one year. So how should we interpret this difference? Is there any risk that this leads to subpar responses in the real world? And then could you talk about the steroid regimen or regimens that are being studied in Study 303? And what do you hope to learn here, given its relatively small size, short duration, and single-arm design? Are there any different scenarios coming out of Study 303 that you foresee playing out?

So the euro label reflects a sort of reasoned conclusion to comparison of the 20-something patients who were directly enrolled into the pivotal clinical trial. And they weren't prospectively filed. That's what separates them from the 112 patients that were subsequently enrolled after enrollment in the trial. When we conducted the interim analysis of the first 17 or 20 patients and saw Factor VIII activity levels that were lower than in the prior trial, investigators intensified their use of steroids with the belief that perhaps that transgene loss or losing activity could be recovered with additional services. We learned that more steroids aren't necessarily better; by just comparing the outcome of those two populations, both from the annualized bleeding rate and also Factor VIII levels that last two years. So when the Europeans looked at the inaugural data, they saw some as good, more is not necessarily better. And so they trimmed back to a regimen that's more like what is described in the label and what's calling for a shorter overall exposure to corticosteroids, principally by virtue of less maintenance as opposed to tapering. We expect the real-world version of this to be actually similar to the trial world because heavy steroids don't make a difference in outcomes, lightening on the steroids will be better for patients than more facilitation. Now shifting gears, we said, okay, well, there still is this difference between the Phase I outcome and the Phase III outcome as regards to maximum Factor VIII activity, and we'd like to understand that a little bit better and see if we started corticosteroids as early as we started them in the prior trial before the concept would be before the transaminitis has begun. With those patients have higher Factor VIII activity levels and would they have a lower overall steroid use because you'd be ahead of it. That trial can fully enroll data that is going to read out in the first quarter of next year. The valuations that health authorities undertaken is exemplified by Europe is that on this application with the information that's in our hand, we have to come to a conclusion on the balance of benefits and risks on the available uncertainties, and the European Commission came to a positive benefit in the absence of the 303 data. The FDA has now accepted our application in the absence of the 303 data, the net number for the corticosteroid study. So I think what we hope to learn out of that, what we've got is good and maybe even a little bit better than where we would have ended if we'd only done a heavy steroid version because I think we do believe we are able to substantially lighten up on steroids closure.

And our next question comes from Gena Wang from Barclays.

I have two on ROCTAVIAN. For the U.S., just wondering, do you plan to submit to the FDA additional genomic analysis data from the leukemia case? And also for AdCom, since the PDUFA date is March 31, 2023, do you expect that there's going to be some time for an AdCom in the January-February timeframe? And for EU monitoring tests, just wondering, do you have any feedback from the doctors regarding those monitoring tests? It seems like it's pretty lengthy, like initially it will be weekly for first 26 weeks and then it will be every 4 weeks for the next 26 weeks. Any feedback from the doctor regarding this testing?

First in whole genome sequence, if we haven't submitted it already, it's going to be submitted. And I don't think that that's going to really create much of a surprise one way or the other for the health authority. As regards to AdCom timing, I mean, it would be entirely speculative to offer when I thought the AdCom was going to be and what they might be looking for. So that would be useless to do. And then maybe I'll say something about the monitoring, and Jeff can say something about it if he wants. Obviously, everybody would love to follow up and go away. This is a point that's simple. But at the same time, because most of the labs are fairly routine types of labs, we should be able to put some systems in place to help patients access laboratory testing. And it gets tapered as the patients get it further out. The docs' perception of all that, especially in Germany, is they got it. This is a lower stuff to do. And they're like part of the deal for that. Because you step back from that, net of all that screening people and counseling people and whatnot, they have an amazing life after they got their transit. Big picture-wise, I think people are very much willing to put up with the short-term castle.

Just to elaborate, we're going to make it as easy as possible for the patients to have this monitoring done. We already have some contracts with home care suppliers. So Jeff, you could explain?

Yes. Thank you, Gena. Good observation on monitoring. Hank said, everybody's interested in a monitoring schedule that is as modest as possible, but while maintaining appropriate safety and monitoring of those patients. So we've extensively researched this as an issue. As Hank said, these tests are routinely available; that's not much of an issue. We have programs in place to help make testing convenient for patients. Examples would be patients can't get routinely to a lab for blood draws. We have programs in place in Germany. We will in the United States also to help facilitate testing that essentially comes to the home or even to the workplace to facilitate convenience. And we think that there's not much more to it than that beyond influencing the buying decision. We think that the benefits on that buying decision are very powerful regarding costs associated with monitoring. So I think we're in good shape.

Definitely lighter than what we faced in week one hour to cut Factor VIII.

Our next question comes from Paul Matteis from Stifel.

I wanted to just clarify two quick things. On the ROCTAVIAN price in Europe, can you just give a little bit more color about what exactly changed over the past, say, six weeks between when you talked about EUR 1.5 million per treatment and now EUR 1.25 million? And how confident are you that as you go past Germany you're going to be able to hold the price in other countries like you have with other products in your portfolio? And then just on the ROCTAVIAN review, just a quick question for Hank. I was wondering how you and the BioMarin management team are viewing the FDA decision on the CSL UniQure heme B gene therapy at the end of November? And what read-throughs you see on ROCTAVIAN and where there are limitations there?

Paul, I'm going to take a shot at the question on pricing, which is confidential, and we have not yet finalized these agreements, as you can tell. But in general, what happened is we determined that the payers we are negotiating with were requesting additional discounts in addition to the 7% mandatory that all of our sales in Germany need to be rebated back to the German healthcare system, and in addition to our obligations under the outcomes-based agreement, we had previously modeled and expected the GBA to be demanding those discounts. So as noted in the prepared remarks, where we think we're winding up is net-net, a little less than EUR 1.5 million, and probably very close to where we'll wind up with the GBA with final federal pricing. Now the pricing in Germany is usually a benchmark for the rest of Europe. And aside from certain named patient sales arrangements, usually, Germany is the high watermark for pricing in European markets. So one of the reasons it's important to get that German price established and out in the public domain when we get that far.

So that's a very important point, is the fact that basically what we're negotiating now is the final price or close to the final price we anticipate to have in Germany after the initial pricing. That's the difference.

On the hemophilia B application that's pending before the agency with the PDUFA date coming up shortly, I would say, let's talk about two scenarios. If they're approved, it speaks favorably. If they're not, we have to see what the basis of their not being approved was in terms of what it could read in terms of ROCTAVIAN. Oftentimes, these are very product-specific considerations. There may not be any read-through or the read-through may be covered by things that we've already done.

Our next question comes from Debjit Chattopadhyay from Guggenheim Partners.

On ROCTAVIAN, how confident is the company expanding, I'm sorry, on ROCTAVIAN, how confident is the company in expanding VOXZOGO to younger patients? And incrementally, how many patients will this add to the tribal population?

Operator, maybe we'll go to the next question, and we'll try to get the caller back.

Our next question comes from Olivia Brayer from Cantor Fitzgerald.

I want to follow up on ROCTAVIAN. You guys have been pretty transparent around the likelihood for a three-month PDUFA extension. So can you give us a sense for what else you plan to submit between now and March? I assume it will include the year data, but anything else you guys can give us color on? And as for the European launch, any sense for the number of patients in some of those initial countries like Germany, the waiting and ready to get treated once those payer agreements are in place?

In terms of ongoing back and forth with the FDA, they can't file an application and look to be complete and sufficient to address the review. So we don't anticipate anything specifically because they haven't asked for anything specifically because they wouldn't have filed the allocation if they still have pending requests of that means. During the course of the review, they can ask for what are called information requests all the time, and we don't get comments on the information requests that are going back and forth. There's oftentimes a variety of different types of questions that come up during the review, and it would be possible to share all of that. The main encouraging thing is that, as I said, we dropped seven vessels worth of data on them, and they made their filing decision pretty quickly. So we're encouraged by that.

On the other question, Olivia, regarding numbers of patients that might see in queue, between our market research and some of the other surveys that you may have seen from other analysts, there's certainly a signal that there are early adopters that are interested in treatment with ROCTAVIAN. We don't have the same ability in Europe due to GDPR to get patient-specific data like we do in the United States. So our numbers are a little rounded. Regarding our initial treatment centers, we think that there are certainly double-digit patients that could be early adopters in the first few months following reimbursement approval that we could be pushing through the system. That doesn't count the second wave of intended treatment centers, and as we've spoken about previously, in the hub-and-spoke model we anticipate for Germany and other European markets. Those centers, which would be characterized as bespoke centers have patients that would be pushing into treatment centers. So the very tip of the spear, let's call it, low-ish double digits, probably more when we get beyond to the next layer of treatment centers.

I want to clarify that there was a question asked by someone who may not have the complete information. The net price in Germany is expected to be $1.25 million, but that is not what we initially stated. The figure mentioned seems to be a speculation from the questioner. We believe the final price will likely be under $1.5 million, but we have not confirmed it to be $1.25 million. As we've mentioned, we are still working towards determining the final price for ROCTAVIAN, which we expect to be a significant amount.

At this time, there are no further questions. I would like to turn the call back over to Chairman and CEO, JJ Bienaime, for closing remarks.

Well, thank you, operator, and thank you all for joining us today. Our record year-to-date results underscore the strength of our brands and execution across the organization. As anticipated, the addition of VOXZOGO to our commercial portfolio is an important component of our growth story and paves the way for our transition to sustainable GAAP profitability for this year and beyond. We look forward to the European launch of ROCTAVIAN this quarter and the potential approval in 2023. Combined, we believe VOXZOGO and ROCTAVIAN will drive substantial value for our patients, our employees, and our shareholders. Thank you all for your continued support. We look forward to seeing you soon.

This concludes today's conference call. Thank you for attending.