Welcome to the BioMarin fourth quarter 2021 financial results conference call. Hosting the conference call today from BioMarin is Traci McCarty, Vice President of Investor Relations. Please go ahead, Traci.
Thank you, operator. Thank you all 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 authority, 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 Form 10-Q, 10-K, and 8-K reports. On the call today from BioMarin's management team are Jean-Jacques Bienaimé, Chairman and Chief Executive Officer, Jeff Ajer, Executive Vice President, Chief Commercial Officer, Henry Fuchs, President, Worldwide Research and Development, Greg Guyer, 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, Jean-Jacques Bienaimé.
Thank you, Traci, and good afternoon, everyone. Thank you for joining us on today's call. I'm very pleased with our performance and progress in 2021 and also pleased to share our outlook for the year ahead for 2022. Last year we laid the foundation for our transition to sustainable GAAP profitability beginning in 2022. The addition of our seventh commercial product, VOXZOGO, is expected to drive a meaningful step-up in revenues beginning this year, as indicated in the increase in full year 2022 VOXZOGO revenue guidance announced today. $2.1 billion or 14% growth year-over-year represents the midpoint of our 2022 full year guidance, and demonstrates in terms of revenues and demonstrates the return to significant double-digit sales growth for BioMarin.
It is important to note that our anticipated top line growth in 2022 is expected despite the reduction in Kuvan contribution since the loss of exclusivity in the United States in late 2020. This further underscores the strength of our base business and the opportunity that lies ahead with VOXZOGO, especially considering how early we are in the global launch. Jeff will provide, you know, more details on the launch in a moment. Also, I guess you noticed in our release that we generated $5.8 million in Q4 for VOXZOGO. That was the first quarter that the product was on the market, mainly in Europe. And the vast majority of the sales were in Europe, and that does show that once you have the right products, European launches can go up, take off pretty fast.
Beyond the strength of our financial outlook and the robust launch of VOXZOGO, the recent two-year update from our pivotal study with Roctavian provided further evidence of the transformational nature of gene therapy treatment for people with severe hemophilia A. The results from our 134-subject study that we shared in January demonstrated durable, consistent bleeding control with annualized bleeding rates reduced by 85% and with 95% of participants remaining off Factor VIII prophylactic therapy through two years. To those people with severe hemophilia A seeking bleeding control that is superior to standard of care prophylaxis, we believe Roctavian represents a very attractive treatment option.
Based on the results observed in our phase II and phase III study, we believe that this data will provide supportive evidence of efficacy as part of the review currently underway in Europe, as well as the BLA we intend to resubmit in the U.S. in June. To summarize, we have set the stage for transformational growth for the company and the people we seek to treat. In 2022, we expect to turn the corner to sustainable GAAP profitability, ramp up our largest pediatric opportunity to date with VOXZOGO, advance our applications to Europe and the United States with Roctavian, and progress and continue the progress of the broadest early stage pipeline in the history of BioMarin. The financial, commercial, and regulatory momentum at BioMarin has never been stronger, and we want to thank you for your continued support throughout our foundation-building journey.
I especially want to thank our BioMarin colleagues for their continued commitment to developing the essential medicines that help so many. We'll now turn the call over to Jeff to discuss the commercial business update. Jeff?
Thank you, JJ. I am pleased with the team's performance across all brands and regions during 2021, and I'm very excited about our outlook for 2022. As noted in today's press release, 2021 VOXZOGO revenues were $5.9 million and today we increased VOXZOGO 2022 full year guidance to between $90 million and $115 million based on strong prescription demand seen so far this year. We continue to believe that VOXZOGO represents our largest brand to date.
As JJ already noted, the underlying demand for our products is expected to drive double-digit sales growth this year, with VOXZOGO being an important contributor to the growth story. On that note, and starting with the VOXZOGO launch, we are pleased to share that by February 15, 2022, or midway through Q1, an estimated 210 children were being treated with commercial VOXZOGO across 10 active markets with an estimated additional 54 children in process in the United States. The active markets include Germany, France, the U.S., Switzerland, Austria, Israel, Singapore, Argentina, Luxembourg, and Chile. In Europe, we have been fortunate to have access to the two largest markets, Germany and France. This has resulted in rapid uptake early in the European launch, which we expect will continue through 2022.
As noted in the list of active markets, we are also seeing uptake in smaller individual countries, which collectively will contribute to meaningful revenue uptake also this year. We are pursuing reimbursement in other material European markets such as Italy and Spain, and expect that it will take time to reach price and reimbursement approvals in these markets. Outside of the EU, Russia and Middle East markets are also expected to come online this year. In the U.S., we have the ability to quickly respond to prescription demand following approval. While U.S. payers are numerous and diverse, we have been successfully navigating the medical exception process to facilitate access to commercial VOXZOGO. We have seen the first coverage policies being published by U.S. payers, the details of which are consistent with our expectations.
As expected, we are seeing prescriptions mainly from geneticists and pediatric endocrinologists, which is a new and targeted call point for VOXZOGO. In summary, we're very pleased with the pace of uptake during this ramp year for VOXZOGO. Launching in the EMEA region ahead of the United States was a first for BioMarin, and our experienced commercial teams are managing the dual launches as planned. We look forward to registrations in Japan and Australia later this year as these markets are expected to generate a high level of demand for VOXZOGO. Turning now to our enzyme replacement therapy brands, Vimizim, Naglazyme, and Brineura, we were pleased to have achieved 8% growth year-over-year in 2021 for these brands in total.
Starting with Vimizim, revenues in 2021 were robust as expected, and benefited from additional Q4 ordering to end the year at $623 million or 14% growth year-over-year. As mentioned with Naglazyme, 2021 year-over-year results were impacted by the timing of large orders from Latin America in 2020. We remain encouraged by high compliance rates and year-over-year patient growth of approximately 5% and 1% for Vimizim and Naglazyme, respectively. For Brineura, 16% revenue growth year-over-year and sales of $128 million represents continued growth in North America and the EMEA regions principally. Children on Brineura therapy increased by approximately 18% year-over-year. Moving now to Palynziq.
Net product revenues grew 39% in 2021 as compared to 2020, and reached $238 million for the full year. Sales were driven in the U.S. by a combination of new patient initiations and patients achieving maintenance dosing. Patients on therapy increased approximately 15% in 2021 as compared to 2020. We are seeing the majority of growth from the U.S. market, which continues to be impacted by reduced PKU clinic bandwidth due to the pandemic. Continuing with the PKU franchise, Kuvan contributed $286 million in revenues in 2021, reflecting incremental erosion to generics. Revenues decreased by 38% year over year compared to full year 2020, primarily due to the U.S. loss of market exclusivity in October 2020.
We continue to expect a material contribution from Kuvan in 2022, as noted in our full year guidance. Lastly, with the CHMP opinion on Roctavian expected in the second quarter, 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 an attractive value proposition and treatment option for those with severe hemophilia A. 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. Our ERT products are expected to contribute significantly to revenue growth this year. We also expect our newest brand, VOXZOGO, to be a meaningful factor in this ramp year.
The global launch is on a strong trajectory, and while it is early days, we believe the robust early prescription demand represents the foundation for continued growth, including in new markets through 2022. The commercial team is energized to be in global launch mode with VOXZOGO, our largest potential revenue opportunity to date, and we look forward to keeping you apprised of our progress over the year. Thank you for your attention, and I will now turn the call over to Hank to provide an R&D update. Hank?
Thanks, Jeff. The R&D organization echoes your enthusiasm and appreciates all the hard work of the commercial team making available the first and only treatment option for children with achondroplasia
Following VOXZOGO approvals in Europe and in the United States last year, as well as other territories. Based on the targeted mechanism of VOXZOGO, which promotes endochondral bone growth while growth plates are open, treatment can have a meaningful and lifelong impact on children with achondroplasia. For families in Europe seeking treatment, we're very pleased that health authorities approved VOXZOGO for children ages two and up, underscoring the importance of beginning treatment as early as possible to provide maximum benefit. Today, we provided a top-line update from the phase II randomized double-blind placebo-controlled VOXZOGO study in infants and young children up to five years of age with achondroplasia. We are encouraged to share that 52 weeks results trended in favor of VOXZOGO compared to placebo on height Z-score, annualized growth velocity, and no worsening of proportionality in the overall study population.
This is a relatively small phase II study when one considers the high variability between age cohorts. Regarding the safety profile, it was generally consistent with older subjects from the phase III VOXZOGO 301 study in currently labeled populations. Serious adverse events were higher in the placebo group, 18%, compared to VOXZOGO-treated children at 7%. All serious adverse events, including a fatal event of sudden infant death syndrome in the treatment group, were deemed by investigators to be unrelated to treatment. A small increase in events of sleep apnea were reported in the treatment group that were mild or moderate in severity and did not require treatment discontinuation. These events will be fully assessed when sleep study and MRI data are available.
Our next step is to engage with regulatory authorities to discuss next steps regarding efforts to expand access to VOXZOGO treatment for this younger age group. We plan to share more detailed results at a medical meeting as we received these data less than 24 hours ago, so please stay tuned. Briefly on Roctavian, as JJ said, 2022 regulatory milestones are tracking to plan. CHMP opinion is expected in the second quarter, and resubmission of the biologics license application is planned for this June. This resubmission will be followed by an expected 6-month review procedure should the resubmission satisfy the Food and Drug Administration's thresholds and appreciating that there has been inconsistent communication in this field with this novel platform.
Based on the dramatic reductions in bleeding rates, factor utilization, and factor infusion rates at year two following treatment with Roctavian as shared in January and again at EHA earlier in February, we remain confident in Roctavian's potential to be an important treatment option for those with severe hemophilia A. Turning now to BMN 307, gene therapy for phenylketonuria. As we announced last week, the FDA has requested data from additional new non-clinical studies to assess oncogenic risk to human participants, which is expected to take several quarters or more. As a reminder, the hold was based on safety findings from a non-clinical non-GLP pharmacology study in immunodeficient mice. As we said when we announced the clinical hold, and what holds true today, the scientists striving to serve patient needs, we remain committed to understanding these findings.
We are in the process of collaborating with the FDA on specific next steps, and we'll provide you with an update when we have meaningful information to share. Finally, turning to the earliest stage pipeline at R&D Day last November, we were very pleased to have shared a detailed overview of the many products currently under development. We have a number of candidates advancing this year, including BMN 331, gene therapy for hereditary angioedema. That trial is currently open for enrollment. With BMN 351 for Duchenne muscular dystrophy, we expect to file the IND in the first half of this year with a goal of treating the first Duchenne boys in the fourth quarter of this year.
We also hope to advance studies following dose selection with BMN 255, which addresses the subset of chronic renal disease in the second half of the year. We look forward to keeping you apprised of our progress across the R&D organization throughout the year. Thanks for your support, and I'll now turn the call over to Brian to update on 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 fourth quarter and full year 2021. 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 our 2022 guidance. As usual, all results will be available in our upcoming Form 10-K, which we are on track to file over the next few days. At the beginning of last year, we referred to 2021 as a quote-unquote "hold the line" year for our financial performance, meaning that our goal was to navigate a handful of revenue growth headwinds with expense control and a focus on operating performance. We are pleased to have accomplished that objective.
Despite 2021 revenue dynamics that included a decrease in Kuvan revenues of $172 million year over year, total revenues were essentially flat in 2021 as compared to 2020. Modest 2021 expense growth resulted in a full-year GAAP net loss of $64 million, landing at the midpoint of our guidance and full-year non-GAAP income of $243 million within the top half of our guidance. BioMarin's strong operating performance in 2021 also translated into substantial cash flow through the year. Total cash and investments grew by $171 million in 2021, finishing the year with over $1.5 billion, fueled by over $300 million of positive cash flow from operations.
Contributing to those bottom-line results were operating expenses that fell in line with our expectations for the fourth quarter and full year 2021 and were mostly consistent with 2020 levels. R&D expenses for the fourth quarter and full year 2021 were $161 million and $629 million, respectively. SG&A expenses for the fourth quarter and full year 2021 were $218 million and $759 million, respectively. SG&A expenses increased in the fourth quarter of 2021 as compared to last year, mostly due to the global launch of VOXZOGO and some year-over-year increases in administrative costs.
Now moving to 2022 guidance. As noted by JJ, the expected continued strong growth of our base business, plus a significant contribution from VOXZOGO in its launch year, we expect total revenues in 2022 of between $2.05 billion and $2.15 billion, which at the midpoint represents 14% growth over 2020. Within that revenue guidance, we observe that our base business marketed brands, except for Kuvan, are growing by 13% year-over-year at the midpoint. As Jeff highlighted, we're pleased to improve our 2022 VOXZOGO total revenue guidance from the preliminary guidance that we shared earlier in the year based on our observations of the VOXZOGO launch these first two months of 2022.
Lastly, regarding revenues, given the estimated timing of Roctavian approvals and launches in the second half of 2022, we anticipate that Roctavian will be a modest contributor to 2022 revenues. Moving to our expectations for expenses and bottom line in 2022. Consistent with our plans to increase leverage from the operational foundations built in recent years, our estimated increases to SG&A and R&D expenses in 2022 are at rates significantly lower than our expected revenue growth. Importantly, as we recognize the importance of fueling our innovation into the future, R&D expenses are increasing at a rate higher than SG&A expenses. This measured growth in expenses is a key component to our transitional GAAP profitability objectives for 2022, where we estimate earning GAAP net income of between $95 million and $135 million.
Noteworthy is that our GAAP profitability expectations for 2022 are expected to benefit from, but are not dependent upon, the after-tax gain from the expected sale of our recently obtained priority review voucher announced earlier this month. With respect to non-GAAP income, we plan to adjust out the gain on the expected sale of the PRV. As further illustration of our journey into P&L leverage in 2022, we expect non-GAAP income for the year of between $350 million-$390 million, which at the midpoint is over 50% growth as compared to 2021.
In closing, while 2022 is expected to be a transitional year into our long-term strategy, we are pleased to see our longtime goals for BioMarin start to materialize, which include building an enterprise that can support both continued product approval and innovative pipeline growth, while at the same time generating sustainably increasing profits and positive operating cash flow. We believe that the strength of our base business, the recent approvals and launches of VOXZOGO, and the commercial prospects of Roctavian after observing the two-year phase III data represent three strong pillars of near-term growth. These are followed by the increasing number of opportunities in our early-stage pipeline that have the opportunity to drive BioMarin's growth further into the decade. Thank you for your attention, and we'll now open the call to your questions. Operator?
As a reminder, to ask a question, you will need to press star one on your telephone. To withdraw a question, press the pound key. Please stand by while we compile a Q&A roster. For the first question, we have Salveen Richter of Goldman Sachs. Your line is open.
Good afternoon. Thanks for taking my questions. One on VOXZOGO. How are you progressing with expansion to the dedicated achondroplasia centers versus the initial targeting of skeletal dysplasia or geneticists? Secondly, on the clinical hold that's playing out with the PKU program, could you just talk about what exactly the FDA is requesting and whether there is something about PKU itself that makes it, you know, more of a concern or less amenable to gene therapy?
Hi, Salveen. I'll take the first question on VOXZOGO. What we've experienced so far, which is consistent with our expectations, are that some, a portion, a minority of achondroplasia children are being seen and followed by geneticists, including in skeletal dysplasia clinics. This is a prescriber base that we have very good relationships with that are established. What we think is that, and our experience has been that that gives us kind of quick access to that group of patients based on our existing relationships. What we also think is that because the majority of achondroplasia patients, particularly in the United States, are not being actively managed by that prescriber audience, we think that driving to a new treatment home with pediatric endocrinology or endocrinologists is an appropriate strategy.
Pediatric endocrinologists being both the growth disorder specialists and also having capacity that we don't currently see in genetics clinics. Our early experience has been a lot of children in the United States referred in by geneticists and skeletal dysplasia clinics. That's great. And other children getting into a referral network and being seen by what is a new call point for BioMarin, but a very interested and engaged new call point, and that is a relatively small number of pediatric endocrinologists that specialize in growth disorders and are proving to be very interested in treating achondroplasia and prescribing VOXZOGO. Good news and good progress on both of those fronts.
On the second part of your question, Salveen, it's a little bit hard to say exactly what the FDA is looking for insofar as we only just received their letter. It appears that while we satisfied some of their concerns, they appear to be looking for more direct evidence of the mechanism of the underlying cancer causation, and therefore they've asked for these additional preclinical experiments and we'll provide updates when we have more specific updates to provide. As to the role of, you know, PKU in this consideration in general, I think the only thing I can say there is the agency has made no secret of commenting that they consider gene therapy approaches for conditions for which there is available therapy, different from conditions for which there isn't available therapy.
Exactly how that fits into their overall decision making is not crystal clear to us at this point.
I mean, Hank, you might wanna comment also on the fact that, you know, gene therapy for PKU would be for adults only and adult PKU is, there's less of a, you know, need for treatment in some parts of the world than pediatric PKU.
Yeah. Putting this in a positive way, I mean, I think the burden of illness is really quite substantial for children with hyperphenylalaninemia. For adults with hyperphenylalaninemia, there's less compelling evidence of effectiveness of the products. All that said, I think it's hard to dial in exactly how much PKU as a therapeutic indication is contributing to the agency's conservatism around the 307 findings.
Thank you.
Thank you. For the next question, we have Cory Kasimov of J.P. Morgan. Your line is open.
Hey, good afternoon, guys. Thanks for taking the question. Hank, I was hoping you could provide some more details on the VOXZOGO data in the zero-five-year-olds. I'm curious, was this powered for statistical significance and then intended to be a registrational phase II, or was it too small for that? On the safety front, it's nice to see overall adverse events lower than placebo, but can you just address the sleep apnea and single case of SIDS to just kind of any description or color around that'd be helpful. Thank you.
Yeah. You know, we're obviously hoping to get an amazingly great signal out of the 206 study, and we're very encouraged that in fact, we did see trends. The key lesson learned out of all this was that these different age ranges are a little bit more complicated in regard to both signal and noise. You know, we just got these data. We need to dig into it a little further to generate some hypotheses about why we didn't get a gigantic signal of effectiveness. I'd say on that score, stay tuned. I mean, we are encouraged by the safety, insofar as very low rates of hypotension that was clinically significant, consistent with the older population.
In the older population, by the way, we did not see a meaningful imbalance of sleep apnea. We're reporting this now because these were adverse events that were reported to us, even though we haven't had a chance to fully dig into laboratory or MRI evidence of what's going on for these children in the main. As I said, and I apologize, I might have said it really fast, that the events of sleep apnea that occurred were mild to moderate in severity, were deemed unrelated by the investigators. A large part of that has to do with the fact that sleep apnea is not an uncommon occurrence in this patient population. As I mentioned, even in the older population, there's a little bit of sleep apnea that's been recorded.
Whether this is really drug related or it's just a bad luck signal, we're gonna need to get more information. The good news about it so far is, like I said, mild to moderate didn't result in discontinuation deemed unrelated by investigators.
Okay. Thank you.
Then the child with the sudden death is a child who again the event was deemed unrelated by the investigators. You know, these children, you know, the standardized mortality rate for children with achondroplasia is like 50 times that of an unaffected child. These events will happen unfortunately in children. I guess at a minimum you conclude that VOXZOGO didn't rescue this child. You know, we'll have to look at the overall pattern of safety that we saw in the trial with a lot more detailed laboratory evidence still yet to come.
That's helpful. Thank you, Hank.
Your next question is from Chris Raymond. Piper Sandler, your line is open.
Hi, this is Allison Bratzel for Chris today. Thanks for taking our question. So just on VOXZOGO, could you talk about your expectation for the geographic patient split that's embedded in your 2022 guidance? I think just by our math on VOXZOGO patient numbers, if you include those 54 U.S. patients in process, the split right now is around 20% U.S., 80% rest of world. So should we expect that split to hold up for the full year? Related, I know you've talked about Japan actually being a more important country for you with the VOXZOGO launch.
Could you sort of talk about what's driving your optimism on the VOXZOGO opportunity there, and just how you expect launch dynamics there to play out compared to the U.S. and EU? Thanks.
Okay. Good question. The Q4 revenue that we reported was predominantly from ex-U.S., as you would expect, because we got a U.S. approval late in Q4, whereas we were able to start patients in Q4 in Europe and start driving that revenue. As we begin the year, we're off to a quick start in the United States. We're also off to a quick start in Germany and France, which are the two largest markets in Europe. We've got smaller contributions coming now from a number of smaller countries outside of the United States. As you noted, we are expecting an approval in Japan around mid-year. The picture is gonna be pretty diverse. I'm not gonna help you sort out the specifics of geographic mix.
I am going to point you back to our revenue guidance for the year starting out this year. Relative to Japan specifically, Japan is depending on how you measure it, either the second or the third largest pharmaceutical market in the world, and a market where BioMarin has long invested in having capabilities to operate on our own. It happens that with the rare disease portfolio that we have, we haven't had the right opportunity to have a brand that would be representative of the second or third largest market in the world. That picture is about to change with VOXZOGO, where we have relatively uniform incidence and prevalence of achondroplasia, which means that Japan is a large market. Japan is a large market with a large population.
We expect a large population of achondroplasia kids. We know that Japan is developed already for achondroplasia, the only place in the world where growth hormone is approved for the treatment of achondroplasia. I think the prevailing opinion there would be pretty straight from prescribers that growth hormone is not particularly effective, if at all. There's a lot of excitement, including from clinical investigators in Japan, about VOXZOGO. That's what's driving our enthusiasm about Japanese opportunities.
I mean, but yeah, I think you're right. I mean, we before the launch, we emphasized the fact that the ex-U.S. market was significantly larger than the U.S. market by 80/20, even 85/15. It's very likely that, you know, over time, the Europeans, the ex-U.S. sales are gonna be greater than the U.S. sales. Also, the U.S., you know, as Jeff said, we only got approval in the U.S. in very late 2021. Obviously the Europeans had almost like a four-year head start over the U.S. But that being said, the demand and the enthusiasm by the U.S. patient community for VOXZOGO treatment is very good. Definitely similar to the U.S., to ex-U.S.
Got it. Thank you.
Your next question is from Phil Nadeau of TD Cowen. Your line is open.
Good afternoon, thanks for taking our questions. A couple on Roctavian. First, you had been guiding to an FDA meeting during the first quarter of this year, pre-submission meeting. Any update on the status of that meeting, whether it's happened or what's likely to be discussed? Second, in the recent presentation of the updated phase I/II data for Roctavian, there was a disclosure of one salivary gland cancer that was deemed unrelated to Roctavian. We're curious to hear more about that case, how long after dosing, and any other information around that patient that you have would be interesting. Thanks.
Yeah, thanks, Phil, for the questions. As far as the, you know, status of individual interactions with the FDA, you know, given the ongoing nature of our regulatory interactions, we plan to update you only at the major milestones of submission of the file by us and then, of course, FDA's action date. I mean, I think at this point, given the history of inconsistent communications from the agency, I think it would be unwise to provide interim updates, because those are so much subject to interpretation and potential misinterpretation. If you can bear with us, we're gonna just stick to the basic facts of the U.S. review of submission and U.S. action.
As far as the scientific report at EHA of the individual patient, again, this was an individual who had a serious adverse event, the occurrence of cancer in the context of a clinical trial, but was deemed by the investigator as unrelated. We actually undertook an internal review that was really quite extensive in regard to the case, partly because we have a lot more information from preclinical and other sources about potential safety considerations. We also discussed this case with our independent data monitoring committee and concluded that out of an abundance of caution and not due to any particular regulatory requirements, we would go ahead and convey our understanding of the case when it occurred, which was, I think, in late November, early December, that we communicated with the agencies.
Since then, they've been, you know, fully aware of the case. To remind you, this is an individual who was dosed more than 5 years ago and has an isolated salivary gland cancer. You know, we plan to undertake genomic analysis of the tumor. For all of us in this field, we're gonna expect that cancers are gonna be observed in individual patients. By protocol, where possible, we collect tumoral data to try to understand if there is any relationship at a molecular level between the occurrence of the cancer and the presence of the virus of Roctavian. That analysis concluded. When that analysis is concluded, we'll share that information in a scientific context.
Again, this appears to be an unrelated adverse event that is in an individual that's dosed five years ago and has been under a lot of review by the investigator, by our independent data monitoring committee, by us, and by health authorities around the world. The important point at this point is Roctavian trials continue to be open for enrollment.
That's very helpful. Thanks for all the color.
Yep.
Your next question is from Geoff Meacham of Bank of America. Your line is open.
Hey, guys. Thanks for the question. Just had a couple on Roctavian. I know, Hank, you obviously don't wanna give a play-by-play, but just to be clear, are there any other, you know, ongoing, say, you know, CMC or preclinical or any other parts of the filing that, you know, that will be new beyond the second, you know, phase III and the two-year data? And then the second question, more commercially, I know in the past you guys have talked about, you know, COVID still being a bit of a headwind in PKU clinics. How is that progressing? Do you still see that, you know, having a bit of a lingering effect in 2022 or is that gonna generally work itself out as we move to the middle part of the year? Thank you.
I'll start with the first part. You know, the thing I can say, Jeff, about the submission play in the United States, again, getting into the blow by blow, what's above, what's between the blow by blow, and we're gonna update you at submission and the FDA review. There's maybe not a whole lot in there. What I can say is, since it's practically March, we're targeting a submission in June. That doesn't leave a lot of time for a whole lot of new studies to be assembled and digested.
I think we feel, you know, especially with the two-year efficacy update, that we've really got the evidence that we believe would support a positive benefit risk conclusion, and we'll be providing that to the agency, you know, in the first half of this year if all goes well. Greg, you wanna talk about CMC and inspections done already by
Yeah. The only thing that we would be looking at from a U.S. standpoint is that we would be expecting an inspection later this year after the filing and before the six-month time period has ended. That'd be probably in the third or early fourth quarter. We're prepared for that. In terms of CMC, as Hank said, the majority of the refile will be clinical. There's some minor things, but nothing of significance from a CMC perspective that we'll be including in the file.
You remember that we were inspected by the EU.
Yeah. That facility has been inspected by Europe. As you know, we're in the midst of that review right now. There's no re-inspection necessary for Europe, so that's not an additional step for approval there. But it will be a step for the U.S. since they have not inspected that facility yet.
Maybe moving over to the question about the pandemic impact on PKU. If you look at the Palynziq results for 2021, on the one hand, we're really pleased with the growth in revenue, and we have experienced growth of patients on therapy. On the other hand, that growth of patients on therapy is slower than it otherwise would have been, but for the impact of the pandemic on PKU clinic capacity. I think that earlier on, we were expecting as the pandemic moved from some acute phase to post-acute phase, that we would see further opening of PKU clinics. As you know, the pandemic has behaved as it has, and we have been disappointed that we haven't seen PKU clinics open back up, as much as we had hoped for the treatment of adults with PKU.
Some of that is due to the fact that these genetics clinics, PKU clinics, more specifically, tend to be located in tertiary medical centers and major metropolitan areas, and those facilities have been impacted by the pandemic. Another part of it, probably is that for the clinic bandwidth that does exist, the geneticists see desperately ill, children, and it's likely that, PKU adults that require some attention to start Palynziq are not at the top of the priority list. Having said that, we do expect continued patient growth, and we are taking tactical measures to try to address the, bottlenecks in the PKU clinics and help out where we can with tactics to help adult patients, more adult patients get started on therapy.
That being said, you know, so we reported, you know, revenues for Palynziq in 2021 of $237.5 million, and our guidance for 2022 is $280 million-$310 million. We do anticipate some, still some pretty significant growth here in 2022.
Thanks, guys.
Your next question is from Gena Wang of Barclays. Your line is open.
Thank you for taking my questions. I have one regarding Roctavian safety data. For the PKU program that FDA asked you to do, the preclinical studies, do you have the same data package for hemophilia A? The second related question is, what is the latest human biopsy data regarding the AAV integration analysis, from current patients. Like what is the longest on drug, you know, the data you have from these patients?
Very complicated question. Let's see if I can help there. You know, as regards to the Roctavian and preclinical data package and its similarity of what the FDA is asking for from BMN 307, since we just got the clinical hold letter from the FDA on BMN 307, and they've requested additional studies, but they haven't specified additional studies, and as I mentioned, we're gonna be working with them to try to understand what those additional studies will likely be. It would be impossible to compare and contrast the, what's been asked for on BMN 307 with what's available already for BMN 270.
I think that a clear picture can be arrived at from just saying that whatever they're asking for for BMN 307 is not in the way of enrollment in the ongoing BMN 270 or BMN 331 trials. This appears to be the clinical hold appears to be vector specific in the United States. And then the second part of your question remind me. It's also very
The AAV integration analysis. The patient, say, taking Roctavian, what is the longest data set? How many years, you know, you have?
Yeah. Off the top of my head, I wanna come back to you, Gina, on more specifics, and Traci and I will do that. Exactly what's been published, I think there's something in the works on this subject, but I don't think it's yet appeared. Here's an important consideration. You know, it's been known that AAV can be found to be integrated into the genome of all different species. The question is, what's the relationship between any of those molecular findings and the occurrence of cancer? It's almost impossible to answer that question in the context of human biology because there are no cancers that have been tied to AAV in humans. At this point, that would be a scientific curiosity of undefined significance.
Now, I mentioned that we'll be sequencing this parotid tumor. We fully expect to find evidence of AAV and integration, that sort of thing. As to whether that's causal, we don't think it will be obviously, but that's why we're gonna do the additional analysis. Just to remind you, with uniQure, they did a tumor analysis of integrations in the ACC individual they found, and they found pretty much what was expected, which is a non-clonally dominant, relatively low frequency event of integration. With those results, the agency lifted the clinical hold for uniQure. I suspect, but you know, until we have all these data in hand, that our case is gonna follow a similar trajectory.
Do you think the FDA will ask you that data, or do you think other data will be sufficient enough to show there are no concern?
You talking about the BMN 270 or?
Yeah. Sorry. That's for Roctavian, for hemophilia.
Well, as I said, you know, we're in the regulatory cycles right now, and any individual question could easily be misinterpreted. As regards to U.S. submission process, I'm just gonna stick with submit in June, six-month review.
Okay, that's fair. Thank you.
Your next question is from Kennen MacKay of RBC Capital Markets. Your line is open.
Hey, thanks for taking the question. A question on the VOXZOGO launch. First, I know you're doing a lot of patient access early in the launch. Can you help us understand the impact of gross to net in the quarter and how we should think about that as the launch continues? Second, just hoping you could help us with some color on the U.S. launch and really towards the types of patients that are now on commercial drug and that your reps and MSLs are hearing from as they're seeking out treatment. Are there any commonalities, for instance, based on age or size or disease severity or stature versus normal ranges? Thanks so much.
Hey, Kennen, this is Brian. I'll start to answer your gross to net question, and then I'll let Jeff answer the second part. Yeah, not much color, frankly, to offer behind the gross to net on Q4 revenues. While we're pleased with the nearly $6 million in Q4, you know, it's a relatively immaterial sum overall, so the gross to net is therefore even further immaterial. We have said that we expect VOXZOGO gross to net to be similar to our other products. You know, perhaps where your question was going is in these territories where you get early access, you set a price, and then you negotiate a final price over the course of time. We do make a best estimate of what that final price will be and set up those reserves.
Any of that is gonna be included in the net sales we report.
Maybe, Kennen, to address your question about color on the U.S. launch. I would start by noting that the most striking thing about the U.S. launch is the diversity that we're seeing in patients and prescribers and geographies and payers. We're seeing patients being referred in by a mix of prescribers and parents. In the case of patients that get referred in by parents, we have an opportunity to help those families get connected with an appropriate prescriber of VOXZOGO. As I mentioned earlier, we're mainly seeing a mix of geneticists and pediatric endocrinologists in terms of prescribers. We're also seeing some pediatricians in the United States, which is not unexpected.
In terms of age segmentation, I've been a little surprised to see really a variety of age segmentation, including, in a gratifying way, older patients that are referring and starting on therapy. As for disease severity, that's not something that we have access to, so I can't really comment on that. As I said, geographically, we're getting patients from all over the United States. As you might expect, we're seeing some correlation with how population is distributed in the United States. I would characterize the U.S. as being highly diverse and probably strong in its diversity.
Your next question is from Debjit Chattopadhyay of Guggenheim Securities. Your line is open.
Hi. Good afternoon. This is Robert, not Debjit. Thanks for taking our questions. Two questions from us today. Can you provide any details on update cadence for the earlier stage portfolio, such as BMN 255 or BMN 331? And two, any current thoughts on capital allocation framework now that the company is clearly on the path to GAAP profitability would be helpful. Thanks, team.
You know, there was a word in the BMN 255 and BMN 331 question that I didn't quite get. Can you comment?
Cadence maybe.
Cadence. Two five five is in human clinical trials, and we're looking to establish a dose to take forward into efficacy trials, which we hope to complete by the dose finding to complete by the end of the year so we can initiate studies of efficacy. And then on three three one, that trial is open for enrollment. We haven't guided to a specific enrollment timeline expectation. You know, as with many of these things, it depends on how many dose level escalations and expansions you have to go through to find your target dose. We tend not to give specific timeline guidance for those kinds of studies, so stay tuned.
Yeah. Great. Thanks, Robert, for the question on capital allocation. This is Brian Mueller. You know, first of all, just note great to have a question like that after years of diluted financing, cash burn, and losses. We're talking about profits and positive cash flows now, so great to take that question. Similar to the journey into our, you know, long-term profitability growth and leverage, you know, we're at the early stages of our capital allocation strategy journey as well. You can imagine as we grow and we start to generate, you know, true free cash flow, that we're gonna explore all the traditional, you know, capital allocation mechanisms that you've seen in our larger profitable peers.
just a reminder in the near term, you know, while we're pleased and thrilled to be generating operating cash flow and make this transition to GAAP profitability, we do have over $1 billion of debt on the books with our convertible debt maturities coming in 2024 and 2027. Those would, you know, likely be the top priority and then we'll, you know, think about more strategic alternatives. Thanks for the question.
Excellent. Thanks, team.
Your next question is from Paul Matteis of Stifel. Your line is open.
Thanks so much for taking my question. Appreciate it. On the new Vosoritide data in patients up to five years old, can you comment a little bit more on the efficacy signal you saw? How big was the effect size compared to what you observed in the phase III study? Do you think it'll be convincing to regulators and clinicians? I guess maybe more of a direct way of asking, do you feel like these data are fileable to expand the label in the U.S.? Thanks.
Well, I think it's premature to talk about what the impact of the data on health authority response is gonna be because we just got the data, and we need to have a next round of interactions with them based on the data. As far as the specific data, what I don't wanna do is get in the way of scientific investigators presenting their scientific data at medical meetings. Stay tuned to updates from us in terms of where those data can appear. I think when you examine the transcript and you realize you use the word trend, what that's gonna come to mind is sort of a signal and a noise. I mentioned this is a noisy heterogeneous population.
I think bear that in mind when you're looking at the data, and you'll come to your own interpretation about how strong and robust the evidence is. I think, you know, the context of this investigation is, people are most importantly, keen to see that there was no cardiovascular access safety in these very young children. I think we feel really good about that. I think most people think that earlier treatment of genetic conditions is warranted. Again, you've gotta put the data side by side with those questions and beliefs and, come to your own conclusions. For now, it's premature to comment on, you know, what health authorities are gonna do.
I would say, if I may, for competitive reasons, we don't wanna get into too many specifics at this time.
All right. Thank you.
Your next question is from Joseph Schwartz of SVB Leerink. Your line is open.
Hi, thanks very much. When do you think we might see data for VOXZOGO in other non-achondroplasia statural conditions? How much more of a patient population could that represent relative to achondroplasia? Can you talk about your plans for VOXZOGO outside of achondroplasia?
Yeah, very excited about that. I think Dr. Andrew Dauber has been a guest of ours at a couple of R&D days. One of the things he's most excited about is investigating statural deficiencies that are due to other etiologies than just the achondroplasia mutation. I mean, his feeling about the achondroplasia mutation, this is what he said to us before we unblinded the pivotal phase III trial that led to the approval. His comment was, "Boy, that's a strong driver mutation. It may be difficult to overcome that.
Maybe you wanna be investigating other skeletal dysplasias that are not so dominantly driven by a constitutive negative mutation." Well, when Study 301 turned out to be positive, you know, his enthusiasm, like, quadrupled because his attitude was like: Well, wow, if you can make an impact in that, then there's all these other statural conditions that are likely to be genetically mediated, likely to be responsive to VOXZOGO. So he initiated this study in genetically defined subsets of patients. It's really a signal-generating study. He presented at R&D Day in November just to remind everybody that that trial's ongoing. He's actually been pleased with enrollment. I think he gave the Cheshire Cat grin of, you know, I haven't really looked at the data.
It's an ongoing study, it's preliminary, but I hope to see you at a medical meeting in the first half of next year where we can talk about, you know, the data more definitively. We don't know exactly when those data are going to appear, otherwise I would be telling you exactly when they would appear. I think we need to look at those data and start to develop our own plan. One of the things that we talk about is, do you want to go after specific mutations, or do you wanna go after a more general crowd? If you go after a more general crowd of statural conditions, we wanna be careful that we don't erode the value of the achondroplasia opportunity that we alone have created, and now others are slowly awakening to.
We don't wanna erode that value, and at the same time, we recognize that there are a lot of patients who have pretty significant statural deficiencies that could be addressed by a drug like VOXZOGO. Just to put that into perspective, if you said that we wanted to investigate children who are predicted to be four standard deviations of deficiency in their stature when they arrive at their final adult height, you'd be talking about something like 0.1% of the incidence population. Talking about fairly large. You know, to put a much more specific quantitative framework around that, I think we're gonna have to get into, like, what are the eligibility of the trial that we would plan to conduct, which is still a bit in front of us. Let's see Dr.
Dauber's data, when it's available, and then let's see what the company's plans are in regard to how to access that opportunity and, you know, protect the achondroplasia indication.
It's likely that Dr. Dauber will present his data at a medical meeting in Q2.
Very helpful. Thanks for all the color.
Your next question is from Akash Tewari of Jefferies. Your line is open.
Hi, this is Leo for Akash Tewari. Thank you for taking our question. I have two questions. One is related to Roctavian. Is it possible that Roctavian may have a black box warning around the integration risk on its label? And if so, how much of this a commercial impediment would that be? The second question is about achondroplasia VOXZOGO. Based on your current data, it looks like over half of achondroplasia market is ex-U.S. and EU5. Could you walk us through your plans to commercialize that market? And what is the scope of opportunities in places like EMEA and NA versus the U.S.? Thank you.
Well, just starting with the safety thing, it's a little premature to talk about what the label might look like in any territory, given that we're under review. Although what I would say is that so far we've not observed anything that would warrant a black box warning. As to how health authorities process, you know, potential uncertainties related to Roctavian, remains to be determined at the tail end of the review cycles. Maybe Jeff, you wanna talk about the other part of the question?
Yeah, happy to. The question was about the market potential as defined by patient achondroplasia patient populations in different markets around the world. I think the more specifically, how about beyond ex-US or the US, and you referred to EU5, I think you meant EU4 now. If you recall from our launch call, you know, we characterized the available population in the EMEA, our Europe, Middle East, Africa operating region, as roughly three times the size of the North American opportunity. Fortunately, we have two things going for us to tap into that opportunity over time. The first is we have a experienced commercial, including medical, regulatory and other functions that support our existing business in those markets. In short, we are operating in those markets.
We have know-how in getting into those markets. It'll be a combination of registrations where we require them, pursuing the inpatient sales channels where they are available.
The commercial capabilities to promote VOXZOGO in those markets. We've got all that. It's gonna take some time to properly tap into that big opportunity, but that's consistent with how BioMarin is operated with all of our previous products, which is to capitalize on rapid uptake in the markets like the U.S., Germany, France and others, where they exist. Then the long-term growth is driven by getting penetration into those other markets around the world, which would include markets like Latin America, Brazil, Argentina, Chile, Australia, where we have a file under review, and we have a very engaged investigator, and Japan, which I've already commented on. All of those over time. Thank you.
Your next question is from Matthew Harrison of Morgan Stanley. Your line is open.
Hi, this is Ahart John on for Matthew. A couple questions. Firstly, not to beat a dead horse, but just to clarify, specifically, has the FDA asked you to investigate cancer risk of Roctavian? Second, what KPIs do you plan to provide going forward for VOXZOGO? And then finally, how do you see the financial leverage profile of the company developing in the near term?
Yeah. On the first question, you know, without getting into the specifics of back and forth dialogue with the agencies, what I can tell you about VOXZOGO, about Roctavian and cancer risk is that trials are open for enrollment, and the agency apparently is therefore happy with the submitted preclinical plan. As to what that means in the context of the larger question of regulatory review or you know commercial authorization reviews internationally, again, we're not gonna comment on that because we're in the middle of review. The second part of your question. VOXZOGO KPIs. A reminder, as we noted in the approval call, we are going to report for you, in addition to quarterly revenues, for six quarters, we will report on the quarter end number of patients on commercial therapy.
We will note the number and the identity of active commercial markets, and we will provide other color commentary intended to help you gauge the success of our launch. We'll do that, those additional figures of patients on therapy and active markets, we'll do that for 6 quarters, starting with the Q4 of 2021. The last question was on our views on financial leverage going forward. Thanks. To touch on a few dynamics there. You know, first, important to note when we talk about the foundations that we've built over the last few years that we're now getting the leverage from. You know, this was our growth, if you think about how we doubled the size of the company from $1 billion to roughly $2 billion in revenue.
With that came the construction of fully end-to-end integrated capabilities, whether it be the early stage research, clinical research, manufacturing through to commercialization. That same infrastructure that we built, while we'll continue to invest in it, is the point of leverage for now these larger market size opportunities. The base business still growing, as I mentioned. VOXZOGO, you know, new, potentially our largest brand, opportunity, getting leverage from that infrastructure that's already been built. Long way of saying revenue to continue substantial growth, we're seeing the you know, return to double-digit growth this year, but importantly, expenses growing at a much slower rate. If you look at our SG&A growth as an example over the years, with the exception of last year, that hold the line year, this is the lowest percentage increase of SG&A growth in a sort of growth year for BioMarin.
Importantly, still growing R&D at about 10% this year because we need to make sure that the R&D engine is sustainable as well. The leverage story is a combination of growing revenues faster than expenses, continuing the investment in R&D, which over time is gonna create P&L capacity. This gets back to the capital allocation question earlier. With more P&L capacity, you know, we plan to increase our internal R&D, but it's also gonna open us up to external collaboration opportunities. Again, this first year, transitional year, relatively modest amount of GAAP profit, but you know, this is how we're gonna plan the future.
Thank you.
Your next question is from Robyn Karnauskas of Truist Securities, your line is open.
Hi, good evening, guys. Thanks for taking our question. This is Nicole on for Robin. Just like a big picture question here. With so many gene therapy companies in the competitive landscape, can you just talk a little bit about your next gen capsid, how you're going to differentiate yourselves from other players? And when will we see those coming into the clinic and in the pipeline? I think the short version of our next gen capsids and even next gen delivery strategies is we have a lot of research going on in that area, and we have some interesting ideas, but we're also a little bit waiting for there to be an unmet need to be addressed.
At EHA this year, we presented the second year of the post-Roctavian transduction data.
Just to remind you, in year one of 134 dosed patients, only two of those patients were returned to prophylactic Factor VIII administration, therefore could even conceivably be eligible for a redosing approach. That number was re-examined at the end of year two. You know, if it turned out that, you know, half the patients had lost control of their bleeding, this might be a much bigger issue and a bigger opportunity. And in fact, the number of patients who returned prophylaxis two years after a single dose of Roctavian gene therapy was an additional four people. There's just not that compelling right now, a reason we're aware of the potential consideration in the far future, doing a lot of research about, but not pulling the trigger on anything in particular just yet.
Great. Thank you.
Your next question is from Joel Beatty of Baird. Your line is open.
Hi. Thanks for taking the question. The first one is on the recent request from FDA on BMN 307. Earlier in the Q&A, if I heard right, I think it was mentioned that this is a vector-specific concern in the U.S. Could you elaborate on what you mean by vector-specific? And is it specific to the vector in BMN 331 or more broad to the AAV5 vectors? And then the second question is, in the prepared remarks, you mentioned that Roctavian is expected to be a modest contributor to revenue in 2022. Could you discuss that, you know, given that it's a gene therapy and gene therapies, you know, may have the opportunity to have front-loaded revenue compared to more traditional drugs?
Maybe it's just a little nomenclature. You know, the vector consists of a bunch of, you know, packaging parts, promoter, spacers, and then the gene of interest. Most of our vectors have different genes of interest in them. What I meant by vector-specific is their questions pertain to the 307 vector with the gene of interest encoding the phenylalanine hydroxylase. We think that the questions that they have are vector-specific because trials of BMN 270 with the gene of interest, the hemophilia factor VIII product and 331 with the gene of interest being C1 esterase inhibitor are ongoing trials that are not under on clinical. That's why we think that this is specific to the vector being used in 307, not to the parts that overlap among other vectors.
The second question was related to.
Front loading Roctavian.
Front-loading of revenues. You're right. We are expecting that gene therapies being a one-time and durable treatment will generate substantial upfront costs, which are not repeatable chronically as we see with our other chronic therapies. There will be a different revenue pattern associated with them. I'll ask Brian if he wants to comment further, but we are similarly expecting that for the most part we will be recognizing revenue at or around the time of treatment and not recognizing that revenue over time in some fashion. Yes, expect a different pattern of revenues from Roctavian when Roctavian is approved and we're in the market relative to our base of chronic therapies.
That's right. Nothing else to add on that specifically. Thanks, Jeff, but it sounded like your question, you were trying to reconcile that revenue recognition pattern with our comments around 2022 Roctavian revenue. Those aren't related. The comment that we made on 2022 expected Roctavian revenues is mostly due to the timing of the anticipated approvals. It almost looks similar to VOXZOGO, if you think about it. A potential second quarter CHMP opinion would mean a third quarter European launch, and then an end of year U.S. launch. You know, modest contribution, but included. You know, we are expecting revenue, just not mentioning specifics at this point until the product gets approved.
Great. Thank you.
Your next question is from Tim Lugo of William Blair. Your line is open.
Hey, this is Lachlan, not the Tim. Thanks for taking the questions. I was wondering on the VOXZOGO launch in the U.S., you know, you've previously mentioned that most patients are already diagnosed, so identification isn't as much of an issue here as it has been in prior launches. So, I mean, can you talk about how many of these patients or the physicians you've actually been able to access so far and what that looks like? And then secondly, just on Kuvan, you know, it seems like it's stabilizing a bit. Do you think we're reaching a pretty stable level this year, or would you expect continued erosion, you know, 2023?
Good questions. Thank you. I'll start with the question about the VOXZOGO and the U.S. launch. As described on our approval call, one of the issues that we face with, for example, our enzyme replacement therapies is helping patients gain a diagnosis. We don't really face that challenge with achondroplasia because essentially all kids with achondroplasia are diagnosed periparturient. They and their families know that they've got a diagnosis of achondroplasia. The challenge in the United States is to connect with the physicians that are caring for these kids and their families because there really isn't, for the most part.
A well-established medical home for the treatment of achondroplasia beyond limb lengthening, which is a very specific procedure. Before VOXZOGO, there was no real standard of care treatment. You wouldn't expect there would necessarily be a medical home. Our challenge in the United States, which is a large and diverse country, as you know, is to connect with prescribers, whether that's a pediatrician or ENT doc or orthopedist or even a geneticist that has a patient that's under their care and drive that patient to an appropriate prescriber of VOXZOGO. As I noted, we're doing pretty good so far. I'm really happy with the results, and I'm expecting that will continue.
Unlike with, for example, our enzyme replacement therapies, we don't have which enzyme replacement therapies we would count patients in, you know, the dozens or maybe 100 or a couple 100. We don't really have a system in place where we're trying to track patients individually and monitor them over time. This is just a bigger market opportunity that we're not doing that with. Very good progress so far. Expect that to continue. With respect to Kuvan and stability, as Brian noted, we lost a lot of revenue for Kuvan in 2021, and that was following a loss of revenue in Q4 of 2020. All of that essentially being dropped from the U.S. market. Yes, we are expecting the erosion to slow down.
Partially that's because a lot of the base of business in the United States has already converted over to generics, as we would have expected by this point in a generic cycle. It necessarily is slowing down from, you know, a higher place, going forward. I refer you back to our full year revenue guidance, for expectations.
Thanks.
No further questions. I would like to turn the call back to Jean-Jacques Bienaimé for final remarks.
Yeah, thank you operator, and, thank you all, for joining us today. We're pleased with our performance that year. We look forward to a year of momentous growth in 2022, thanks to the addition of VOXZOGO, which again we expect will be our largest, opportunity to date. We have transitioned to the development and commercialization of innovative therapies for larger genetic conditions. Our R&D engine has never been more productive, and we expect to put forth many early-stage candidates, as development advances over the coming quarters. The financial health of the company has never been stronger. We are turning the corner to sustainable GAAP profitability in 2022. This is an important achievement, and it marks the beginning of the next stage of growth for BioMarin.
Thank you all for your continued support, and we look forward to seeing you soon.
This concludes today's conference call. Thank you for participating. You may now disconnect. Presenters, please stay on the line for your post-conference.