Welcome to BioMarin's third 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, Grace. Thank you, everyone, for joining us today. To remind you, this non-confidential presentation contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc., including expectations regarding BioMarin's financial performance, commercial products, and potential future products in different areas of therapeutic research and development. These 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 development by competitors.
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 management are JJ Bienaimé, Chairman and Chief Executive Officer; Jeff Ajer, Executive Vice President and 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. We hope to keep the call to an hour, so respectfully request that you limit yourself to one question during the Q&A portion of the call. Thank you so much. I will now turn the call over to BioMarin's Chairman and CEO, JJ Bienaimé.
Thank you, Traci, and good afternoon, everyone. Thank you for joining us today. BioMarin's commercial organization is excited to be launching our seventh commercial product following the August approval in Europe of Voxzogo for the treatment of achondroplasia for children ages two years and up. We see that the level of initial prescription demand for patients seeking Voxzogo treatment in Europe has exceeded our expectations. Voxzogo revenue this year will come from France and Germany, where there are a number of children already on therapy, as well as a number of select early access countries in Europe, the Middle East, and Africa, and actually also Latin America.
As the first and only approved medicine that targets the underlying cause of achondroplasia and improves bone growth in children, we are very pleased with the early indicators of product demand. In the U.S., we are in late- stage labeling and post-marketing requirement discussions with the FDA. We remain encouraged about the potential positive FDA approval action outcome in less than a month time. Adding the U.S. approval would pave the way for our largest global product launch to date and set the stage for significant revenue growth starting in 2022. Getting to 2021 financials, it is important to understand the dynamics of our global business to appreciate the underlying strength.
Despite the impact from anticipated uneven ordering in the first half of the year as compared to what is expected in the second half of the year, we are pleased to be improving full-year top- and bottom-line guidance. This despite Kuvan having faced generic competition since the fourth quarter of last year. We actually despite this anticipate generating full-year 2021 revenues mostly in line with our 2020 revenues to illustrate the strength of our base business. This is a result of underlying growth in net product revenues from products marketed by BioMarin, excluding Kuvan and also operating expense management. The number of patients treated with BioMarin therapies has increased this quarter for all our products, all other than Kuvan, of course, and has reached record levels.
We expect revenues to be down in the fourth quarter as compared to the third quarter, so as to end up with a strong finish in 2021. With the addition of Voxzogo in Europe and the anticipated U.S. approval, we expect a significant step-up in revenues beginning next year in 2022, leading to anticipated sustainable positive GAAP income for full- year starting next year. We will provide full- year 2022 guidance as usual during our fourth quarter quarterly calls on next February. Suffice it to say that our strategy to layer on Voxzogo and potentially Roctavian to our strong base business, leveraging our global infrastructure and manufacturing capabilities to drive meaningful profitability is rolling out as planned.
In support of that plan, cash flows from operating activities increased to nearly $300 million and are driving the expansion of BioMarin's earlier stage pipeline. With six early-stage products on the agenda for our upcoming R&D day, we expect to initiate clinical trials for multiple new products over the coming years. Harnessing genetic technologies to speed our discovery capabilities has resulted in an exponential growth in our clinical assets, and we are very excited to share our progress with you on November thirtieth. The past 18 months have been challenging for many reasons. The global pandemic, regulatory setbacks, et cetera. We have remained focused on our mission and goals. BioMarin has never been better positioned to achieve the next level of growth, and we plan to capitalize on the many opportunities that lie before us.
I wanna thank our BioMarin colleagues and associates for their continued commitment to developing the essential medicines that help so many. Thank you all for your continued support. I will now turn the call over to Jeff to discuss the commercial business. Jeff?
Thank you, JJ. I'm very pleased with the team's performance across all brands and all regions during the quarter. Not only are we improving top-line guidance for the year, but we are at the start of launching what may be our biggest brand to date, Voxzogo. As JJ already described, the impact of large, unevenly timed orders for our enzyme replacement therapy brands in the first half of the year, as well as the U.S. loss of Kuvan market exclusivity a year ago, was notable in the third quarter. Despite those dynamics, we achieved $409 million in total revenues, reflecting solid demand in the third quarter and year-over-year growth in net product revenues marketed by BioMarin, excluding Kuvan. Q3 revenues were consistent with our expectations around quarter timing and the balance between first half and second half revenues communicated previously.
Keep in mind, patient demand remains a key indicator to gauge product demand. For both Naglazyme and Vimizim, patient numbers increased by more than 10% respectively year-over-year. For Brineura, in the third quarter, children on therapy increased by more than 20% year-over-year. Moving to Palynziq, where 32% year-over-year growth translated to $61 million in net product revenues in the third quarter, reflecting a combination of revenues for more patients receiving maintenance dosing as well as new patients initiating therapy. This growth was achieved despite continued COVID impacts, resulting in many PKU clinics operating at partial capacity. Consistent with our commentary last quarter, it is important to note that PKU clinics in the U.S. have not opened up to new patient starts at the rate we anticipated.
As expected, the U.S. was the main contributor of growth in the quarter, driven by U.S. patient increases of approximately 20% year-over-year. While we remain optimistic about the growth prospects for Palynziq for the balance of the year, we expect U.S. PKU clinics to increase new patient starts at a slower pace than originally anticipated. The commercial launch of Palynziq in BioMarin's Europe, Middle East, and Africa region continues to progress through individual country-level pricing and reimbursement negotiations. Continuing with the PKU franchise, Kuvan then contributed $68 million in revenues in the third quarter, reflecting incremental erosion to generics in the U.S. Revenues decreased by 44% year-over-year, primarily due to the U.S. loss of market exclusivity in October 2020, as anticipated. Moving on to Voxzogo, our newest commercial opportunity and likely the largest launch to date.
We've been very pleased with the level of prescription demand from patients seeking Voxzogo treatment since receiving European approval in August. A reminder that in Europe, price and reimbursement processes are the primary gates to being able to treat patients and generate revenue, and these processes can be lengthy. Therefore, for revenue purposes, we are focused on the set of markets where we can quickly begin treating patients and generating revenues. These markets include France, Germany, and a number of other markets in which we are pursuing the inpatient sales. Importantly, we are seeing robust prescription demand already, and we are optimistic about the prospects of being able to convert that demand to patient treatment and revenue. The small revenue recorded for Q3 was from France, and for the first patients there starting treatment.
Already in Q4, additional patients have started therapy in France, and we have shipped Voxzogo to Germany and Switzerland to begin treating patients in these markets. Concurrent with the EMEA launch, our U.S. commercial team is planning for the potential launch at the end of the year, assuming a positive PDUFA action outcome in November. As has been our experience with prior launches in the U.S., we do have the ability to quickly respond to prescription demand following approval. While U.S. payers are numerous and diverse, we have experience navigating the medical exception process to facilitate early prescription demand while we work through the process yielding payer coverage policies. As with the launch of previous BioMarin brands in the U.S., this experienced team is in place and prepared for potential approval. We look forward to providing full- year Voxzogo guidance for 2022 when we report fourth quarter results next February.
We would also like to set expectations for quarterly metrics that we will report on for the next six quarters. For the quarter being reported, we will report net Voxzogo product revenues, active markets with sales, the total number of commercial patients at the end of the quarter, and other color on the progress of the launch that will help you evaluate the commercial status of Voxzogo and inform your expectations. In conclusion, results in 2021 for our established brands are tracking to expectations with the improved top-line guidance provided today, raising the low end of the total revenue guidance by $30 million, as well as the low end of the ranges for Vimizim, Kuvan, and Palynziq. Demand for our essential medicines in the 75 countries where we do business is robust and growing.
The commercial team is energized to be launching our newest, potentially largest product opportunity with Voxzogo in the EMEA region, and we are eagerly preparing for the potential launch in the United States should we receive approval in November. Thank you for your attention, and I will now turn the call over to Hank to provide an R&D update.
Thanks, Jeff. Similarly, the research and development organization echoes your enthusiasm for the European approval of Voxzogo. Families have been waiting for a long time for a treatment option for their children, and we believe the targeted mechanism of Voxzogo, which promotes endochondral bone growth during the time period when growth plates are open, can have a meaningful and potentially lifelong impact on children with achondroplasia. We're so pleased that this important medicine is now available in Europe, and we look forward to hearing real-world treatment experiences of parents as families access Voxzogo over the coming months and years. The European approval of Voxzogo for children ages two and up further demonstrates the importance of beginning treatment as early as possible to provide maximum clinical benefit while growth plates are open.
We look forward to the readout of our 52-week placebo-controlled study in children newborn through five years of age around the middle of next year as the next potential step toward expanding access to Voxzogo should those data be supportive. In the United States, we look forward to the PDUFA target action date of next month. We believe the robust dossier of data under review provides clear signals of clinical benefit from Voxzogo treatment. I also want to take the opportunity for everyone to thank everyone who contributed to this important milestone on behalf of families seeking a treatment option for achondroplasia. Thank you very much. Quickly, on Roctavian regulatory milestones are tracking with plan. At the end of November of 2021, we will reach the two-year mark for the phase III study, and the two-year follow-up observation period.
We continue to expect resubmission of the U.S. biologic application for Roctavian in the second quarter of 2022, assuming supportive two-year data, followed by an expected six-month review procedure for the United States. In Europe, with the Marketing Authorisation Application validated and under review, we continue to expect a CHMP opinion in the first half of next year, assuming supportive two-year data, which will be shared with the EMA when it is available. We remain confident in Roctavian's potential to be an important treatment option for those with severe hemophilia A based on the clinical evidence observed to date, demonstrating dramatic reductions in bleeding rates, platelet utilization, and factor VIII infusions following treatment. Turning to BMN 307 therapy, gene therapy for phenylketonuria.
Following the clinical hold placed on that phase I/II study by the Food and Drug Administration, we've now received communication from the agency with guidance on next steps. We're in the process of addressing the agency's request for additional information, so we do not have an update on when the hold might be lifted. The hold on our PKU gene therapy study was based on recently identified safety findings for a nonclinical, non-GLP pharmacology study in immunodeficient mice. As scientists striving to serve patients' needs, we're committed to understanding these science findings. As we've shared previously, and it was corroborated during the FDA panel discussion on the AAV space in September, it remains uncertain and, in our view, unlikely that these specific findings with BMN 307 will translate to a safety issue with this or other AAV gene therapy candidates.
We're working through the process with the FDA, and we'll keep you posted as we have relevant updates. Turning to our R&D Day event, now planned for November 30th, we look forward to sharing new data and new program updates with you. The R&D organization has hit its stride melding our own internal discovery capabilities with genetic tools to understand underlying mechanisms of disease in order to develop targeted medicines. We're excited to share these advances with you in greater detail and describe the many assets under development in the early-stage pipeline. We hope you will all tune in. Thank you so much for your support, and I'll now turn the call over to Brian to update financial results in the quarter. Brian?
Thank you, Hank. Please refer to today's press release summarizing our financial results for full details on the third quarter of 2021. As usual, our comprehensive report on the quarter will be available on our upcoming Form 10-Q, which we're on track to file over the next few days. As JJ and Jeff mentioned, the previously anticipated order timing in 2021 has created a meaningfully uneven revenue flow between the first and second halves of the year. To illustrate the impact of select individual country order timing on Q3 2021, last quarter, Q2 2021, there was approximately $90 million more revenue, excluding Kuvan from Brazil, Russia, and the Middle East, which did not recur in the third quarter, substantially accounting for the quarter-over-prior-quarter total revenue fluctuation.
Importantly, however, as Jeff mentioned, the key underlying business driver of patient demand continues to increase in all of our products, except for Vimizim in the United States. Based on these timing dynamics, we anticipate to emphasize our full-year 2021 guidance as the best metric to measure our top-line financial performance. To that point, the strong start in the first half of the year drove a previous upward revision of full-year 2021 revenue guidance back in July, including Vimizim and Palynziq, as well as improved GAAP to non-GAAP bottom-line guidance. We're pleased to announce today that we are again improving total revenue guidance, including both Vimizim and Palynziq, by raising the lower end of our guidance for the full-year 2021.
As noted by JJ, despite the impact of a full- year of Kuvan generic competition in the United States and the continued COVID-19 impact on our growth, total revenue for 2021 is expected to be mostly in line with total revenues in 2020, which is better than our expectations at the beginning of this year. Moving to operating expenses, R&D expense for the third quarter was $158 million, which is $11 million higher than the R&D expense of $147 million for the third quarter of 2020, which reflects increases in our early-stage research and development. Based on our R&D expense trends through Q3 2021 and expectations for the fourth quarter, we're lowering the range for R&D expense guidance by $10 million for the full- year.
Next, with respect to SG&A expense, Q3 2021 SG&A totaled $183 million, which was essentially flat compared to third quarter of 2020. As we are launching Voxzogo in the EMEA region and preparing for the launch in the United States, SG&A expenses in 2021 are weighted towards the fourth quarter of the year. Turning to bottom- line results, we reported a GAAP net loss of $37 million in the third quarter of 2021, compared to GAAP net income of $785 million in the third quarter of 2020. Please recall that GAAP net income in the third quarter of last year included a large tax benefit totaling $835 million related to the transfer of certain intellectual property rights between BioMarin entities that showed a significant level of GAAP net income last year.
Non-GAAP income of $34 million in the third quarter of 2021 was lower than non-GAAP income of $99 million in the Q3 2020, primarily due to lower revenues this quarter as a result of the previously discussed timing. We're very pleased with the company's GAAP and non-GAAP bottom line performance through the first three quarters of 2021, and based on our expectations for the fourth quarter, we have improved full-year GAAP and non-GAAP bottom line guidance. We've reduced the full-year 2021 GAAP net loss guidance to between $85 million and $45 million, and have increased non-GAAP income guidance to between $215 million and $255 million, representing an increase of $20 million at the mid-point of the range.
That substantial level of non-GAAP income helped generate a continued increase in our total cash and investments at the end of the third quarter of 2021, with $1.55 billion compared to $1.35 billion at the end of 2020. We set a goal of generating positive operating cash flow in 2021, and the business has delivered nearly $300 million of positive operating cash flow year to date. One brief comment is that the previously discussed timing of revenue and expenses in 2021 also impacts our cash flows, which we observe are also weighted to the first half of the year.
This solid cash position, coupled with our strong operating performance through the first three quarters of 2021, is a strong foundation from which to look forward to the continued European launch of Voxzogo, the potential US launch at the end of the year, and potentially Roctavian next year. The progress of our early-stage pipeline that is leveraging the same R&D organization that developed our portfolio of now 7 approved products and 2 large market late-stage programs is an exciting next chapter in BioMarin's potential future growth story. Thank you for your support, and we will now open up the call to your questions. Operator?
Thank you, sir. At this time, we will begin our question- and- answer session. To ask a question, you will need to press star one on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Here's our first question from Cory Kasimov of JP Morgan. You may now ask your question.
Great. Thanks. Good afternoon, guys. Thanks for taking the question. So, the Voxzogo label in Europe is obviously pretty broad, covering patients as young as two years old. I'm wondering if there's any pushback from either an early access point of view or physician comfort in potentially treating patients under five. Do you have expectations for the FDA label to be equally broad if approved, of course? Thank you.
Jeff, do you wanna answer the first part of the question, and Hank, the second part?
Yeah, happy to. One, we're really happy with the broad and open label as you described it, including for patients two years and up in Europe. We believe that in Europe, the endorsement of the CHMP on safe and effective use for ages two years and up is a powerful statement to both payers and prescribers. It's too early for us to provide specific color in Europe, but we're not anticipating pushback from payers or prescribers on two- to five-year-old patients. I'm gonna turn it over to Hank for the second part of the question.
Yeah, Cory, as you know, there's a close direct connection between the FDA and the EMA, and they tend to operate independently. You know, we're really encouraged that the EMA understood the context of the condition and were scientifically rigorous in consideration of the label. I'd encourage you to come to our R&D Day, where we're gonna share some of that information. You know, we obviously were hopeful that the FDA would be similarly influenced, but as you know, the FDA is a little bit more conservative. We'll just have to sort of muscle through the next month to see where it lands.
Okay. Great. Thanks, guys.
Speakers, our next question from Phil Nadeau of Cowen and Company. You may ask your question.
Good afternoon. Thanks for taking our question. Another one on Voxzogo. Perhaps one of the more controversial aspects of Voxzogo is the language that was in the FDA questions letter discussing the need for two-year placebo-controlled data. Now that you're in late-stage labeling negotiations, could you give some information or some idea of how the FDA reviewers have dealt with, you know, the advisory committee's commentary around two-year placebo-controlled data, and whether it's safe for us to assume that since you're in those discussions, that won't be necessary for Voxzogo at this time around?
Yeah. Thanks, Phil, for the question. You know, we're really in the throes of it, so I can't really give you too much of the exact sausage-making of discussion. What I would say is that we've been fairly transparent from the get-go, as you just reminded, about where the FDA was. You know, at the time, I've continued to say that the U.S. agency's interest, I should say, is on durability. We've provided them what amounts to a two-year placebo-controlled study. It's a little bit unorthodox in its design, but it's essentially two years' worth of data, and we supplemented that with five years of open label treatment data in comparison to some pretty good natural history sources of data. We feel pretty good about the durability of the effect on linear growth.
I think the related question is gonna be, you know, in sort of a one- or two-year growth, you know, does that constitute substantial evidence of a clinical benefit, or is that a benefit that's reasonably likely to predict a clinical benefit? I would just say that you should be aware that in the growth field in the growth hormone administration to children with growth hormone deficiency disorders, that a lot of the language has been around final adult height. This suggests to us that the FDA is also very concerned about final adult height. I think their decision-making about durability is gonna be, you know, related to ultimately not the two-year sort of story, but what this is about what can be expected from final adult height.
All of this, I think, will come to some form of resolution in the next few weeks, so stay tuned.
Got it. That's very helpful. Thanks again for taking our question.
Our next question here is from Chris Raymond of Jefferies. You may ask your question.
Thanks. Just ask maybe a pipeline question on specifically 307. So Hank, I wonder if you could comment on what kinds. I know you said you sound like you've met with FDA. You don't have a sense as to when the clinical hold will be lifted. But you know, can you comment on what additional experiments or analyses the agency requested? And is this something that could be addressed in the near term, or is this maybe longer-term experiments? And you know, maybe can you share what you did provide to the FDA when you met with them? I think you were gonna meet with them this month, to you know, that you thought might get comfort on the you know, this was an issue related only to mice.
If you just like, add maybe a quick Voxzogo question. I'm not sure if you're willing to answer this, but of patients that have started in Europe, what's the average age? Thanks.
I will take the first part of your question, Chris, while Jeff plots the second part of your question. You know, Chris, let's just, you know, meeting with the FDA. We've had correspondence with therapy as we try to get meetings with the agency nowadays. It was a pretty sort of tactical correspondence because what happened was, you know, we observed the finding and felt duty-bound to report it. You know, it turns out that we were in a post evaluation period from the second cohort of patients to discuss that. We were not enrolling patients at that moment anyway. We were transparent with the agency about this preclinical finding as soon as we found it. As a consequence, they've not really seen all that much yet.
What they asked for of us is relatively straightforward and can be wrapped up in a package. You know, they were pretty comprehensive in the kinds of things that they asked for, including how it's gonna reflect an informed consent and protocol minutes and things like that. It's obvious that they've seen these sorts of things before, and they have a pretty prescribed list of the types of questions and considerations. I think the sort of bigger perspective, it goes back to, I think it's your question about the FDA's advisory committee meeting.
You know, the thing that struck a lot of us about that was, when the presentation on T-cell integration and oncogenesis, the presentation was divided into what did we know up through 2016 and what did we know from 2017 and beyond. I think the relevance of that is that, you know, the agency subsequently approved subsequent to 2016, they approved Luxturna, and they approved Zolgensma. Zolgensma, importantly, for IV administration, and importantly, a lot of the vector goes to the liver. In spite of the fact that insertional oncogenesis was or insertions were described in mice, the agency has approved a drug called Zolgensma, and in fact, over 3,000 patients have been treated with gene therapy in clinical trials. 13 patients have been treated with Zolgensma.
You know, the agency, I think, as it says, the agency, on the one hand, aware of the preclinical experiments, but on the other hand, is thinking about that as a sort of not as a risk-benefit issue because a risk has not appeared yet, but it's a risk information for patients kind of an issue. In that discussion, I don't think that there was any real breakthrough in terms of what additional information to be providing. I think rather there was maybe a little bit more of a challenge to the scientific community to try to understand what's going on in mice and to ask the question of is there any vulnerabilities that could go on in humans, given that we haven't seen insertional oncogenesis in humans to date.
Before we expect to see insertions of AAVs that could be one of the ones. Whether that leads to cancer is speculation at this point. I think, you know, the field has been dealing with this issue for quite a while. I do think that there are more experiments to do, none that will directly answer the question of how, you know, does this translate to humans in terms of predicting a risk of oncogenicity in humans, but rather, I would see more delineating technical details about how these experiments should be done and then interpreted and put us at comfort. You're probably all aware of a study in dogs that found clonal abundance of a specific set of mutations.
They postulated that there was a cause-and-effect relationship between the fact that a lot of cells had the indicated insertion and that there was this insertion, and a lot of cells had this indicated insertion. However, the thing I think to keep in mind, and we see this in our 307, is not every cell in the sample has that characteristic. It raises the question of whether these findings are in fact causal in mice or passenger in mice. I think until we have a better idea about the answer to that question, we're not even going to get on first base in terms of understanding the relevance to humans.
We are in the front row of all of this because we have a lot going on in gene therapy, and our scientists are crossing the T's in the front office, and we look forward to providing the agency the info it needs to get us restarted on the 307 pathway. Now I'm going to pass it to Jeff, who can handle your questions about-
Thanks. Thanks, Hank. I'm still digesting all that you had to say. With respect to Voxzogo and Chris, with the implementation of GDPR privacy regulations in the E.U., we don't have the same very specific data about our individual patients that we might historically have had. I'm kind of circling around to your question. As we get some data about product usage by vial strength, we'll be able to make estimates of the size and the age of the mix of patients that we've got on treatment. We don't have enough data yet to work through that. What I might say is the early access patients treated are coming from France under an ATU early access program there.
That ATU was approved separately or in parallel with the EMA negotiations that led to the label of two years and up. Interesting enough, the ATU label indication is for patients five years and up. In France, the early experiences with patients in the range of, let's say, five to nine or 10 years old. We'll keep you posted with that kind of color going forward as we get more data to evaluate the thickness.
Speakers, our next question from Salveen Richter of Goldman Sachs. You may ask your question.
Good afternoon. Thanks for taking my question. On Voxzogo again, you talked about strong demand. Can you just give us some color there of how we should think about not just France and Germany and the select early access countries in 4Q and how the launch so far has exceeded expectations?
Hi, Salveen. Thanks for the question. It's really a pleasure to answer this one. Some of the colors that I would add here is specifically from France and Germany. I would characterize as this. In previous launches, we've had patients come in, you know, generally 1 patient at a time, 1 patient from clinic A, 1 patient from clinic B. A little while later, another patient from clinic C, maybe sometime later, a second patient from clinic A. What we're seeing this time around is we're still seeing some prescriptions emerge from individual clinics with a patient N of 1, but we're also seeing Ns of 4, Ns of 5 coming straight through at once.
We've never really experienced that, and that gives us that drives our comment about the strength of prescription demand in part, so those patients coming through in clusters. In addition, there's been a lot of prescription demand that has emerged from named patient sales markets. I mentioned that we have
We have sales to Switzerland, which by the way is not an EMA market. You know, Switzerland is not covered by an EMA approval, and it is not a named patient outside of registration market. We've seen initial prescription demand from markets in the Middle East, as JJ Bienaimé mentioned, and also in Latin America. We've seen N's larger than one in that experience. That's the combination of quick named patient sales, prescription demand from markets and the clusters of groups of patients, not one or two, that's really driving our comment about prescription demand.
However, I mean, obviously the dollar sales in Q4 are going to be, you know, revenue. You need to increase the demand of 50 because, you know, we only have distributed five runners a month. That bodes well for 2022 and the season converted revenues in 2022. There is definitely a lot of interest. The anecdotal is that we got news from the Russian government, and we got the federal reimbursement for Voxzogo in Russia when we have not even filed. That means it's nice. Okay. Next question.
Speakers, our next question from Akash Tewari of Jefferies. You may now ask your question.
Hey, thanks so much. So one, vosoritide. Can you talk a bit about the use of sentinels for vosoritide in the 202 study? How are they being used to kind of adjust the dosing for these younger patients? And what have you seen from a safety perspective so far in that population? This one's a bit more high level. The stock's been traded down for the last few years despite you guys approaching your two largest, most important commercial launches. Is there a point in time where you would more seriously explore strategic avenues to unlock value, particularly if either Roctavian or vosoritide don't get FDA approval at that time? Thanks so much.
Hi, Akash. I'll start with the first part of your question. This study was put in the field before the phase III trial readout. You know, the comprehensive evidence for safety and efficacy in older children wasn't available at the time of the study. In consultation with health authorities, the study was designed to enroll patients in three cohorts, ages two to five, or let's see. There was two to five. Please help us with the age. I'm coming again. I'm having a brain melt in terms of ages. 62 months and zero-six months. The underlying reason for that was that there were hypotheses about differences in the dose exposure and exposure response relationships.
The concept was to enroll sentinels to evaluate PK/PD and the safety response to that 15 microgram per kg dose that we've been using in older children before then opening the rest of that cohort up to randomization to active medication with placebo. In the two- to- five-year-old cohort, we found that the 15- microgram dose was an appropriate and gave an appropriate exposure and appropriate PD response. We'll actually review those data at R&D Day because that was the information that informed the European health authorities to move forward with the application. We only had a limited amount of efficacy data in those small number of patients because there was no contemporaneous control.
I think that what that tells us is that two- to five-year-olds can be safely dosed with the same dose as children who are older than five. Turning to the children who are under two, we did find a dose exposure relationship such that we had to increase the dose. Off the top of my head, I think that we had to do that also for the infants that were enrolled in the study from zero to six months of age. I think what that means is that we're actually benefited by having a relatively short-acting drug in the sense that short-acting drugs are easier to adjust and accommodate dose and exposure on the basis of response than very long-acting drugs.
Especially since although we did the trial from five to 26 months, humans age in the other chronological direction from six months to two years to five years. It's going to be important to have all this dose exposure safety information. From a safety perspective, with the roughly now well-described safety profile of Voxzogo, we haven't really seen much additionally in terms of significant clinical adverse responses. I feel like we're in pretty good shape understanding the relationship of dose and therapeutic and safety response. We'll get additional European evidence of that in just under a month or just over a month, I should say. Let me pause there.
I just want to get to the second part of your question because that's totally different.
Oh, yeah.
Just checking for that.
No.
I mean, obviously, I think there was a recent survey, 50% of investors who don't believe that Voxzogo will be approved in the U.S. I think that's good news. I think it proves that short-term results is a significant move in the stock.
That event is only, you know, a few weeks away. Let's, you know, have that conversation again after the PDUFA date of October. Then also that will be your presentation to appear in case of this year.
Thank you so much.
Our next question from Gena Wang from Barclays. You may ask your question.
Thank you for taking my questions. The first is, regarding Roctavian. Just curious, what is the latest FDA interaction, regarding Roctavian filing, specifically on durability? Then, the related question is, for the type of animal data, preclinical data that FDA is asking for the PKU program. Do you expect FDA also will ask, you know, for similar type of data for Roctavian?
Well, it's a little bit complicated, but let's see if I can cut to the chase of it. In terms of FDA interaction, there really is no news there in terms of the timing and resetting or differing expectations. We said at the time of the CRL they want two years' worth of data, and it's like them and like Dolly. In spite of our trying really hard, they want two years' worth of data. We've had some lower- level communications and correspondence about, you know, things like statistical analyses which reveal really nothing new other than that they want two years' data. You know, we are interacting with the division and the review. It's just very collegial and very, very much through the process of discussion.
You know, based on what we've seen so far, we believe, and we've had experts in to tell us what they think the FDA may not be telling us, but might be conveying. The experts have advised that this reads like a situation in which they ask for the two-year data, and they're gonna make a decision on the basis of the two-year data. That's good for us and for patients because we're optimistic the hemostatic efficacy will be maintained after two years. It was demonstrated in the first 17 patients that were treated in the phase III clinical trials, and that's been followed for an additional second year, as we reported earlier this year.
We're confident that the remaining 100 or so patients will be adequately controlled from factor VIII expression through the second year. The issue of durability in PKU is a little bit more difficult for the simple reason that in factor VIII expression, you measure the actual gene product itself, whereas within PKU, you measure indirectly the gene therapy product. We will want to see what the pattern of Phe control looks like before committing to a specific answer to that question. But based on preclinical data where we have seen maintenance of gene expression, we believe that there's a stronger argument to be made around PKU and durability, and one year supporting that than there was for Roctavian.
Just recall for Roctavian, you know, because of the nature of the immune response in non-human primates, you don't typically do long-term studies. When we assess the long-term studies that we did do and others have done, and not a lot of them, you can see the effect of the immune response in lower species to the human protein. In PKU, we've been able to demonstrate sustained durability in preclinical species. We hope that argument prevails upon the agency. You know, that discussion is yet to be had in sufficient detail with actual data from patients to inform.
The good news of all of this is that, unlike Roctavian, where we changed the material from phase I to phase III, and we made a tweak to the trial and the steroid regimen, none of those things are happening in the 307 trial. These earliest patients will provide relevant information for long-term exposure.
Sorry, Hank, I wasn't clear. I was referring for the PKU program, or more the safety input that FDA was asking for additional preclinical detail. Whatever detail FDA is asking, do you expect FDA also will ask a similar type of data set to support safety for the Roctavian program?
So far, they have not been requiring preclinical carcinogenicity studies. I mean, if you look at the Zolgensma label, there are no carcinogenicity studies either in the prior to submission studies or post-approval studies. Don't expect additional studies to be required from a safety perspective prior to submissions and approvals. Again, those are discussions to be had as well.
Thank you very much.
Our next question from the line of Paul Matteis of Stifel. You may ask your question.
Thanks for taking my questions. Hank, if I heard you correctly when you talked about the issue of the two-year placebo-controlled study earlier, it sounded as though you feel like at this point in the review, this is a matter of either full approval or potentially accelerated approval. Did I understand that right? And if it is ultimately deemed that this is an accelerated approval, how do you think benefit will be confirmed? Do you think you'd need to do a two-year placebo-controlled study as a post-marketing requirement? Thanks so much.
Well, you know, the approval pathway is specifically the agency's decision and specifically at the tail end of the consideration decision. I don't want to read too much into anything other than just what I was asking. The question was that you know, in the landscape of growth promoting products from the FDA perspective, final adult height is more of a question than interval growth velocities have been a question. If it were to come to pass that a confirmatory study would be required, we would hope that longer term follow up of the patients that we have studied already could constitute a nexus of the or the main, I should say, the main group for evaluation.
We have provided the agency, as you know, we had I think five plus years of treatment data on the first patients treated in open label, several of whom are close to final adult height. The agency seems interested in those patterns. For the patients, it's not a lot of patients for them. We're hopeful that whether it's a post-approval commitment to a conditional to an accelerated approval, or whether it's a post-marketing requirement or even a full approval, that final adult height characterizations will come in when they come in and will be powerful to document the accumulated benefit of Voxzogo. On some level, how we're in
Got it. Thanks a lot.
Our next question is from the line of Geoff Meacham of Bank of America. You may ask your question.
Hey, guys. Thanks for the question. I just got a couple. The main one, you guys have talked in the past about, you know, PKU clinic still not fully reopened, just on the commercial business. Just wanted to get an update on that. Have you started to see a recovery in Palynziq starts? That'd be, you know, kind of helpful in maybe how you think that's going to play out in 2022. Bigger picture, you know, for JJ, I mean, on the R&D side of things, you know, how are you thinking about, you know, new opportunities in light of, you know, what could potentially be a little bit more scrutiny on AAV technology?
Is there something that you're looking for, in terms of, you know, asset diversity by indication or technology diversity, or how are you thinking about that going forward? Thank you.
Jeff, do you want to go over the PKU clinics and the ZT start, question?
Sure. I'd be happy to. As noted in our remarks both this quarter and the previous quarter, what we're seeing is in Europe, but more importantly in the U.S., PKU clinics are continuing to operate at less than full capacity. Of course, in the U.S. there's 125 PKU clinics, so there's some variability across there. There's a lot of clinics that are operating virtually, not live. There are staffing issues in PKU clinics as certain supporting staff in particular have been reassigned during the pandemic. Frankly, for the genetics clinics, while PKU usually is the largest group of patients that they're treating, there are acute needs for patients in those genetics clinics.
We've seen that those acute needs for really terrible conditions for children, you know, are first in line for priority for their capacity. Having said that, we are getting new patient referrals on a steady basis. I would say steady through the pandemic. We're drawing the conclusion that, if we've been optimistic about PKU clinics getting back to their previous pre-pandemic capacity, it hasn't happened. We've been working on other tactical solutions that facilitate, you know, PKU patients to continue, you know, access to therapy, and for new patients to start.
I think what we're trying to do is reset a little bit of expectations here that, while we were optimistic at the beginning of the year, we're less optimistic about that capacity for the balance of the year now. But we're continuing to see overall growth. I might just comment as kind of a read- through to what do we think about that for Voxzogo. In fact, other healthcare providers that we call on, such as pediatric orthopedists and pediatric endocrinologists, both of which are really relevant to Voxzogo, for the most part, you know, with restrictions and protocols in place, those specialties are, you know, they're back in business.
The kind of capacity constraints we're seeing in the PKU clinics, I would say don't let that read through your expectations about Voxzogo.
Regarding your
JJ, maybe.
Sorry. Regarding your PD question. I think so. I mean, that's a good question. Just wanna a few comments. As you know, we have several what we call modalities within our range. We started as a company many decades ago, 14, 15 years ago. But two brands would be responsible. Two was an exception.
If you look at our pipeline today, we have traditional protein therapeutics. We have small molecules. We are moving into oligo, about to get back in the clinic with the second generation of oligonucleotide, and we have some options there, beyond DMD. We are always gonna go beyond one modality. I would say gene therapy is very important for us. It will continue to be in the future, but we have no intent on being a pure gene therapy company.
If you look at our R&D through those new programs and talk about all the programs we have in development, besides Roctavian and PKU gene therapy and HAE gene therapy, which is the best part, the only new program for the gene therapy, potentially gene is in the clinic right now, but BMN-293 is maybe about one point five to two years in hypertrophic cardiomyopathy. We have many other programs that are not gene therapy programs, and that we can see to be the case. At the same time, we are far from giving up on gene therapy. I guess we're not the only company doing so. We still believe it has that major potential.
I mean, it kind of reminds me, I don't know, we've been trying to tell 'em what twenty-five and thirty years ago when, you know, some of the first patients to monoclonal antibodies died. I would say someone would say, "Oh, that's the end of monoclonal antibodies. We shouldn't go forward with this." That would actually be a huge mistake considering that only the aggregate sales of monoclonal antibodies today is over $100 billion a year. So here we are, you know, at the beginning of the adventure with gene therapy. We're learning a lot. I think we, as Hank was illustrating, we continue to learn a lot from people.
We are ahead of most other gene therapy companies in this respect, in our understanding of what happens in the cells after the gene insertion and what leads to expression, durability, inflammatory response or immune response. We believe we can design better and better gene constructs. We also gonna look at gene treatments. You'll hear about all that at R&D Day. We're gonna look at, you know, non-viral gene therapy opportunities. This is basically the framework of what drives our internal research and what drives the kind of stuff coming out. We're just being outside-in. I hope that answers your question. Maybe, Hank, I can get your perspective here, too, in the middle of this.
No, I just think that, you know, the genetic and genomic revolution is unearthing so many opportunities. It just really creates a target-rich environment. We have this kind of seizure program for screening children who have essentially unexplained epilepsy. We find, you know, CLN2 patients who are indicated for Brineura treatment. We also find increasing numbers of mutations that can get associated with pedigrees 'cause we're starting to get some details coming in large enough family trees that they can start to identify things that have genetic etiologies where, you know, it used to be like, "Oh, this sort of runs in families." Now there's actually concrete evidence, and it's actually concretely linked to specific genes with specific annotation of medical history.
It's really an amazing time to be where we are and to be able to leverage the, you know, diverse technology base that we've invested in. We can do small molecules, proteins, peptides, nucleic acids, complex nucleic acid mixtures. It's really a nice coming together of the fundamental thing about BioMarin in terms of our orientation to research and science and therapeutic opportunities that are presenting itself. That all is the way of saying that we've been successful in academic and early partnerships and for the time being, I think that that's where we are.
Great. One more comment. Sorry, one more comment directly related to this. As you know, I'm not gonna disclose the detail out here, but at R&D Day, we're gonna give you our first update on what is now going on with Voxzogo in skeletal indications beyond achondroplasia, which could open up a major additional opportunity for Voxzogo. I would highly recommend you attend that part of the R&D Day presentation.
Thanks.
Our next question from Kennen MacKay, RBC Capital Markets. You may ask your question.
Good afternoon. Hi. Maybe going back to some of the prior questions, with concern that the safety concerns in BMN-Tf7 might break through to Roctavian. Maybe can you address the levels of adeno viral, adeno associated viral integration that's in the vector used in Roctavian compared to that of human BMN-Tf7? Thank you.
It's not really practical to do, you know, head-to-head kinds of things. In general, the levels of integration that can be found across species are relatively low. I don't think that there's really a meaningful likelihood that Roctavian is necessarily any more or any less integrating than anything else. You know, the agency and the company early in the treatment of gene therapy referred to AAVs as vectors that have a low propensity to integration unless they are designed otherwise to integrate. Quite to the contrary, we did not add any designed-to-integrate methods to move genes that should be suspected of resulting in integration.
We've been fairly deliberate to stay on the low propensity integration side and believe that that's likely to be true for all our vectors. As you know, we've done longer term studies, both the HAE vector already and for a vector that is otherwise identical to Roctavian other than its coding sequence. We feel pretty good about the lack of read-through from one vector to another. In fact, we feel pretty good about the lack of read-through from mice to other species.
Okay. Thank you.
It appears there are no further questions at this time. You may now continue, JJ and team, for closing comments.
Thank you again for joining us today. We are hoping to meet you. We are poised for significant growth next year as just described. That's based on our conditional base business on the Voxzogo launch in the EMEA region and anticipated in the U.S. next month. Also, the Roctavian gene therapy potential, potentially later on sometime in maybe late 2022, as well as the key early-stage pipeline that we look forward to sharing with you in the back on November 30 during our virtual R&D Day. We are focused on continuing this strong momentum as we receive our next important catalyst, including the potential approval of Voxzogo in the U.S. by the end of next month.
Thank you for your attention today, and we look forward to speaking with you again soon.