BioMarin Pharmaceutical Inc.

Welcome to the BioMarin fourth quarter and full year 2020 financial results conference call. Hosting the conference call today from BioMarin is Tracy McCarty, Vice President of Investor Relations. Please go ahead, Tracy.

Thank you, Nikoa, and thank you everyone for joining us today. To remind you, this non-confidential presentation contains forward-looking statements about the business prospects of BioMarin Pharmaceutical, Inc., including expectations regarding BioMarin's financial performance, commercial products, and potential future products in different areas of therapeutic research and development. Results may differ materially depending on progress of Biomarin's product program, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical markets, and developments by competitors. And those factors detailed in Biomarin's filings with the Securities and Exchange Commission, such as 10Q, 10K, and 8K reports. On the call remotely from Biomarin Management Today, our J.J. Bien-Aimé, Chairman and Chief Executive Officer, Jeff Ager, Executive Vice President, Chief Commercial Officer, Hank Fuchs, President, Worldwide Research and Development, and Brian Mueller, Executive Vice President, Chief Financial Officer. We do hope to keep this call to one hour today, so we respectfully request that you limit yourself to one question during the Q&A portion of the call. Thank you for your understanding. I'll now turn the call over to our Chairman and CEO, J.J. Bien-Aimé.

Thank you, Tracy. Good afternoon, and thank you for joining us on today's call. We delivered strong results in the fourth quarter and full year 2020, demonstrating our continued operational excellence despite challenges brought about by the global COVID-19 pandemic. Excluding KUVAN contributions, biomarine revenues grew 13% in 2020 as compared to the full year 2019 revenues. And the company generated $85 million of positive operating cash flows for the full year 2020, underscoring our resilience in a challenging environment and the significant admin needs our medicines address. Our 2021 guidance does assume that the business environment remains fluid due to the ongoing effects of the pandemic, but also reflects the underlying global demand for our commercial brands, including KuVan, again, KuVan contributions in 2021. We expect 9% growth in biomarine marketed product revenue based on the midpoint of today's full year 2021 revenue guidance. We also expect continued positive operating cash flows for the full year 2021, both important indicators of the strength of our global brand. And in a moment, Jeff will provide more details on these market dynamics. Turning to our late-stage R&D programs and upcoming milestones, we are planning for a number of key events that we expect will drive substantial value over the coming quarters. Beginning with our European regulatory update, first with vasoetide for the treatment of children with achondrophagia, we are targeting a CHMP opinion this June, followed by the European Commission decision in late summer leading to a potential commercial launch in Europe this fall. To highlight the significance of these key regulatory milestones, we anticipate that Rosaritide's revenues X-to-X over the next five years represent close to 70% of our anticipated global revenues. Rosaritide continues to advance its plan, and we are optimistic that investors will share the same degrees of enthusiasm as the first pharmacological treatment to address the underlying genetic cause of achondroplasia that we have experienced from the patient community. In Europe, with Octavian gene therapy for severe hemophilia, we are also tracking the plan as we prepare for the resubmission of our marketing application in the second quarter of this year, next quarter. So assuming we remain on anticipated timelines in Europe, this could potentially lead to a Octavian CHMP opinion in the first half of next year, with potential European launch in the third quarter of 2022. As a reminder, We believe that there are three times as many severe hemophilia patients in Europe as compared to North America. In the United States, with both Vazoritide and Octavian, we are focused on providing additional phase three data to inform FDA's reviews of these highly innovative products. We look forward to providing the FDA with the recently available Vazoritide phase three results that demonstrate a sustained growth effect for over two years in children with achondroplasia. further corroborating the resort treatment effects and the long-term durability as will be required for the product's full benefits to accrue. In addition, if few patients from Phase 1-2 are now or at near final adult height, that is substantially in excess of that which their age and gender match peers would have achieved. This is great news for the patients and the patient community. So this shows that zoetide addresses the underlying cause of achondroplasia and that has always been our goal so that the patients may benefit in ways that go beyond natural gain. We believe that results to date across our phase three and phase two programs are supportive of zoetide becoming the first pharmacological treatment for this condition. With Roktavion in the United States, we are planning to dialogue with the FDA to explore the potential submission of the DLA based on available one-year data package as planned for submission to the EMA, with provision of two-year data during the review period. We recently convened a meeting with an expert advisory council to seek community and expert advice into our overall strategy and regulatory considerations. The council provided positive feedback on the data based on the dramatic lead control demonstrated with Octavian treatment. We were pleased with the feedback and insight into the regulatory strategy and the approvability of Octavian, and we look forward to further engagement with both the FDA and the EMA. And Hank, in a few minutes, will provide more details on the feedback. Moving to our earlier stage pipeline, we have numerous programs advancing this year. Starting with BMN307, gene therapy for PKU, we are pleased to share that we are moving to the next higher dose in our Phase I-II study, advancing the third potential treatment modality for our PKU franchise. We are encouraged by the sea-lowering and safety results observed in the first 2E13 cohort in our Phase I-II study, and we are now ready to move to the next dose of 2E13, which is similar to the Roktavian dose. Based on this early data from the 2013 cohort and our prior steep dose response experience with Octavian, we are optimistic that the CC13 dose will be our optimal dose. We will share the next update on the BMN307 from the dose confirmation phase of this study once we have selected the dose for registration enabling studies. In addition to BMN307, we have four other earlier state programs advancing that span a variety of therapeutic modalities and indications, including an oligonucleotide for Duchenne muscular dystrophy, gene therapy products for hereditary angioedema, and also hypertrophic poliomyopathies, respectively, and a small molecule for a subset of a chronic renal disease. In conclusion, despite the challenges, Faced against the backdrop of the global pandemic, demand for biomedicine drove strong results in 2020, and we are expected to grow 9% in 2021, again, excluding the contribution from Kuvaan, which is facing generic competition in the U.S. We look forward to this new year and the goals that lie ahead over the coming quarter. With our foundations of brands that constitute a strong-based business, By being positive operating cash flow, enabling the advancement of our next significant product opportunities with Vazorita and Roktavion, we are well positioned for substantial growth over the coming quarters and we anticipate significant revenue growth starting in 2022. After Vazorita and Roktavion, we look forward towards our earlier stage pipeline to ensure a steady flow of new product opportunities on the medium and long-term horizons. And we'll search all these programs in a moment. And finally, I just want to add that we ended 2020 with over $1.3 billion in cash and investments. And we anticipate being operating cash so far this year. So thank you for your continued support. And I will now turn the call over to Jeff for a discussion on our commercial business. Jeff.

Thank you, JJ. 2020 presented the world with extraordinary circumstances and challenges, so I am especially pleased with the performance and determination of our commercial teams through the year. Their efforts resulted in the mitigation of impact from both COVID-19 and the loss of exclusivity of Kuvan in the United States. Despite these headwinds, our teams across the globe collectively contributed to 9% year-over-year growth in total revenues for the full year, delivering $1.86 billion. Excluding KuVan contributions in 2020, our base business grew 13% year-over-year, an impressive result against the backdrop of the pandemic. We saw healthy revenue growth from our smaller, newer brands and maintained our mature enzyme replacement therapy business against threats from COVID-19. A notable milestone in the year, Brainura crossed over the $100 million revenue mark, fueled by continued starts and high patient compliance as clinicians continue to recognize the importance of early diagnosis and treatment of CLN2. In 2021, we expect Berner to continue its growth trajectory and anticipate an approximate 18% increase as compared to 2020 at the midpoint of guidance. Looking more specifically at the quarterly results, BioMarin revenues in Q4 totaled $452 million, or essentially flat to Q4 2019. I'll take a few moments now to share individual product details specific to the fourth quarter. Focusing first on Palantzeek, we're reporting $49.6 million in revenue for the fourth quarter, a 56% increase over the fourth quarter of 2019. For the full year 2020, Palantzeek sales totaled $171 million, representing a 97% increase as compared to full year 2019 results. The majority of that growth came from the U.S., where new patient identification and starts continued, albeit at an inconsistent pace due to clinic closures from COVID. Throughout the year, we observed PKU clinics impacted but adapting to dynamic COVID case surges, and despite factors outside of our control, new patient growth continued. We exited the year with approximately 1,000 patients in the US on commercial therapy, an impressive milestone, but only a fraction of the amenable patient population, given the approximate 30,000 PKU adults in our global territories. In Europe, COVID-19 proved particularly disruptive to Palenzi uptake due to clinic closures, as well as pricing and reimbursement negotiations that was disrupted as healthcare systems focused on the COVID-19 pandemic. As we begin 2021, we have an expectation of making progress on both price and reimbursement approvals and patient starts and that Europe will contribute more materially throughout the year. In its third full calendar year on the market, and even considering the likely continuing impact from COVID, we are expecting a remarkable 35% increase in revenue growth based on the midpoint guidance for Palancek in 2021, making it the largest expected growth driver in the portfolio. Kuvan, which experienced the loss of exclusivity in the U.S. beginning in October 2020, had total revenues in the quarter of $89 million, an anticipated decrease of 27% compared to Q4 2020, and almost exclusively associated with the impact from generic competition in the US. We expect to continue to experience erosion of our revenues in the United States, although not a catastrophic loss of share, due in part to strategies we have taken to retain market share. Our expectations for erosion of U.S. sales are captured in the full-year revenue guidance provided for QVAM. Turning now to our lysosomal storage disease products, I've commented in prior calls on the successful mitigation tactics quickly employed in the first months of the pandemic to ensure continuity of infusions for enzyme replacement patients. As a result, we exited the year close to baseline patient compliance for all three brands, Bimazem, Naglazyme, and Braneura. During 2020, we experienced new patient identification and resulting new patient starts occurring at a slower than anticipated pace due to the impact from COVID-19. In spite of that, Commercial patient counts for Naglothiamine Benzine grew by 5% and 9% respectively. As mature brands, we are highly penetrated of known MPS6 and more TOA patients, and continued growth for these brands is highly dependent on newly identified patients. The kind of patient growth experienced last year bodes well for continued future growth in demand for both brands. At the midpoint, We expect Naglizime revenue to decrease by 3% in 2021. That is entirely a result of expected order timing for certain markets, primarily Brazil, relative to actual orders in 2020. At the midpoint, we expect 8% growth in Vimism revenue in 2021. In 2021, we will continue our launch readiness efforts for Vasortide which we expect to be our largest brand to date if approved. We are busily preparing for possible launches in our two largest regions, North America and EMEA, in the second half of the year. With two applications moving forward in parallel, we have two complementary and attractive commercial opportunities ahead. Based on our experience, the U.S. typically presents a large market characterized with rapid payer approvals, rapid patient uptake, and favorable pricing. In a scenario of parallel launches, we expect the US to drive early revenue. Collectively, Europe presents a larger market opportunity based on larger patient populations. As has typically been the case with our European product launches, the pace of revenue uptake is slower initially as individual markets take time to navigate price and reimbursement approvals. Over several years, the larger EU market drives mid- to longer-term revenue growth and, with other international markets, becomes the engine of revenue growth for the long term. To put this into perspective, the pool of patients in our EMIA operating region, an important indicator of market potential, is roughly three times the size of that of the United States when considering estimates of achondroplasia patients with open great plates and severe hemophilia A patients. Bryson corridors are similar between US and early EU markets in particular. These comments summarize our experience generally with our marketed brands and it can apply to both the psoriasis Rocktavian and future pipeline programs. As we get closer to potential approvals for Visorotide, we will look forward to coming back to you with more details on our efforts to prepare for commercial launches, including our pricing strategy. In summary, and looking forward, we expect continued growth in our base business, with the exception of Kuban, where further erosion of the base is expected in 2021. Palanzit will be the largest growth driver as a single brand with strongest sales in the U.S. and material growth from Europe. Bimism and Brunura will continue on their growth trajectory appropriate to each brand's stage of life cycle, and we will be prepared for a successful launch of the Sorotide once approved. Thank you, and now I'd like to turn the call over to Hank. Hank?

Thanks, Jeff. And I, too, would like to congratulate and thank the commercial team for delivering medicines around the world in spite of all this uncertainty and also congratulate and thank the R&D team for their resilience and commitment and efforts in a year of high uncertainty in 2020. As JJ conveyed, we look forward to a number of important regulatory events in 2021 based on strong Phase III results, both from our Vasortide and Roctavian programs. that we experienced towards the end of last year and the beginning of this year. Accumulating data on durability of our products suggests meaningful clinical benefits will be maintained, and therefore, we remain optimistic about the potential of these two innovative therapies to be transformative to the people who need them. We were pleased to begin 2021 with positive Phase III roctavian results. To remind you, GENERATE-1 is the largest global Phase III study to date for any gene therapy and any indication having enrolled 134 participants. Compared to before gene therapy, there was an 84% reduction in annualized bleeding rate from 4.8 while on standard of care prophylactic factor VIII therapy replacement and before treatment with Ractavian to 0.8 bleeds per year after receiving Ractavian. The treatment burden of this condition in terms of mean annualized factor VIII infusion rate in the rollover population was also substantially reduced by 99% from 136 infusions to two infusions per year after treatment with roctavian. 80% of the participants were bleed-free starting at week five after treatment in the phase three study, again, in spite of the withdrawal prophylactic factory therapy. The findings of the study were all statistically significant as prospectively specified. Additionally, in 17 patients who had received roctavian two or more years prior to the data cutoff, A decline in factor VIII activity level was observed. However, factor VIII levels remained in a range to produce meaningful hemostatic efficacy, and the annualized bleeding rate was also very low at less than one bleed per year. In fact, factor VIII levels at this time point were higher than those observed entering the third year of follow-up after the 4E13 dose was administered to an earlier cohort, who also experienced an ABR of less than one in that third subsequent year. Therefore, the growing body of evidence supporting the clinical benefit of Ractavian and its durability for people with severe hemophilia A has been very encouraging and a tremendous gain for the field and the scientific community. As JJ mentioned, we recently held an expert advisory council meeting with former U.S. and EU regulators from both the FDA and EMA. key statistical experts deeply experienced in both the advisory committee process in the United States and the scientific advice process in Europe, physicians and patients to gain insight into the best path forward given the accumulating evidence demonstrating dramatic lead control in patients and people receiving Lactavian. Additionally, feedback from patient advisory leaders provided helpful insight into the importance of patients' informed choices and critical aspects to support decision-making for patients and prescribers. We are very encouraged with the feedback and the path forward for Octavian approval based on results observed to date and assuming favorable outcomes continue. We remain encouraged with the progress made to date and are continuing our dialogue with the Food and Drug Administration in the form of ongoing discussions both with CBER, Center for Biologics Evaluation and Research, leaders based on discussions with CBER leadership and with the review division about potential paths forward. We have more to share with the agency over the coming months as the Phase 3 program continues to mature with the two-year data for all subjects available in late November. With supportive feedback from the expert advisory council based on dramatic belief control demonstrated across our Ractavian program, we aspire to dialogue with the agency on potentially submitting a BLA with one-year results that could be supplemented with two-year results during review. This is our current thought process and actual guidance on next steps will be forthcoming as we continue our dialogue with the FDA over the coming months. We and the agency are intending to be deliberate in review and take the time necessary to ensure a careful examination of risks and benefits, but also ensure appropriate product label and risk management procedures in the marketplace. In Europe, we're targeting 2Q21 for resubmission of the marketing application authorization pending confirmation of upcoming pre-submission meetings. Under this timing, we could potentially receive a CHMP opinion in the first half of 2022. We've been engaging with the European Health Authority since the one-year data became available, and we are encouraged that the application review will be in progress as the two-year data become available and are prepared to share it should that be beneficial to supplement for the package. Given procedural considerations, it's likely that roctavian will be approved after the second year of data in the phase three are available. And therefore, our hope and intention is to shorten the interval between data availability and regulatory action as much as possible with a goal to enable physicians and patients to have an additional therapeutic choice in their ornamentarium. As for the ongoing phase two study, we intend to share a five-year update with the 6E13 dose as well as a four-year update on the 4E13 dose in the middle of this year. The importance of the Roctavian five-year update and continued durability of bleed control is a key focus, and we hope to see results consistent with what has been observed through year four. Recall that almost all patients remained bleed-free in all prophylactic therapy for four and three years after gene therapy, in spite of declining factor VIII levels among participants. Turning that of a sore type for treatment of achondroplasia, under review both in the United States and Europe, We were very pleased to share positive two-year results from our Phase III program last December, demonstrating that children maintained an increase in annual growth velocity through the second year of continuous treatment. A first analysis comparing all children randomized and treated with the sorotype for two years, 52 subjects, to all children from the run-in study who were randomized to receive placebo with an untreated observation period of two years, NM38, showed improvement in one-year height change in the treated group relative to the untreated group that was similar in the second year of treatment, 1.79, as in the first year of treatment, 1.73. The cumulative increase in height gain over the two-year treatment period was 3.52 centimeters compared to untreated children, which is the sum of the first year, 1.73, and the second year, 1.79. An important consideration in growth studies is the status of bone growth as measured radiographically and in comparison to the subject's chronological age. Some agents promote rapid growth but precipitate early closure of the growth plates, precluding gains from adding up over time. In contrast, measures of bone maturation in patients treated with the psorotide confirm that psorotide is promoting bone growth while maintaining and not accelerating bone maturity. This bodes well for accumulating treatment gains over time as growth plates are not expected to close prematurely. Turning to Versortide regulatory timing updates, with the NAA under review in Europe, we look forward to a CHMP opinion in June, followed by European Commission decision in late summer. If successful, this would enable Jeff's team to launch in Europe in the third quarter of this year. In the United States, we've chosen to provide the two-year phase three data to the FDA, given the opportunity to convey durability of treatment benefits in a larger number of patients. While this may result in a major amendment pushing the current PDUFA action date out three months to November, We believe it is prudent to make these newly available and encouraging results available regardless of potential delay in approval timing. Also new today, in January, FDA granted the SORTID priority review status based on the pediatric indication addresses and the lack of treatment options currently available. The SORTID now qualifies for a priority review voucher upon approval, which would be the third PRV granted to Biomarin. Consistent with the FDA's policies on changes to review classification for an ongoing application review, the PDUCA action date remains August 20, 2021. Turning to BMN307, our investigational gene therapy for PKU, results from the starting dose in the fearless phase 2 study demonstrating meaningful fee lowering in the first two subjects. The study will progress with a higher dose cohort, a three-fold higher dose 6013 vector genome per kilobe. We're hopeful this dose will be registration-enabling based on these early data from the 2E13 cohort and our prior steep dose response experience with Roctavian. We are conducting this study with mature manufacturers with a commercial-ready process to de-risk the program and facilitate rapid clinical development. We are excited about the prospect of BMN307 as it represents a potential third treatment option in our PQE franchise and our second gene therapy development program. We look forward to sharing results from the dose confirmation phase of the study when we've selected dose registration enabling studies. We doubled our early stage pipeline in 2020 via internal growth and external partnerships, advancing several preclinical programs spanning multiple modalities. With gene therapy beyond our Octavian and PKU programs, we're conducting IMD enabling studies with BMN331 gene therapy for hereditary angioedema. Our collaboration with Dynacor on hypertrophic cardiomyopathy, which we announced in May of last year, is progressing well. Together, we and Dynacor have achieved properly localized expression and function of myosin-binding protein C3 in cultured human cardiomyocytes and cardiac stem cell-derived organoids and in vivo with several lead vectors. We plan to select our candidate vector in 2021 for this program, and to commence non-clinical development studies to enable a subsequent IMD filing. BMN351, or DMD2.0, our oligonucleotide therapy for the treatment of Duchenne muscular dystrophy, has demonstrated high level of protein expression in experimental animals, possessing skippable dystrophic mutations, and at doses that are promising in regard to safety. BMN255, our small molecule for a chronic renal disease, for which we filed an IMD in 2020, is also progressing well, And we hope to share more detail on these programs on our R&D day tentatively planned for the second half of the year. The R&D organization is very energized and very busy as we advance a wide range of early and late stage programs to deliver on our goal of bringing transformative therapies to people with rare conditions. Thank you for your continued support. And now I'll turn the call over to Brian to review the financials for the quarter.

Thank you, Hank. Please refer to today's press release summarizing our financial results for full details on the fourth quarter and full year of 2020. Since Jeff touched on many of the top line results from the commercial business, I will primarily focus on bottom line results, operating expenses, and our 2021 guidance. As usual, all results will be available in our upcoming Form 10-K, which we are on track to file over the next couple of days. In terms of the bottom line, for the full year 2020, we provided guidance for GAAP Net Income of between $760 million and $820 million, and have reported a better-than-guidance GAAP net income of $859 million for the year. As a reminder, GAAP net income in 2020 includes the $835 million non-recurring tax benefit recorded in the third quarter of 2020 related to the transfer of certain intellectual property rights between BioMarin entities. Importantly, we observed that BioRen was able to generate positive gap net income for the first time in the company's history, achieving our goal set at the beginning of the year, despite the strains on the business in 2020 and the handful of material non-recurring transactions recognized in 2020. Turning to non-gap income, where the company delivered $312 million for the full year 2020, within the higher range of our guidance, and $40 million in the fourth quarter of 2020, driven by solid top-line results across the commercial portfolio and operating expense controls. Non-GAAP income for the full year 2020 was 87% higher than non-GAAP income for the full year 2019, despite the impacts of COVID-19 and KuVan loss of exclusivity in the U.S. since October of 2020. Moving to operating expenses, both R&D and SG&A expenses in the fourth quarter tracked with both recent trends and our 2020 guidance ranges. R&D expenses were slightly lower year-over-year at $157 million and $628 million for the fourth quarter and full year 2020, respectively. In the fourth quarter, R&D expenses primarily reflected our continued development of our late-stage programs for Sortide and Ractavian, as well as our early-stage programs and research, including BMN 307, our PKUG therapy. SG&A expenses for the quarter and full year 2020 were $196 million and $738 million, respectively, and were higher than 2019, reflecting the preparation for the potential commercial launches of Visorotide and Roctavian. And lastly, for 2020, we finished the year with $1.35 billion of total cash and investments, as compared to $1.17 billion at the end of 2019. The December 2020 balances reflect both the $536 million of net convertible debt proceeds raised earlier in 2020, and the expected $375 million cash outflow upon the maturity of convertible notes in October of 2020. The company generated $85 million of positive operating cash flows for the full year 2020, which is a great indicator of the health of BioMarin's base business, particularly considering the negative impacts of COVID-19 on our revenue. Now moving on to 2021 guidance. Jeff touched on many of the brand dynamics And for total Biomarin top line, we expect 2021 total revenues to be in the range of $1.75 to $1.85 billion. Importantly, as discussed last quarter, 2021 total revenues reflect the impact of several headwinds. Most notably are the impact of the Kuvan generic competition in the U.S. since October of last year and the continued impact of COVID-19 on our commercial business. Our guidance does not assume a rapid recovery and rebound from COVID-19 impact on our revenues, but our guidance does assume that the conditions and effects on our business will not worsen. For example, our guidance assumes that we will be able to maintain similar levels of patient compliance with our therapy regimens and rates of new patient starts that we experienced during the pandemic in 2020. While our total revenue expectations for 2021 are lower than 2020, We note that our core business, except for KuVan, is still growing healthily with 9% growth at the midpoint of our guidance range. And one comment on Aldurazime, which is marketed by Sanofi Genzyme and therefore we do not provide specific guidance, is that BioMoran Aldurazime revenues in the fourth quarter of 2020 were low due to the timing of products applied to Sanofi Genzyme. However, based on data provided to us by Sanofi Genzyme, Aldurazime added 10% more commercial patients during 2020. the product's 17th year on the market, which is a solid indicator that the market demand is increasing despite Biomarin Elders on revenue timing. Lastly, on top line, while we remain optimistic that Vasortide and Roktavion will be approved and launched, we are not expecting significant revenues from either product in 2021. Shifting to bottom line expectations for 2021, we anticipate recognizing a gap net loss ranging from 80 million dollars to 130 million dollars. And while our GAAP profitability goals are delayed while we continue to develop Besortide and Roctavian, we do expect to earn positive non-GAAP income in the range of $170 million to $220 million. This significant amount of non-GAAP net income, plus our expectation to earn positive operating cash flows for the full year 2021, that is able to both generate approximately $1.8 billion of revenues and develop a high-value late and early stage pipeline. In closing, from a financial perspective, 2021 is a year where we plan to hold the line on both our revenues and bottom line through the continued COVID-19 pandemic uncertainty and the pause in our substantial revenue and profitability growth aspiration. As a reminder, if Visorotide and Octavian are approved and launched, the commercial market opportunities for both of those potential products significantly exceed the market sizes of our current products. Therefore, we believe the combination of the positive operating results expected from Bomber and base business, plus the growth potential from the company's large late-stage opportunities that will leverage the infrastructure of the base business, create a compelling value proposition that is further expanded by our commitment to early-stage innovative rare disease research. Thank you for your support, and we will now open up the call to your questions. Operator?

Thank you. Ladies and gentlemen, if you would like to ask a question, you will need to press star 1 on your telephone. To withdraw your questions, just press the pound key. Again, to ask a question, press star 1 on your telephone. Our first question comes from Robin Karnovka with Tourist Securities. Your line is open.

Hey, guys. This is Kirpan for Robin. Thank you so much for taking my questions. So it looks like you've been engaging with the FDA quite a bit and discussing the pivotal data from Roctavian. Can you tell us how much of the data the agency has already seen, what additional data they need to see? And also, based on your commentary, during your engagement with the FDA, was there anything that gave you the indication that you will have to submit the two-year data for approval? Thank you so much.

Yeah, hi there. You know, the agency told us that they would expect to see the two-year data in the N of 134 patients before the product would be approved. And they said that before the one-year data were available, and they repeated that after the one-year data are available. In the short amount of time since the one-year data has available, they've only been able to see the top line. but their stance really was predicted not to have changed given the one-year data. I think the one-year data are strong and they anticipated that they'd be strong and they have reiterated their preference for making their approval data, their approval decision on the basis of having seen the two-year data.

Great. And then you talked about the feedback you received from the external counsels. In addition to the feedback being generally positive, was there anything new you learned that you think could help strengthen your case? To get approval for the one-year data?

Yeah. Well, we convened the Ad Council as kind of our version of an advisory committee reasoning that we wanted to hear the worst possible version of our story as told to us by highly critical people. Uh, and I would say that what we learned is, is that we have a pretty good program. One of our colleagues who is incredibly disciplined reviewers characterize the results as impressively strong. Uh, and I think the thing that we learned is that, um, this is, uh, it is really more like it was confirmed that the agency's decisions are more of a qualitative nature. and that they're just going to feel more confident about the application when they see the two-year data with the full 134 patients. So we're working very closely with our colleagues to try to discern the most facile regulatory pathway. And at this point, these are, to some extent, largely procedural discussions.

Our next question is from Corey Kasimov with J.P. Morgan. The line is open.

Hey, good afternoon, guys. Thanks for taking the question. Hank, you were hard to understand on some of your scripts, so I just want to make sure I got this correct. It sounds like based on that independent expert counsel and preliminary discussions with the agency that you may resubmit the Roctavian BLA on one year of data and supplement that mid-review with the two-year. So assuming I did hear that correct, I guess when do you expect to finalize this, and is Is this latest thinking, which sounds like a pseudo-acceleration from what we were talking about earlier this year, is this being driven more by the feedback you got from this outside counsel or more by the conversations with the FDA today?

Corey, you heard correctly in a little bit of both. I think on the one hand, the data package is impressive. On the other hand, novel therapy and hemophilia patients are deserving of a very careful examination of the data. And the part that, you know, is a little bit out of our control is just sort of, like I said, a procedural part, which is when do agencies have bandwidth and capacity to take on, you know, an additional chunk of data for review? Would they prefer if to get started before the two-year data are available, knowing that the two-year data are going to be available for them when they finish, or do they want to get started after that? Those are discussions that we're having. There are a lot of examples where agencies accept data during a review, and there are a lot of examples where the agency just doesn't want to get themselves in a position of accepting the data immediately. And oftentimes that doesn't have anything to do with, you know, necessarily what the data are. It has to do sometimes with other circumstances, you know, that the reviewers have to. As I mentioned, for example, at the end of last year with the EMA, their preference for reviewing the additional data was entirely procedural related to staffing levels within the EMA and the rapporteurs. So, you know, these are discussions that, you know, ordinarily don't get a lot of attention. in terms of synchronizing things. I know there's a lot of interest in regulatory actions on Roctavian. I think that we're encouraged with the really good data turned out the way we expected it to turn out at the one-year mark. And given what we've seen in our earlier trials, we have every reason to believe that things will turn out positively with the two-year data. And it's a matter of being patient and collaborating with them to assure that the review is given the full attention it deserves.

Okay. And did you say there were ex-regulatory officials on this committee?

Oh, yeah. Very senior. Very seasoned.

Top of the shelf. Okay. Perfect. Thank you very much.

Our next question is from Salveen Richter with Goldman Sachs. Your line is open.

Good afternoon. Thanks for taking my questions. Could you just talk about the – the commercial dynamics playing out with your PKU franchise and how you made the assumption of erosion to KUVAN and your guidance and what's playing out, you know, to offset that with Palantir?

Jeff, you want to cover that question?

Yeah, JJ, thank you for the question, Salveen. So we've provided some guidance on... on KuVan erosion and our expectations. And we've caveated this guidance by saying, one, we don't have any enterprise experience with loss of exclusivity of a product in a major market. And two, there's very few analogs to look to to guide expectations. And so we've guided that we think we would experience material but not catastrophic loss of share, like you might see in a retail prescription-driven product that goes generic, for example. And indeed, if you look at the drop of revenue in the fourth quarter of last year for Kuban relative to the fourth quarter of 2019, we were really right on top of our internal expectations at the 2020 revenue, the midpoint of the guidance, that captures our expectations for the further erosion of that KuVan business in the United States. Now let's turn to our expectations for Palantique. And though both products are part of the same PKU franchise, their paths are now relatively disconnected So our expectations for what happens with Pal and Zeke is not highly tied to what happens with Kuven now in the marketplace. It is true that we have a great base of business of Kuven and a great deal of patient level knowledge, particularly in the United States. And it is true that about 30% of our Pal and Zeke patients have transitioned from PKU. So these would be patients that are not achieving a desired strength of clinical benefit from KUVAN and that are thus appropriate for a more powerful agent in PAL and ZEKE. And so we continue to expect that we would be tapping into adults that have not received an adequate benefit from Kuban. But those two products are essentially on different paths at this point.

Thank you. Our next question is from Phil Nadu with Cohen and Company. Your line is open.

Good afternoon. Thanks for taking my question. Hank, your comments on procedural benefits on the Ractavian refiling was intriguing to me, and I guess I'm trying to work through in my head what would be more advantageous for Biomarin or the FDA filing early versus filing after you have the Phase II data. I guess what strikes me is from a Biomarin perspective, if they're going to give you a three-month Purdue extension when you file the two-year data anyway, it doesn't really buy you that much time to file early. But conversely, I guess for the FDA, maybe it gives them more time to contemplate the full range of the data, both the one year and two years. So I guess, how are you thinking what would be most advantageous to you based on where you think the FDA needs questions and maybe concerns are about the data package?

Uh, I could, the thing I focus on is when do we think we're going to finish? Cause that's obviously the point in time in which patients have a different choice available for them. And, um, You know, you could do the game theory in both directions, like you just said. The part that we don't know about is what's the workload and what are the considerations on their side. And, you know, how much time, you know, where did they leave the complete response letter off in the U.S.? You know, we still have inspection to do. How do they see the management of the workload? And so I think we just need a little bit more information from them about what their preferences are. But our focus is going to be on on getting the decision on the one hand in the most expeditious way possible and on the other hand to ensure that the review is thorough and that the considerations for product labeling are appropriate and well understood and that our post-approval commitments and risk management plans are the right ones. I think there's a lot of work that can be done before the two-year data. but they may choose to decide to wait for the two-year data before they get started. So it's a bit of a wait and see. I know everybody's looking for certainty about this, and we're working hard to deliver it.

And our focus is on trying to enable a choice for patients with hemophilia A. And just a brief follow-up, will they be definitive on what they prefer when you have your meeting with them or when you conclude your conversations that sound like they're ongoing now?

I think that we will be in a much better position to provide information after we've had a couple more dialogues with them as to, you know, definitive. That's the hard thing with the FDA. You know, it's sort of a step at a time. You know, you submit, they file. So a bit of a stay tuned on the U.S. regulatory status.

Perfect. Thanks for taking my questions.

Mm-hmm.

Our next question is from Chris Raymond with Piper Sandler. The line is open.

Thanks. So I wanted to just probe maybe a little bit more on the PKU commercial dynamic. I heard your comments, Jeff, around how KuVan and Palantir are somewhat disconnected, but I guess it sounds to me like as you described the KuVan erosion dynamic, it might be more price-driven than share-driven. So you guys would seem to maybe have a little bit more control over that conversion dynamic than otherwise. But maybe more importantly, I guess as I see it, it seems like you'd have a pretty decent sense of any kind of patient warehousing effect that might, you know, happen as the effects of the pandemic, you know, wane in sort of that timing. Can you maybe give a little bit more color on that, Jeff, you know, in terms of what you're seeing in terms of warehousing? Is this even something we should be asking about, I guess, as we think about the infection rate and all the other measures and metrics of the pandemic change over time?

Thanks, Chris. So good observations on your part. Maybe I'd start with saying that without disclosing details that would constitute competitive intelligence for one of our competitors, It is true that our revenue from KuVan loss of exclusivity is both a price and a volume mix. So you're right on that point. In terms of patient warehousing, it's a great question. The rate-limiting step for growth of Palantzeek in the United States has always been clinic capacity. And that condition existed before the pandemic hit. And when I say clinic capacity, I mean the ability and willingness of clinics to be prescribing Palanzeke and inducting patients and titrating them up on dose, either one patient at a time or maybe small multiples of patients at a time. And so as clinics were closed down, last year and as clinics continue to be operating under reduced capacity this year, it's really that clinic, PKU clinic capacity for dealing with new patients that's the great limiting step to growth of our business. So how does that point to a warehousing effect? Certainly there will be patients that are wanting access to Palenzeke and waiting for their clinics to either have the capacity or to be back in operation to be able to help them on Palenzeke, get a prescription, induct, titrate, and get to a maintenance phase. Certainly, that'll be the case. We'll still be dealing with overall clinic capacity during this year. Hopefully, the pandemic will let up. But one way or another, we're back to the issue of PKU clinic capacity as the rate-limiting step. I'm looking forward to working with clinics in the U.S. in particular and meeting the demand from patients that may be in that kind of warehouse category. Thank you.

Our next question is from Jeff Mecham with Bank of America. Your line is open.

Hey, guys. Thanks for the question. Also wanted to focus a bit on guidance. You know, when I look at other commercial biotechs or pharma, I didn't hear a lot about the continued COVID impact or headwind for this year. So I want to dig in to the guidance for the whole portfolio, not just PKU. Is it more the geographic mix? Is it the orphan nature of the business that you're still seeing a COVID impact? I didn't hear from you that there are headwinds on new starts.

compliance and so I just trying to figure out the Delta here thank you yep yeah thanks Jeff for the question so we did try to address some of the dynamics of how the the pandemic is affecting our business in in the guidance and so one of the things that we said was We're exiting 2020 having, at least for now, pretty much solved the patient compliance problems that we experienced early last year. So things could turn around on that front, but right now we think that we've got patient compliance under control. The bigger issue that we pointed to in the script is... is the rate of new patient identification and new patient starts. So last year we, we did in fact have material new patients for, um, for an Aglazyme 5% patient growth, Vimazem 9% patient growth and, uh, Palenzeke, you can read that from the revenue growth. Um, but as, as I described, uh, just a moment ago, the rate of new patients starts for Palantir was severely impacted by COVID-19 last year and will continue to be impacted this year until PKU clinics kind of get back to operating as normally pre-pandemic. And even then, we've got the clinic capacity issues and overall gaining factor. For the enzymes, we're expecting that the the new patient starts will continue to be slower than we would have expected had there not been the COVID-19 pandemic. So it's kind of that new business that results from patient identification and patient starts for our LSD brands that are affected there. And you're right. These dynamics may be unique to biomarins, enzyme replacement therapy and PKU business globally relative to some of the other companies you're covering.

And if I may add, Jeff, regarding specifically Palenzyk, the issue here is that, as you might remember, Palenzyk revenues really start taking in four months or so after initiation of treatment because of the titration period. And in the first three to four months or so, the revenues generated per patients are pretty limited. And consequently here, you know, since we had the PKU clinics were closed for most of 2020, and then they were starting to reopen. And then when the second wave hit in the winter, starting in November, they closed again. And until January, they're starting to reopen now. So in a sense, we've missed a lot of new patient starts, even in Q4 of last year, which are impacting the revenue this year. But again, the good news is that, you know, with the vaccinations and the pandemic, hopefully going away, those clinics are going to reopen and, and, uh, and that's going to allow us to accelerate the growth of forensic again.

Gotcha. Okay.

Jeff, sorry, this is Brian Mueller. I thought I just, uh, I'm in and yeah, clarify. So we were trying to clarify that the headwind, the COVID headwind is still there. But the assumption in our guidance is that it won't worsen. So even during 2020, we were able to add new patients, albeit at a slower rate due to the pandemic. We had some disruptions in weekly infusions, which we were largely able to recover. So we're assuming we're going to be able to maintain the current levels in 2021. OK.

Thanks for clarification, guys.

Our next question is from Paul Matisse with Seesaw. Your line is open.

Hi, thanks for taking the question. This is Thor on for Paul. Quick question on HAE. Given kind of like the evolving competitive landscape, what are you kind of assuming and what are you expecting to need to hit with the gene therapy to be competitive in that space?

I think one simple way of looking at therapies for which they're – conditions for which there are therapies is the extent to which the available therapies carry their own burden in the condition. And clearly that's the case in hemophilia A. Clearly that's the case in PKU. And similarly in HAE, you can get reasonably low attack rates, but it requires – a high degree of compliance, which is not easily maintained. And patients are looking for the opportunity, essentially, to be attack-free and prophylaxis-free. And as we've shown with Ractavian, I think with Ractavian, of the 134 patients, I think two have returned to prophylactic factor replacement therapy. And in our long-term studies of three and four years, nobody's returned to prophylactic factor therapy. And bleed rates are very low. So, You know, an HAE population, I think, would want the same sort of thing, which is a meaningful proportion of patients experiencing no attacks and no need for prophylaxis. And I think that would be an important therapeutic advance for some of these patients.

Great. Thanks.

Our next question is from Akash Tiwari with Wolf Research. Your line is open.

Thanks a lot. So it looks like consensus models have operating margins approaching 25% by next year and 42% by 2024. Given the delays in Besor, Tide, and Valrox, do you feel like those figures are hitable organically? And has there been any discussions internally about how to improve the cost structure beyond just COG, but maybe to R&D and SG&A? And do we know broad strokes what's baked in for 2021 R&D spend for Besor, Tide, and Valrox? Thanks.

Ryan, do you want to take this one?

Yeah, I can take that, CJ. Thanks. Yeah. So thanks for the question. And you touched on, you know, one of the key elements we view in our, you know, value proposition, which is both margin growth and, you know, profitability growth with the potential of besoritide and roctavian. So while we haven't given long-term guidance, you know, we've talked about the larger market potential for both of those potential products. and the leverage, to your question, that we hope to get out of our existing infrastructure. So, you know, the infrastructure we've built, whether it be sales and marketing or R&D support or G&A support that we've got in place today to support the $2 billion of revenue and, you know, non-GAAP income at a positive level, which you can approximate to operating profits, it's that same infrastructure that we plan to use to launch Visorotide and Rocksavian. So while there's going to be some incremental investments for both of those products, we expect a lot of those revenues to drop to our profit margin. And side note is we also expect lower cost of goods sold from those two products. So while we're not given specific numbers for the future, that's how you can think about the trajectory, the P&L. And on R&D, you know, we do want to increase the investment in R&D. We've got an exciting early stage pipeline and research engine. that we want to continue to fund, but we believe we can do that and increase R&D on an absolute dollar basis, but reduce it as a percentage of revenue, thereby increasing profits. And I think you asked about Resortide and Rocktavian R&D specifically. We don't give specific product-level R&D guidance, but with both of those products still being in registration and requiring a lot of our internal efforts, And you'll see that we do disclose historical R&D by program in our 10-K, so you'll see that when we file the K. You can expect similar levels of roctavian and basurotide R&D this year. Does that help?

Yeah, thanks so much.

Thanks.

Your next question comes from the line of Keenan McKay of RBC Capital Markets. Your line is open.

Hi, thanks for taking the question, and congrats on wrapping up 2020 on a strong note. Maybe just another question on coupon. I would love to understand a little bit more just what the assumptions are around built into the guidance around additional generics entering the market, if that's something, again, after that six-month exclusivity period, it is sort of built into guidance, or again, just... Just sort of what is built into guidance there. Thank you again.

I'll start, and then maybe Jeff or Brian can comment. But at this time, we don't anticipate any – we only anticipate one additional generic this year because I think there is no other – there is no third generic so far that has filed for an AD application in the U.S. So we do assume that the second generic will be launching this year. Jeff or Brian, do you want to add something to this?

That is our assumption, JJ.

Jeff?

Yeah, just very briefly. So we were aware and expecting two generic entries. We haven't seen, as JJ said, a third generic entry. And relative to our expectation that we can retain some meaningful share of KuVan business in 2021, our modeling suggests that it's exactly when you see a third, fourth, fifth generic enter the market that it becomes difficult to retain that share. So our assumption right now is two generics, we can retain meaningful share in the U.S.

Next question, please, operator.

Yes, ma'am. Your next question is from Jenna Wang of Barclays. Your line is open.

Thank you for taking my questions. Just two very quick regarding the gene therapy. First is Octavian. Hank, did I hear you correctly for EMA approval? They actually, given the timeline, they likely also will see the two-year data. If that's the case, would that be any requirement for approval regarding the two-year data for EMA. And the second question is regarding the PTU gene therapy. So if I recall correctly, the first dose is a 2E13. And what kind of factor or data pack from the initial dose make you decided to choose a 6E13 as a second dose?

Yeah, hi, Gina. I'll do the second one first. We used the 2E13 dose as a starting dose that was based on preclinical studies where we thought there was a decent chance to see some efficacy, and indeed we did see some evidence of effectiveness. And we had preplanned that dose intervals would proceed in half log, meaning we would go from 2 to 6 E13. And we're not anywhere close to as concerned about the potential for overexpression with phenylalanine hydroxylase as we were in consideration of it for roctavian because we've shown that you can't really get a fee of, you can't get really sick from a low fee. And the enzyme is such that it shouldn't cause low fee. So we skipped the 4E step, if you will, and went to the 6E step as originally planned. And given the steep dose response curve that we observed with roctavian and the initial signs of efficacy that we've seen, both in terms of fee lowering but also relatively low, no evidence of liver dysfunction from the transgene, we're encouraged to take the next step at 6013. And as far as your question about the EMA, I think it's important to understand that these procedures with the health authorities take some time and that when you talk about, well, we have the one-year data and then the two-year data are available one year later, you know, for the EMA, that's almost the length of a review cycle. So you have to imagine that they're going to have to go through the intellectual process of thinking through where do they want that data at what time point and what role will it play in the decision? And as I've said before, the Europeans were less focused on the two year data than the FDA were. So again, these are discussions with the health authorities that we have to have about their procedures, their timing, their considerations, what they think they need in terms of ensuring effective, adequate time for review. So we'll be in discussion about that. We've not received anything from the EMA that says anything different than we've represented to you before. That is, you know, we believe that the one-year data are very important to them, and we're just acknowledging that reviews will not conclude until the two-year data are available.

Did you get any feedback regarding minimums, the ADR they will be looking for, just directionally, for two years?

Uh, no, but I'll, but, but what is clear is, like I said, the, you know, even the hard, even hard edge reviewers view our reduction in the annualized bleeding rate from 4.8 to less than one. And, and it's been less than one, more or less everywhere we've looked, you know, the second year after gene transfer with the phase three material, the third year after gene transfer with 4013, the fourth year after gene transfer with 6E13, by and large, these are very low annualized bleeding rates. And so I don't think there's any real quarrel with the magnitude of the activity on the clinical endpoint. The issue of the CRL, as we've talked about, is the ability to project the future trajectories of factor VIII expression. And with two years of data and the N of 134, we have to lay the issue to, maybe not rest, but at least know how to characterize it in the product label in a benefit-risk decision.

Great, thank you. Your next question is from Matthew Harrison of Morgan Stanley. Your line is open.

Hello, everyone. This is Costa Son for Matthew. One quick question on Vosoritide. Can you provide some color around the launch preparation in Europe, and how are you thinking about pricing?

Jeff, you want to cover that?

Yeah, happy to. So, you know, go back to some of the things we said in the prepared remarks. One is Europe represents a very, very large patient opportunity for us over time. And in Europe, it takes a little time to go market by market, navigate price and reimbursement approvals, get patients started in generating revenues. We really expect Europe to be the long-term driver of revenue for Vasorotide. In terms of pricing, we've done a fair amount of pricing research in the US and in Europe. And as is typical for our practice, we won't set a price until we've gotten approval, we've got a label. that sort of thing. But we think that pricing corridors between our initial European markets, call that France, Germany, Italy, for example, and the United States will be relatively similar for list pricing in particular. And as we've guided to previously, based on the size of the patient population, we're probably not thinking about ERT types of pricing maybe something more similar to Pal and Zeke type of pricing for the sorotide. And then in terms of launch preparations, achondroplasia patients, we don't need to go through the disease awareness and screening and patient identification. All of the achondroplasia patients are essentially known as having achondroplasia from or shortly after birth. So that's an important step that we can skip, and it's a powerful step to skip. What we do have to do is we have to, upon launch, kind of track down and corral those achondroplasia patients and get them to an appropriate treatment home. That treatment home, in some cases, might be geneticists and genetic clinics that we're already connected with. or it might be a new specialty and a new call point for us like pediatric endocrinologists who are very accustomed to treating growth disorders, but who don't know achondroplasia because there's not been a treatment for achondroplasia, pharmacologic treatment, to date. So those are the kind of big things that we're focused on, finding achondroplasia patients where they exist today, lining up an appropriate treatment home for them, and homing in on our final pricing strategy. Very helpful. Thank you.

Your next question is from Mohit Mansal of Citigroups. Your line is open.

Hi, guys. This is James on for Mohit. Just had a question. Since presenting the one-year data in early January for Roctavian, were you able to engage in any discussions with the physicians or payers? We'd love to get any feedback on or call on feedback there.

Maybe I could start with the physicians. You know, as I said, we had a number of different kinds of physicians on our external advisory council that was intended to be convened kind of like an FDA adcom. So it It included those skilled in the practice of hemophilia A treatment who gave voice to the importance of having a treatment option and the importance of both ADR and factor VIII in considerations for choosing Ractavian or an alternative therapy. But also the group was augmented by physicians who are primarily, let's call them regulatory physicians, who have really seen everything under the sun and internationally for the past couple of decades. As I said, one of our colleagues came away making a comment, and this person has an extremely high bar of saying, this is an impressive data package. So on the basis of all that, we look forward to the two-year evidence package holding up, and if that's the case, then we should be able to make available a choice for patients. And Jeff, do you want to speak anything about payers in response to one-year data?

Yeah, happy to. Great question, James. So we're really happy with the way the one-year Octavian data came out. We have not had a chance to go back explicitly with payers and refresh our payer research with them And we will during the course of this year. What I would say is the one-year data was highly consistent with the product profiles that we were putting in front of payers, both in the United States and in Europe last year. So I concluded upon seeing the one-year data that the feedback that we've gotten from payers to date is probably going to be consistent with the feedback we'll get from payers after we've explicitly stepped through that one-year data. Appreciate it, guys.

Thank you so much.

Your next question is from Liana Misatos of Redbush Securities. Your line is open. Thank you.

If 30% of Palinzeq patients came from Kuvon, What percent of KUVAN patients are going to Palantik versus the generic?

Okay, so let me see if I understand the question. You said what percent of KUVAN patients are moving over to the generic product, and I think that's independent of your observation that 30% of Palo Alto patients are, uh, transitioning from QN. So, um, we're, we have that data. Um, that's important and valuable data that we consider competitive intelligence that we don't want to give to, uh, the generic competitors. Um, and so I would guide to saying that if you follow the, uh, the revenue erosion for the quarter and the revenue erosion that, um, that we've projected for 2021. I've already commented that the revenue is a mix of volume and price erosion, and I'm afraid you'll have to reduce those percentages at your end.

I mean, if I may add, Liana, also the other dynamic is that Kuvani is only approved in the U.S. Sorry, Palantir is only approved in the U.S. for adults. And there are a lot of kids, there were a lot of kids on KUVA, and obviously they cannot be switched to polyethic at this time, or until they reach age 18.

Okay, thank you.

Your next question is from Michelle Gilson of Kanagard-Dinuwiki. Your line is open.

Hi, thank you for taking my question. I'm just wondering, on PKU gene therapy, you mentioned you're escalating the dose to 6E13. I guess compared to what you saw in 2E13, what are you looking for to see in that next dose? And what gives you confidence that 6E is going to be the dose? And then just kind of, if I can have a side question here, is there any indication that you're seeing in the data so far that the modified steroid regimen is... is, I guess, better than what was used in the GENERATE studies?

Yeah, it's too early to comment on steroids just yet. And what gives us confidence the 60-dose group is going to do it? You know, the preclinical data that we have reasonably predicted, actually, what we would see in the starting dose level. And as I mentioned, both on the preclinical data for Octavian, clinical data on Octavian and preclinical data on 307, you know, we do observe there to be a steep dose response curve. So that's, it's the amalgam of that because it's confidence that the 6E13 dose will do it. And when I say it, you asked, what are we looking for? I think the dream of everybody with phenylketonuria is normal feeding, normal diet, and I don't have to take anything for it. And I do think that, you know, again, when you go back to what Octavian offers, it's You know, we reduced factor VIII infusions from 136 per patient per year to two per patient per year. That would represent a very substantial reduction in the burden of care for patients with phenylketonuria. And those patients also experienced fewer than one bleeding event in a year, which would kind of relate that over to the PKU. arena, that would be like, you know, no fog events, no confusion events, no mental cloudiness events. So the it that we're looking for with PKU gene therapy is normal feeding, normal diet.

Okay, thank you. Your next question is from Tim Lugo of William Blair. Your line is open.

Hi, guys. This is John on for Tim. Thanks so much for taking my question. I was just wondering if there's anything the team has been seeing or any comments that you've been hearing from physicians about the entrance of generic cuvon and how that might be influencing your expectations for erosion over the near and medium term. Thanks.

I mean, you can cover that, Jeff, but I think we've covered that since you've been to the call. Jeff, do you have anything to add here?

The only thing I'd add here is we think that the generics are essentially a specialty pharmacy substitution type of activity. We don't think that the generics are promoting like in a branded generic fashion to our physicians. And one thing that we have going in our favor is I think physicians and patients have been have been and are continuing to be sensitive to the ranges of services that Biomarin provides around our drugs, including Kuvan and the value of those services. And so that's a good thing for us.

All right, thanks so much.

And there's no further questions. I would like to turn it back to JJ Bien-Aimé for closing remarks.

Thank you, operator. So I would say that, again, despite the business challenges that were caused by the COVID-19 epidemic last year, the demand for Balmain's medicine drove some strong results in 2020, and they are expected to grow 9% in 2021, including contributions from CUBAN. So with our strong revenues base, driving positive operating cash flows, enabling the net advancement of our next significant product opportunities, We are well positioned for substantial growth over the coming quarters. Importantly, if Zoetat and Roktavion are approved and launched as we expect, the commercial market opportunities for both of these potential products significantly exceed the market sizes of our current products. These large-stage opportunities combined with our established-based business create a compelling value proposition that will enable the continued growth and expansion of our innovative research programs. I want to thank you for your continued support and stay safe.

Thank you. You may now disconnect.