Q4 2020 Biomarin Pharmaceutical Inc Earnings Call

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Welcome to the Biomarin and fourth quarter, and full year, 'twenty and 'twenty financial results and conference call.

Unknown Executive: Biomarin Fourth Quarter and Full Year 2020 Financial Results Conference Call. This concludes the conference call today from Biomarin. President of Investor Relations, please go ahead. Thank you, Nikoa, and thank you everyone for joining us today.

Hosting the conference call today from Biomarin is Traci Mccarty Vice President of Investor Relations. Please go ahead Traci.

Thank you Nicole and thank you everyone for joining us today to remind you. This non confidential presentation contains forward looking statements about the business from.

Unknown Executive: To remind you, this non-confidential presentation contains forward-looking statements about the business prospects of Biomarin Pharmaceutical Inc., including expectations regarding Biomarin's financial performance, commercial products, and potential future products in different areas of therapeutic research and development. Results may differ materially depending on the progress of Biomarin's product 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 10-Q, 10-K, and 8-K reports.

And pharmaceutical Inc, including expectations regarding Biomarin and financial performance commercial products and potential future products and different areas of therapeutic research and development.

And may differ materially depending on progress with Biomarin is product and program.

And as the regulatory authorities and availability of capital future actions and the pharmaceutical market and developments by competitors and those factors detailed and Biomarin filings with the Securities and Exchange Commission, such as 10-Q 10-K, and they can't report.

Unknown Executive: On the call remotely from Biomarin Management today are JJ Bien-Aimé, Chairman and Chief Executive Officer, Jeff Ajer, 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 will now turn the call over to our Chairman of the Studio, JJ Bien-Aimé.

On the call remotely from Biomarin management today are J J D anime, Chairman and Chief Executive Officer, Jeff <unk> Executive Vice President and Chief Commercial Officer, Hank Fuchs, President worldwide Research and development and Brian Mueller Executive Vice President and Chief Financial Officer.

You have to keep this call from 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 will now turn the call over to our chairman and CEO.

JV entity.

JJ Bien-Aime: Thank you, Traci. 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 revenue. And the company generated $85 million of positive operating cash flow for the full year 2020, underscoring our resilience in a challenging environment and the significant administrative needs our medicines address.

Thank you Traci and good afternoon, and thank you for joining us from today's call are we delivered strong results and the fourth quarter and full year 'twenty and 'twenty.

Demonstrating our continued operational excellence despite challenges brought about by the global COVID-19 pandemic.

Excluding kubota contributions Biomarin revenues rose, 13% in 'twenty and 'twenty as compared to the full year 'twenty swap and 2019 revenue.

And the company generated $85 million of positive operating cash flow.

For the full year, 'twenty and 'twenty underscoring our resilience and.

A challenging environment.

And the significant unmet need and our medicines address.

JJ Bien-Aime: Our 2021 guidance does assume that the business environment remains fluid due to the ongoing effect of the pandemic, but it also reflects the underlying global demand for our commercial brand. Excluding Kuvan, again, Kuvan contributions in 2021, we expect 9% growth in Biomarin 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 are important indicators of the strength of our global brand, and in a moment Jeff will provide more details on these market dynamics.

Our 'twenty 'twenty, one guidance does assume that the business environment remains good.

The ongoing effect of the pandemic, but also reflects the underlying global demand for our commercial brands.

Food and coupon and again cause and contributions in 'twenty and 'twenty, one we expect 9% growth and Biomarin marketed product revenue based on the midpoint up today's full year 'twenty 'twenty, one and revenue guidance.

And so we expect continued positive operating cash flow for the full year 2021.

Both are important indicators of the strength of our global brands and in a moment, Jeff will provide more details on these market dynamics.

JJ Bien-Aime: 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 Zoetides for the treatment of children with achondrophagia, we are targeting a CHMC opinion this June, followed by a 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 Zojikai's revenues x to x over the next five years will represent close to 70% of our anticipated global revenue.

Turning to our late stage R&D programs and upcoming milestones. We are planning for a number of T events, and we expect will drive substantial value over the coming quarters.

Beginning with our European regulatory update.

Firstly, the Missouri tide.

For the treatment of children with Achondroplasia, we are targeting and you see a change in your opinion. This June.

Goodbye.

Iraq and commission decision in late summer, leading to a potential commercial launch in Europe. This fall.

To highlight the significance of this key regulatory milestones, we anticipate that revenue.

Revenue extra exits over the next five years represents close to 70% of our anticipated global revenue.

JJ Bien-Aime: Zorica continues to advance the status, and we are optimistic that investors will share the same degrees of enthusiasm for the first pharmacological treatment to address the underlying genetic cause of achondrophasia that we have experienced from the patient community. In Europe, with Vocabulary and Gene Therapy for Sophismophilia, we are also tracking the plan as we prepare for the resubmission of our marketing application in the second quarter of this year. Assuming we may remain on anticipated timelines in Europe, this could potentially lead to an Octavian CHMP opinion in the first half of next year, with potential European launch in the third quarter of 2020. As a reminder, we believe that there are three times as many severe hemophilia patients in Europe as compared to North America, the United States.

Was there any tie continues to advance the standard and we are optimistic that investors would share the same degrees of until we get the first of all a pharmacological treatment.

Address the underlying genetic closer if he comes from phase yeah.

We have experience from the patient community.

And Europe, with Leucadia and gene therapy for COPD and with video and we also tracking to plan and prepare for the Resubmission of our marketing application in the second quarter of this year next force.

And as you need we may we may not anticipated timelines in Europe, which could potentially lead to a lipstick and th empty opinion and the first half of next year, which.

And with potential European launch and the third quarter of 'twenty and 'twenty two.

As a reminder, we believe that there are three times as many severe hemophiliac teaching and Europe.

As compared to North America.

And in the United States, and we suppose there's always sad and we'll give you and we are focused on providing additional phase III data to inform fda's reviews of these highly innovative products.

JJ Bien-Aime: With both Zoetide and Octavian, we are focused on providing additional phase 3 data to inform FDA's reviews of these highly innovative products. We look forward to providing the FDA with the recently available Vazoretide phase 3 results that demonstrate a sustained growth effect for over two years in children with achondroplasia, further corroborating the Vazoretide treatment effect and the long-term durability as will be required for the product's full In addition, a few patients from Phase 1-2 are now or at near final adult height, so that is substantially in excess of that which their age and gender-matched peers would have achieved.

We look forward to providing you with the recently available zoisite phase III results.

Demonstrate a sustained growth effects from over two years and children with achondroplasia and further corroborating and if it's the only tax refunds effects and the long term durability and should be required.

Acquired from a product school benefits to a true.

In addition, a few patients from our phase went through or not or a deal a day.

Our final adult height cause that is substantially and access.

And that's reached their age and gender matched peers would have achieved this.

JJ Bien-Aime: This is great news for the patients and the patient community. It shows that Zoetide addresses the underlying cause of achondroplasia, and that has always been our goal so that patients may benefit in ways that go beyond statistical gain.

And it's great news for these patients and the patient community.

This shows that.

And there's always that addresses the underlying cause of achondroplasia and the household and it's always been our goal.

So that the patients may benefit and ways that go beyond natural game.

JJ Bien-Aime: We believe that results to date across our Phase 3 and Phase 2 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 the available one-year data package 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 on our overall strategy and regulatory considerations.

We believe that our results to date of course, our phase III and phase two programs are supportive of Zoe tied becoming the first from a source pharmacological treatment for this condition.

With rotating and even United States, we are planning to dialogue with the FDA and explore the potential submission of the BLA based on available one year data package.

And for submission to the EMA with provisional to you they are doing the music.

We recently convened a meeting with and expert Advisory Council and seeks community and expert advice and to our overall strategy and regulatory considerations.

JJ Bien-Aime: The Council provided positive feedback on the data based on the dramatic beat 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 BMN-307 gene therapy for PKU.

The council and provide us with positive feedback on the data based on the dramatic decontrol demonstrated with what David and treatment.

We were pleased with the feedback and insight.

Through the regulatory strategy and the probability of raw materials, and we look forward to further engagement and we bought the F E M H and Hank.

And a few minutes, we'll provide a more detail from the feedback.

Moving to our earlier stage pipeline and we have numerous programs advancing this year, starting with B M and three or seven Jean said he for PKU and we are pleased to share that we are moving to the next higher doors and I'll squeeze one each day.

JJ Bien-Aime: We are pleased to share that we are moving to the next higher dose in our Phase 1 pre-study, Advancing the Third Potential Treatment Modality for PPU Projects. We are encouraged by the sea lowering and safety results observed in the first 213 doles, a cohort in our Phase 1-2-3, and we are now ready to move to the next dose of 15 to 30. [inaudible] Based on this early data from the 2013 cohort, and our prior steep-dose response experience with Octavian, we are optimistic that the CFC13 dose will be our optimal dose.

Advancing the third potential treatment modality for picking your franchise.

We are encouraged by the sea Laurie and safety results observed in the first two researching those.

Our cohorts in our phase one two study and we are now ready to move and ex those two pieces of it.

<unk> 13, and which is EBITDA to their books, even though.

Based on these early data from the 2013 cohort.

And our prayers team does respond to 60 years, we've looked at and.

We are optimistic that the 60 13 dose will be our optimal dose.

JJ Bien-Aime: We will share the next update on BMN PURE 7 from the dose confirmation phase of this study once we have selected the dose for registration and the enabling study. In addition to MnCO7, we have four other earlier-stage programs and grants 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.

Moving to share the next updates on the B M and she was seven from the dose confirmation phase of the study once we have selected the dose for <unk>.

Registration, enabling studies.

In addition to the M and T O seven react for all their earlier stage programs advancing that's funny variety of therapeutic modalities and indications into net.

Including and Alibaba nucleotide for Duchenne muscular dystrophy.

And so that people ask for Henry already Kelly and good enough.

So hypertrophic cardiomyopathy is respectively, and a small molecule or a subset of a chronic renal disease.

JJ Bien-Aime: In conclusion, despite the challenges... Based against the backdrop of the global pandemic, demand for biomarine medicines drove strong results in 2020, and we are expected to grow 9% in 2021, again excluding the contribution from Kuvan, which is facing generic competition in the US. 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, driving positive operating cash flows, and enabling the advancement of our next significant product opportunities with Rosoritat and Roktavion, we are well positioned for substantial growth over the coming quarters, and we anticipate significant revenue growth starting in 2022.

In conclusion, despite the challenges.

Based against this backdrop and the global pandemic demand for Biomarin medicines drove strong results in 'twenty and 'twenty and we are expected to grow 9% through 2020 once again, excluding the contribution from Cuba and when she finishes.

And the competition and the U S.

And we look forward to this new year and the goals that lie ahead over the coming quarters.

With our foundation of brands that constitute a strong base business.

Having positive operating cash flow and they.

And the advancement of our next day, Michigan, and Florida opportunities, which was already thought and what gave you and we are well positioned for substantial growth over the coming quarters, and we anticipate significant revenue growth starting from 2022.

JJ Bien-Aime: After Vazoritan and Rokavian, we look forward to our earlier stage pipeline to ensure a steady flow of new product opportunities on the medium and long-term horizon. Thanks for the update on this program in a moment, and finally, I just want to add that we ended 2020 with over 1.3 billion dollars 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 of our commercial business.

After it was already tied a rope gave you and we look forward to.

Those are all your stage pipeline.

Sure and steady flow of new products opportunities on the medium and long term horizon.

Ankle and search all these programs and a moment and finally I just want to add the Yonder 22, one and we had over $1 $3 billion and cash and investments and.

And we anticipate operating cash flow positive this year.

So thank you for your continued support and I will now turn the call over to Jeff for a discussion on our of our commercial business.

Jeff: Thank you.

Jeffrey Robert Ajer: 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 the impact from both COVID-19 and the loss of exclusivity of QVAN 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

Thank you J J F 'twenty.

<unk> 'twenty and 'twenty, you 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 Kuban and the United States.

Despite these headwinds our teams across the globe collectively contributed to 9% year over year growth and total revenues for the full year delivering $1.86 billion.

Jeffrey Robert Ajer: Excluding Kuban 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, Branura 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.

Excluding two van contributions and 'twenty and 'twenty, our base business grew 13% year over year and 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 and here, Brian Noura crossed over the 100 million dollar revenue Mark fueled by continued starch and high patient compliance as clinicians continue to recognize the importance of early diagnosis and.

And treatment of C O M. Two.

Jeffrey Robert Ajer: In 2021, we expect Bernard 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.

In 'twenty and 'twenty, one we expect printer to continue its growth trajectory and anticipate and approximate 18% increase as compared to 2020 at the midpoint of guidance.

Looking more specifically at the quarterly results Biomarin revenue.

I'll take a few moments now to share individual product details and specific to the fourth quarter.

Jeffrey Robert Ajer: Focusing first on Palantzic, 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, Palanzec 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 started continued, albeit at an inconsistent pace, due to clinic closures due to COVID. Throughout the year, we observed PKU clinics impacted by 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.

Focusing first on Pal and <unk> were reporting $49 $6 million and revenue for the fourth quarter, a 56% increase over the fourth quarter of 2019.

For the full year, 'twenty and 'twenty pounds, each sales totaled $171 million, representing and 97% increase as compared to full year 2019 results. The.

The majority of that growth came from the U S where need patient identification and starts continued, albeit at and inconsistent pace due to clinic closures from Covid.

Throughout the year, we observed PKU clinics impacted but adapting to dynamic COVID-19 case searches and despite factors outside of our control new patient growth continues.

We exited the year with approximately 1000 patients and the U S on commercial therapy and in price a milestone, but only a fraction of the amenable patient population given the approximate 30000, PKU adults and now global territories.

Jeffrey Robert Ajer: In Europe, COVID-19 proved particularly disruptive to palindseek uptake due to clinic closures, as well as pricing and reimbursement negotiations that were 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 Palantik in 2021, making it the largest expected growth driver in the portfolio.

And Europe, COVID-19 proved particularly disruptive capella Lindsey uptake due to clinic closures as well as pricing and reimbursement negotiations that was disrupted as health care systems folks focused on the COVID-19 pandemic.

As we begin 2021, we have and expectation of banking progress on both price and reimbursement approvals and patient starts and that Europe will contribute more materially throughout the year.

And its third full calendar year on the market and even considering the likely continuing impact from Covid, we are expecting a remarkable 35% increase and revenue growth based on the midpoint guidance, propel and <unk> and 'twenty and 'twenty, one and making it the largest expected growth driver.

And the portfolio.

Jeffrey Robert Ajer: QVAN, 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 of generic competition in the U.S. 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 Kuvan.

Kuban, which experienced the loss of exclusivity and the U S. Beginning in October 'twenty, and 'twenty had total revenues and the quarter of $89 million and.

And in T. Spaded decrease of 27% compared to Q4, 'twenty and 'twenty and almost exclusively associated with the impact from new generic competition in the U S.

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 repay and market share.

Our expectations for erosion of U S sales are captured and the full year revenue guidance provided for Covid.

Jeffrey Robert Ajer: 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, Vemezem, Naglozyme, and Brunnera. During 2020, we experienced new patient identification and resulting new patient starts occurring at a slower than anticipated pace due to the impact of COVID-19. In spite of that, commercial patient counts for naglothiamine benzene grew by 5% and 9%, respectively.

Turning now to our license almost storage disease products I've commented in prior calls on the successful mitigation tactics quickly employed and the first months of the pandemic to ensure continuity of infusions for enzyme replacement patients.

As a result, we exited the year close to the baseline.

Patient compliance for all three brands Vimizim and that goes on and bring in Iraq.

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 accounts for and that assignment bins and grew by 5% and 9% respectively.

Jeffrey Robert Ajer: As mature brands, we are highly penetrated with 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 Naglotheim revenue to decrease by 3% in 2021.

As mature brands, we are highly penetrated of known M b assets and more T. OA patients and continued growth for these brands is highly dependent on newly identified patients.

The kind of patient growth experience last year bodes well for continued future growth and demand for both brands.

At the midpoint, we expect <unk> revenue to decrease by 3% in 'twenty and 'twenty. One that is entirely a result of expected order timing for certain markets, primarily Brazil relative to actual orders in 'twenty and 'twenty.

Jeffrey Robert Ajer: 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 Basorotide, which we expect to be our largest brand to date, if approved. We're busy preparing for possible launches in our two largest regions, North America and India, in the second half of the year. With two applications moving forward in parallel, we have two complementary and attractive commercial opportunities.

At the midpoint, we expect 8% growth and Vimizim revenue in 'twenty and 'twenty one.

And in 'twenty and 'twenty, one we will continue our launch readiness efforts from the sore tide, which we expect to be our largest spray and debate. If approved we are busily preparing for a possible launches and our two largest regions North America, and EMEA and the second half of the year with.

And two applications moving forward in parallel we have two complementary and attractive commercial opportunities ahead based on our experience. The U S. Typically present and large market characterized with rapid payer approvals rapid patient uptake and favorable pricing.

Jeffrey Robert Ajer: Based on our experience, the U.S. typically presents a large market characterized by rapid payer approvals, rapid patient uptake, and favorable pricing. In a scenario of parallel launches, we expect the U.S. to drive early revenue. Collectively, Europe presents a larger market opportunity based on larger patient populations. However, 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 negotiate price and reimbursement approval.

And the scenario of parallel launches, we expect the U S to drive early revenue.

Collectively Europe presents a larger market opportunity based on larger patient populations and.

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.

Jeffrey Robert Ajer: 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 immune-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-gray plates and severe hemophilia A patients. Price-priced corridors are similar between US and early EU markets, in particular.

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 and our EMEA operating region and 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 and Grace late.

And severe hemophilia a patients.

Right price and corridors are similar between U S and early EU markets in particular.

Jeffrey Robert Ajer: These comments summarize our experience generally with our marketed brands, and they can apply to both the Solitide, Roktavian, and Future Pipeline programs. As we get closer to potential approvals for Soratide, 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.

These comments summarize our experience generally with our marketed brands and it can apply to both the solar tide rock, Daisy and and future pipeline programs.

As we get closer to potential approvals for the sore tide, we will look forward to coming back to you with more details and our efforts to prepare for commercial launches, including our pricing strategy.

In summary, and looking forward, we expect continued growth and our base business with the exception of Kuban, where further erosion of the base is expected in 2021.

Jeffrey Robert Ajer: Palanzeet will be the largest growth driver as a single brand, with strongest sales in the U.S. and material growth from Europe. Bimism and Bernoura 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 Storytide once approved. Thank you, and now I'd like to turn the call over to Hank.

<unk> will be the largest growth driver as a single brand with strong net sales in the U S and material growth from Europe.

Vimizim and burner and will continue on their growth trajectory appropriate to each brand and stage of lifecycle and we will be prepared for a successful launch of the sore tide once approved.

Thank you and now I'd like to turn the call over to Hank Inc.

Henry J. Fuchs: Thanks, Jeff. 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 to congratulate and thank the R&D team for their resilience, commitment, and efforts in a year of high uncertainty in 2020. As J.J. conveyed, we look forward to a number of important regulatory events in 2021 based on strong Phase III results for both our Versortide and Roktavian programs that we experienced towards the end of last year and the beginning of this year.

Thanks, Jeff.

And.

And I too would like to congratulate and thank the commercial team for delivering medicines around the world.

Right and all this uncertainty and also to congratulate and thank the R&D team.

For their resilience and commitment and efforts and.

And a year of high uncertainty and 2020.

And as J J conveyed and we look forward to a number of important regulatory events in 'twenty and 'twenty, one based on strong and phase III results, both from a resource and Octavian programs that we experienced towards the end of last year and the beginning of this year.

Accumulating data on durability of our products suggest meaningful clinical benefit 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.

Henry J. Fuchs: Accumulating data on the 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 3 Roctavian results.

We were pleased to begin 2021 with positive phase III Octavian results to remind you generate one and that's the largest global phase III study to date for any gene therapy and any indications on Inc.

134 participants.

<unk>, two before gene therapy doors, and 84% reduction and annualized bleeding rate from 4.8, while on standard of care Prophylactic factory therapy replacement.

Henry J. Fuchs: To remind you, Generate 1 is the largest global Phase 3 study to date for any gene therapy in any indication, having enrolled 134 participants. Compared to before gene therapy, there was an 84 percent reduction in annualized bleeding rate from 4.8 while on standard of care prophylactic factory therapy replacement and before treatment with Ractavian to 0.8 leads 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 2 infusions per year after treatment with Lactavien.

And before treatment with rotation to zero point, Inc. Bleeds per year after receiving <unk> Octavian.

The treatment burden of this condition in terms of mean annualized factory and infusion rate and the rollover population was also substantially reduced by 99% from 136 infusions to two infusions per year after treatment and that's why Octavian.

And 80% of the participants were bleed free starting at week five after treatment and the phase III study again in spite of the withdrawal prophylactic factory therapy.

The findings of this study were all statistically significant and that's prospectively specified.

Additionally, and 17 patients who had received Octavian two or more years prior to the data cut off the decline and decline and factory activity level was observed.

Henry J. Fuchs: 80% of the participants were bleed-free starting at week 5 after treatment and in a phase 3 study, again in spite of the withdrawal of prophylactic factor VIII therapy. The findings of this study were all statistically significant as prospectively specified. Additionally, in 17 patients who had received Roctavian two or more years prior to the 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.

From a factory 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 factory levels at this time point were higher than those observed entering the third year of follow up after the four and 13 doses administered two and earlier cohort, who also experiencing a b R of less than one and that third subsequent year.

Therefore, the growing body of evidence supporting the clinical benefit of Octavian and its durability for people with severe hemophilia, a and that's been very encouraging and a tremendous gained from the field and the scientific community.

J J mentioned, we recently held and expert Advisory Council meeting with former U S and EU regulators from both the F D E and M. A key statistical experts deeply experienced and both the advisory committee process and the United States and the scientific advice process and help physicians and patients to gain insight into the best path forward.

Henry J. Fuchs: 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.

And given the accumulating evidence demonstrating dramatically and control and patients when people receiving lifesaving.

Henry J. Fuchs: Therefore, the growing body of evidence supporting the clinical benefit of Roctavian 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 J.J. 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.

Additionally, feedback from patient advisory leaders provided helpful insights into the importance of patients informed choices and critical aspects to support decision, making for patients and prescribers and we were very encouraged with the feedback and the path forward for us to even approval based on results observed to date and assuming favorable outcomes contango.

We remain encouraged with the progress made to date and continue our dialogue with the food and drug administration and.

And the form of ongoing discussions.

Most with Seeber center for Biologics evaluation and research leaders based on discussions with senior leadership and with our review division about potential paths forward.

Henry J. Fuchs: Given the accumulating evidence demonstrating dramatic lead control in patients and people receiving Larkavian,

We have more to share with the agency over the coming months as the phase III program continues to mature with the page with the two year data for all subjects available in late November.

Henry J. Fuchs: 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 by 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 I'll continue our dialogue with the Food and Drug Administration in the form of ongoing discussions with CBER, the Center for Biologics Evaluation and Research, 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 the support of feedback from the export and Advisory Council based on dramatic sleek control demonstrate across our rush JV and program.

Aspire to dialogue with the agency and potentially submitting a BLA with one year results that could be submit supplemented with two year results during review.

And 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 any agency are intended to be deliberate and review and take the time necessary to ensure a careful examination of the risks and benefits, but also ensure appropriate product label and risk management procedures and the marketplace.

Yeah.

And Europe, we're targeting to Q 21 for Resubmission of the marketing application authorization pending confirmation and upcoming pre submission meetings and.

This timing, we could potentially receive a C. H M P opinion and the first half of 2022.

We've been engaging with European health authorities and for one year data became available and we are encouraged from the application review will be and progress is the two year data become available and are prepared to share.

Henry J. Fuchs: With supportive feedback from the expert advisory council based on the dramatic lead control demonstrated across our Roktavian 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 intend to be deliberate in the review and take the time necessary to ensure careful examination of risks and benefits but also ensure appropriate product labeling and risk management procedures in the marketplace.

To share it should that should that be beneficial to supplement for the package.

Good and procedural considerations its likelihood Octavian will be approved after the second year of data and the phase three are available and therefore, our hope and intention is to shorten the interval between data availability and regulatory actions as much as possible with a goal to enable physicians and patients to have and additional therapeutic choice.

And their armamentarium.

And for the ongoing phase two study, we intend to share a five year update with the 60 13 dose as well as a four year update on the 40 13 dose and the middle of this year.

Accordance of Octavian 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 your four recall that almost all patients remained bleed free and a prophylactic therapy for four and three years after gene therapy in spite of declining accurate levels among participants.

Henry J. Fuchs: In Europe, we're targeting 2Q21 for the resubmission of the Marketing Application Authorization, although 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 the package.

Turning now to the sore type for treatment of Achondroplasia under review broke and the United States and Europe, We're very pleased to share a positive two year results from our phase III program last December and demonstrating the children, maintaining and increasing annual growth velocity through the second year of continuous treatment.

A personnel assist comparing all children randomized and treated with the sore type for two years 52 subjects to all children from Iran. And study who are randomized to receive placebo placebo with and untreated observation period of two years, and and 38 showed improvement and one year height change and the treated group relative to the untreated group.

Henry J. Fuchs: Given procedural considerations, it's likely that Roctavian will be approved after the second year of data from phase III are available. 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 arsenal. As for the ongoing Phase 2 study, we intend to share a 5-year update on the 6E13 dose, as well as a 4-year update on the 4E13 dose, in the middle of this year.

It was similar and the second year of treatment and $1 seven nine and in the first year of treatment and 1.73.

The cumulative increase and hiking over the two year treatment period was $3 five two centimeters compared to untreated children, which is the sum of the first year and 1.73 and the second $1 79 and <unk>.

And consideration and growth studies is the status of pros and some growth as measured radio graphically and in comparison to the subject chronological age.

Henry J. Fuchs: The importance of the Roctavian 5-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 4. Recall that almost all patients remained bleed-free and off prophylactic therapy for 4 and 3 years after gene therapy, in spite of declining Factor VIII levels among participants. Turning now to the sorotype for treatment of achondroplasia, under review both in the United States and Europe, we were very pleased to share positive 2-year results from our Phase 3 program last December.

Some agents promote rapid growth like precipitated early closure of the growth plates precluding gains from adding up over time and.

In contrast measures of bone maturation and patients treated with a contract with the sore Todd confirm that the store tied with promoting bone growth, while maintaining and not accelerating from a maturity. This bodes well for accumulating treatment gains overtime as growth places and not expected to close prematurely.

Turning to restore tied regulatory timing updates with the MAA under review in Europe, We look forward to a CHF <unk> opinion and June followed by European Commission decision in late summer. If successful this would enable jeff's team to launch in Europe, and the third quarter of this year and.

Henry J. Fuchs: Demonstrating that children maintain an increase in annual growth velocity through the second year of continuous treatment.

And the United States, we've chosen to provide the two year phase III data from the FDA given the opportunities we convey durability of treatment benefit from March and number of patients.

Henry J. Fuchs: A first analysis comparing all children randomized and treated with the sorotype for two years, 52 subjects.

While this may result in a major amendment pushing the current producer action day out three months through November we believe it is prudent to make these newly available and encouraging results available regardless of potential delay and approval time.

Henry J. Fuchs: All children from the run-in study who were randomized to receive placebo with an untreated observation period of two years and 38 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's 1.73 and the second year's 1.79.

Also new today and January FCA granted the sore tied priority review status.

Just on the pediatric indication of dresses and the lack of treatment options currently available of.

The sore tied now qualifies for a priority review voucher upon approval, which would be the third P. R V granted to Biomarin.

Consistent with the Fda's policies on changes to review classification for and ongoing application and the view the Paducah action date from the main August 20th 2021.

Turning to B M and three of seven and our investigational gene therapy for PKU results from the starting dose and a fearless phase two study demonstrating meaningful free lowering and the first two subjects.

Henry J. Fuchs: An important consideration in growth studies is the status of bone growth as measured radiographically and in comparison to the study'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 a basorotide confirm that basorotide is promoting bone growth while maintaining and not accelerating bone maturity.

And he will progress with a higher dose cohort a threefold higher dose 60, 13 vector genomes per kilo.

Were hopeful this dose will be registration enabling.

On these early data from the two and 13 cohort and our prior steep dose response experience with avian.

We are conducting this study with mature and manufactured with a commercial ready process to Derisk and Derisk the program and facilitate rapid clinical development.

We are excited about the prospects of the N and three or seven as it represents a potential third treatment option and our PKU franchise, and our second gene therapy development program.

Henry J. Fuchs: 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 MAA under review in Europe, we look forward to a CHMP opinion in June, followed by a European Commission decision in late summer. If successful, this would enable Jeff's team to launch Versortide in Europe in the third quarter of this year.

Look forward to sharing results from the dose confirmation phase of the study when we selected those registration enabling studies.

We doubled our early stage pipeline and 2020 by internal growth and external partnerships and advancing several preclinical programs spanning multiple modalities.

The gene therapy beyond our Octavian and PKU programs, we are conducting IND, enabling studies with B M and 331 gene therapy for hereditary angioedema or.

Henry J. Fuchs: In the United States, we chose 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 the potential delay in approval time. Also new today, in January, FDA-granted Soratide Priority Review Status based on the pediatric indication addresses and the lack of treatment options currently available.

Our collaboration with Dana Corp, and hypertrophic cardiomyopathy between announced in May of last year is progressing well.

Together, we and die and a core has achieved properly localized expression and function of mice and binding potency three and cultured human Cardiomyocyte and.

Cardiac stem cells derived word and.

Stem cell derived organoid and and vivo with several lead actors.

Plan to select a candidate and in 'twenty and 'twenty one for this program and to commence non clinical development studies to enable and subsequent filings.

Ian and 351 and D. M. D 2.0, oligonucleotide therapy for the treatment of Duchenne muscular dystrophy and has demonstrated high level of protein expression and experimental animals possessing skippable the stroke with mutations and at doses that are promising and regard to safety.

Henry J. Fuchs: Soratide 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 PDUFA action date remains August 20, 2021. Turning to BMN-307, our investigational gene therapy for PKU, results from the starting dose in the FEARless Phase 2 study demonstrating meaningful free-lowering in the first two subjects. The study will progress with a higher-dose cohort, a three-fold higher-dose of 6013 vector genomes per kilo.

And $2 55, and a small molecule for chronic renal disease for which we filed and in R&D in 2020.

Also progressing well and we and I hope to share more detail on these programs and our R&D day tentatively planned for the second half of the year.

And the R&D organization and its very energized and very busy as we advance a wide range of thoroughly and late stage programs and 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.

Henry J. Fuchs: We are hopeful this dose will be registration-enabling based on these early data from the 2E13 cohort and our prior steep dose response experience with Lactavien. We are conducting this study with mature and manufactured with a commercial ready process to de-risk the program and facilitate rapid clinical development. We are excited about the prospect of BMN 307 as it represents a potential third treatment option in our PQE franchise and our second gene therapy development program.

Thank you.

Please refer to today's press release summarizing our financial results for full details on the fourth quarter and full year of 2020.

And as Jeff touched on many of the topline results from the commercial business I will primarily focus on bottom line results operating expenses and our 2021 guidance as usual our results will be available and our upcoming form 10-K, which we are on track to file over the next couple of days and.

In terms of the bottom line for the full year 'twenty and 'twenty, we provided guidance for GAAP net income of between $760 million and $820 million and and.

We've reported a better than guidance GAAP net income of $859 million for the year.

As a reminder, GAAP net income and 2020 includes the $835 million.

Nonrecurring tax benefit recorded in the third quarter of 2020 related to the transfer of certain intellectual property rights between Biomarin entities and importantly, we observed that biomarin was able to generate positive GAAP net income for the first time and the company's history, achieving our goal set at the beginning of the year. Despite the strength.

Henry J. Fuchs: We look forward to sharing results from the dose confirmation phase of the study when we've selected those for registration-enabling studies. We doubled our early stage pipeline in 2020 via internal growth and external partnerships, advancing several preclinical programs spanning multiple modalities.

And the business and 2020 and the handful of material nonrecurring transactions and recognized in 2020.

Henry J. Fuchs: With gene therapy beyond our Octavian and PKU programs, we're conducting IND-enabling studies with BMN331 gene therapy for hereditary angioedema. Our collaboration with Dynacor on hypertrophic cardiomyopathies, 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 such an IND filing.

Turning to non-GAAP income, where the company delivered $312 million for the full year 2020 within the higher range of our guidance and $40 million and the fourth quarter of 2020, driven by solid top line results across the commercial portfolio and operating expense control non.

Non-GAAP income for the full year 2020, with 87% higher and non-GAAP income for the full year 2019, despite the impact of COVID-19 and <unk>.

And loss of exclusivity and the U S. Since October of 2020.

Moving to operating expenses, both R&D and SG&A expenses and 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, and the fourth quarter R&D expenses, primarily reflected our continued development of our late stage program and the store tied and rock JV and as well as our early stage programs and research, including the M and three of them.

Henry J. Fuchs: DMN-351 or DMD-2.0, 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, BMN 255, our small molecule for chronic renal disease, for which we filed an R&D in 2020, is also progressing well, and we hope to share more detail on these programs at our R&D date, tentatively planned for the second half of the year.

And then our PKU gene therapy.

SG&A expenses for the fourth quarter, and full year, 2020 were $196 million and $738 million, respectively and.

And were higher than 2019, reflecting the preparation for the potential commercial launches of the door type and rock paintings.

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 and.

2020 balances reflect both the $536 million of net convertible debt proceeds range earlier in 2020, and the expected $375 million cash outflow upon and maturity of convertible notes in October of 2020.

Brian R. Mueller: 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.

The company generated $85 million of positive operating cash flows for the full year 2020, which is a great indicator and health of Biomarin and base business, particularly considering the negative impacts of COVID-19 on our revenue.

Brian R. Mueller: 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.

Now moving on to 2021 guidance.

Jeff touched on many of the brand dynamics and for total Biomarin topline and we expect 'twenty, one 'twenty and 'twenty, one total revenues to be and the range of 175 to $1 $85 billion importantly, and as discussed last quarter 2021 total revenues reflect the impact of several headwinds most notably.

We are the impact of the <unk> generic competition and the U S. Since October of last year, and the continued impact of COVID-19, and our commercial business.

Brian R. Mueller: As usual, I'll resume.

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 won't be able to maintain similar levels of patient compliance with our therapy regimens and rates of new patient starts that we have.

Brian R. Mueller: 10K, 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 Gap Net Income of between $760 million and $820 million and have reported a better-than-guidance Gap Net Income of $859 million for the year. As a reminder, Gap 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. Importantly, we observe that Biomarin 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.

Experienced during the twice during the pandemic and 2020.

While our total revenue expectations for 2021 are lower than 2020, we note that our core business, except for Kuban, It's still growing healthily with 9% growth at the midpoint of our guidance range.

And one comment on others, which is marketed by Sanofi Genzyme and therefore, we do not provide specific guidance is at Biomarin aldurazyme revenues and the fourth quarter of 2020 were low due to the timing of products supplied to Sanofi Genzyme.

However, based on data provided to us by Sanofi Genzyme Aldurazyme added 10% more commercial patients during 2020, the product 17th year on the market, which is a solid indicator that the market demand and increasing despite biomarin elders and revenue timing.

Lastly on top line, while we remain optimistic that the sore tied and rock Tavy and will be approved and launched we are not expecting significant revenues from either product and 2021.

Shifting to Bottomline expectations for 2021, we anticipate recognizing a GAAP net loss ranging from $80 million to $130 million and while our GAAP profitability goals are delayed while we continue to develop <unk> and Roc JV and we do expect to earn positive non-GAAP income in the range of 107.

Brian R. Mueller: Alan Gaffney

Brian R. Mueller: 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 control. 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's loss of exclusivity in the U.S. since October of 2020.

<unk> million dollars to $220 million.

This significant amount of non-GAAP net income plus our expectation to earn positive operating cash flows for the full year of 2021 are again indicators of a healthy core business and is able to both generate approximately $1 8 billion of revenues and develop high value late and early stage pipeline.

And closing from a financial perspective, 2021 is a year, where we plan to hold the line and both our revenues and bottom line through the continued COVID-19, pandemic uncertainty and the pause and our substantial revenue and profitability growth aspiration.

And as a reminder.

Sure tied and rocked hazy and are approved and launched the commercial market opportunities for both of those potential products significantly exceed the market sizes of our current products and therefore, we believe the combination of positive operating results expected from Biomarin and base business plus the growth potential from the company's large late stage opportunities that we are.

Brian R. Mueller: Moving to operating expenses, both R&D and SG&A expenses in the fourth quarter tracked both recent trends and our 2020 guidance. 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 Soratide and Roctavian, 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 $196,738 million, respectively.

Leverage the infrastructure and the base business create a compelling value proposition that has further expanded by our commitment to early stage innovative rare disease research. Thank you for your support and we'll now open up the call to your questions.

Operator.

Thank you, ladies and gentlemen, if you would like to ask a question and you will need to press star one on your telephone.

A question just press the pound key.

And again to ask a question Thats star one on your telephone.

Our first question comes from Robyn <unk> Moscow with tourists Securities. Your line is open.

Hey, guys. This is kipp on for Robyn. Thank you so much for taking my questions.

And so it looks like you've been engaging with the FDA quite a bit and discussing the pivotal data from rocket hazy and can you tell us how much of the day does it agencies already seen what additional data they need to see and also based on your commentary.

Brian R. Mueller: And we're higher than in 2019, reflecting the preparation for the potential commercial launches of the Zorotides and Ractase. And lastly, for 2020, we will finish 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 the convertible notes in October of 2020.

During your engagement with the FDA was there anything that gives you the indication that you will have to submit the two year data from a proven and thank you so much.

Yeah, Hi, there and you know the agency told us that they would expect to see the two year data and the end of it.

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.

Brian R. Mueller: 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 lines, 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.

And the short amount of time since the one year data is available and they've only been able to see the top line.

But their stance really was predicted not to have changed given the one and your data I think the when your data are strong and they anticipated they would be strong and they.

And have reiterated their preference, we're making their approval data their approval decision and the basis of having seen the two year data.

Okay.

Right and then you talked about the feedback you've received from the external councils and addition to the feedback being generally positive was it anything new you learned that you think it could help and then you're okay.

And get approval narrow body of data.

Yeah, well, we convene the and <unk>.

And counsel as we kind of have our version of an advisory committee and reasoning that we.

Brian R. Mueller: Most notably, the impact of 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.

And we wanted to hear the worst possible version of our story.

As told to us by highly critical people are.

And I would say that what we learned is and so we have a pretty good program one of our colleagues tourism Ratably disciplined reviewers characterize the results as impressively strong.

Brian R. Mueller: 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 for 2020, we note that our core business, except for Kuvan, is still growing healthily with 9% growth at the midpoint of our guidance. And one comment on Alderzyme, which is marketed by Sanofi Genzyme and for which we do not provide specific guidance, is that Biomarin Alderzyme revenues in the fourth quarter of 2020 were low due to the timing of product supply.

And I think the thing that we learned is that.

This is and it's 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 a 434 patients. So we're working very closely with our colleagues to try to discern the.

And most facile regulatory pathway.

And at this point these are to some extent and largely procedural discussions.

Yeah.

And my next question is from Cory <unk> with Jpmorgan. Your line is open hey, good afternoon, guys. Thanks for taking the question. Hank you are hard to understand on some of your script. So I just want to make sure I got this correct. It sounds like based on that independent expert counsel and and preliminary discussions with the agency.

Brian R. Mueller: However, based on data provided to us by Sanofi Genzyme, Aldurazine 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's revenue timing. Lastly, on the top line, while we remain optimistic that Physorotide and Roctavian will be approved and launched, we are not expecting significant revenues from either Shifting to bottom-line expectations for 2021, we anticipate recognizing a gap net loss ranging from $80 million to $130 million.

And that you mace resubmit, Directv and B L. A on 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 as is this latest thinking which sounds like Oh.

Pseudo acceleration from what we were talking about earlier. This year is this being driven more by the feedback you've got from this outside counsel or more by the conversations with the FDA to day.

Of course, you heard correctly and a little bit of both.

And I think on one hand, the data packages impressive on the other hand people sort of novel therapy and.

Brian R. Mueller: And while our GAAP profitability goals are delayed while we continue to develop Sorotide 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, are again indicators of a healthy core business that is able to both generate approximately $1.8 billion of revenues and develop a high-value late and early stage pipeline.

And no hemophilia patients are deserving of a very careful examination of the data.

And the part that and you know is a little bit.

And 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.

And additional chunk of data for review would they prefer to get started before the two year data 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 and now those are discussions.

And that we're having there there are a lot of examples where agencies and accept data during the review and there are a lot of examples where the agency just doesn't want to get themselves and a position of accepting the data and oftentimes that hasn't had anything to do with you know necessarily what the data are it has to do sometimes with other circa.

Brian R. Mueller: 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 aspirations. As a reminder, if Zortide and Roktavien 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 Biomarin's base business plus the growth potential from the company's large late-stage opportunities that will leverage the infrastructure of the base business creates 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?

Stances.

And the viewership because as I mentioned.

And for example at the end of last year with the EMEA their preference for reviewing the additional data was entirely procedural.

And related to staffing levels within that E N E and the rapid tours. So these are discussions that ordinarily don't get a lot of attention in terms of synchronized and things I know theres a lot of interest and regulatory actions on rocks avian.

I think that we're encouraged with the really good data turned out the way we expected it to turn out at the one and your Mark and.

Given what we've seen and 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 and being patient and collaborating with them to assure that the review is give them the full attention it deserves.

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

Oh, Yeah, very senior very seasoned top top of the shelf.

Operator: Ladies and gentlemen, if you would like to ask a question, you will need to press Star 1 on your telephone. To withdraw your question, just press the pound key. Again, to ask a question, press Star 1 on your telephone. Our first question comes from Robyn Karnauskas with Tourist Securities. Your line is open. Hey guys, this is Kirpan for Robyn.

Okay perfect. Thank you very much.

Our next question is from Celgene with true with Goldman Sachs. Your line is open.

Good afternoon, and thanks for taking my questions could you just talk about the the commercial and commercial dynamics playing out with your PKU franchise, and how you made the assumption that erosion to a day Kuban and your guidance and and what's playing out you know to offset that with them.

Kirpan: Thank you so much for taking my questions. 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 would have to submit the two-year data for approval? Thank you so much.

Townsend.

Jeff do you want to cover that question.

Yes, J J. Thank you for the question Salvi and so we've provided some guidance on.

Kuban erosion, and our expectations and with the caveat of this guidance both thing.

We don't have any.

Enterprise experience with loss of exclusivity of a product and a major market and two there is theres very few analogs.

Henry J. Fuchs: Yeah, hi there. The agency told us that they would expect to see two-year data in 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 were available. But in the short amount of time since the one-year data were 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 decision on the basis of having seen the two-year data.

To look to the guide expectations.

And so we've guided that we think we would experience material, but not catastrophic loss of share like you might see me and a retail.

Prescription grip and product that goes generic for example, and indeed, if you look at the drop of revenue and the fourth quarter of last year.

And for Kuban relative to the fourth quarter of 2019, we were really right on top of our internal expectations. If you then look further at the 2020 revenue.

The midpoint of the guidance.

And that captures our expectations for the further erosion of that Kuban business.

And I did state.

Henry J. Fuchs: Great, and then you talked about the feedback you received from external counsel. 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.

Now, let's turn to our expectations for pounds Zeke and both products are part of the same PKU franchise.

Their tasks are now relatively disconnected so our expectations for what happens with Palin Z is not highly.

Henry J. Fuchs: 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. And I would say that what we learned is that we have a pretty good program. One of our colleagues who were incredibly disciplined reviewers characterized the results as impressively strong. And I think the thing that we learned is that this is, it's 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 results. So we're working very closely with our colleagues to try to discern the most feasible regulatory pathway, and at this point, these are, to some extent, largely procedural discussions.

Tied to what happens with conversion now and the marketplace. It is true that we have.

We have a great base of business of Kuban and a great deal of patient level knowledge, particularly in the United States and it is true that about 30% of our Pelham Zeke patients have transitioned from PKU. So these would be patients that are not achieving.

And desired strength.

Clinical benefit from from Kuban and net debt are thus appropriate for a more powerful agent and talent Zeke and so we continue to expect that we would we would be tapping into adults.

And that have not received and adequate benefit from from Kuban, but those two products are essentially on on different paths at this point.

Corey Kasimov: Our next question is from Corey Kasimov with J.P. Morgan. The line is open. Hey, good afternoon, guys.

Okay cool.

Corey Kasimov: Thanks for taking the question. Hank, you were hard to understand in some of your scripts, so I just want to make sure I got this right. It sounds like, based on that independent expert counsel and preliminary discussions with the agency, that you may resubmit the Rocktavian BLA based on one year of data and supplement that mid-review with the two-year. So assuming I heard that correctly, I guess when do you expect to finalize this?

Our next question is from Phil Nadeau with Cowen and company. Your line is open.

Good afternoon, and thanks for taking my question I think your comments on procedural benefits on the T V and Refiling was intriguing to me and I guess I'm trying to.

Worked for and my head what would be more advantageous for biomarin for the FDA filing early.

Corey Kasimov: And is this latest thinking, which sounds like a... This is 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 council or more by the conversations with the FDA today?

Versus falling after you have the phase II data I guess, what strikes me is from a farmer and prospective if they're going to give you a three months produce extension and when you filed the two year data anyway. It doesn't really bother you that much time to file early.

But Conversely, I guess for the FDA maybe.

Henry J. Fuchs: Corey, you heard correctly in a little bit of both.

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.

Henry J. Fuchs: 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 is a little bit out of our control is, like I said, a procedural part, which is when do agencies have the bandwidth and capacity to take on an additional chunk of data for review? Do they prefer 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?

The thing I focus on is when do we think we're going to finish.

Because that's obviously the point in time, and which patients have a different choice available to them.

And then.

You could do the game theory, and both directions like you just said.

And we don't know about is whats the workload and what are the considerations on their side.

Henry J. Fuchs: And those are discussions that we're having. You know, 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 itself in a position of accepting the data. 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 that the reviewers have to connect.

And how much time, you know where where do they leave the complete response letter off and the U S. You know, we still have inspection would do.

How do they man and you know how do they see the manager and was there 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.

And you know getting the decision on one hand, and the most expeditious way possible and I and the other hand to ensure that the review is thorough and and.

Henry J. Fuchs: 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 ordinarily don't get a lot of attention in terms of synchronizing things.

And all the considerations for product labeling or.

Appropriate and under and well understood and that our post approval commitments and risk management plans are the right ones I think theres a lot of work that we can be done that can be done before the two year data but.

Henry J. Fuchs: I know there's a lot of interest in regulatory actions under Octavian. I think that we're encouraged that, with the really good data, it turned out the way, you know, 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.

They may choose to decide to wait for the two year data before they get started.

It's a bit of a wait and see I know everybody is looking for certainty about this and we're working hard to deliver it.

And our focus is and I'm trying to enable the choice for patients with hemophilia a.

And just a brief follow up what 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 are ongoing now.

Henry J. Fuchs: And did you say there were ex-regulatory officials on this committee?

I think that we will be and a much better position to provide information and after we've had a couple more dialogues with them as too definitive that's always hard thing with the SBA social and the step at a time you know you submit and they file.

Henry J. Fuchs: Oh yeah, very senior, very seasoned, top of the shelf. Okay, perfect.

Corey Kasimov: Okay, perfect. Thank you very much.

Salveen Jaswal Richter: 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 commercial dynamics playing out with your PKU franchise and how you made the assumption of erosion to KUVAN in your guidance and what's playing out, you know, to offset that with Townsie?

So.

So a bit of a stay tuned on a U S regulatory status.

Perfect. Thanks for taking my questions.

Mhm.

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

Thanks.

Jeffrey Robert Ajer: Jeff, do you want to cover that question?

So I wanted to just probe, maybe a little bit more on the PKU commercial dynamic.

Jeffrey Robert Ajer: Yeah, JJ, thank you for the question, Salveen. So, we provided some guidance 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 are very few analogs to look to to guide expectations. And so, we've guided that we think we would experience a material but not catastrophic loss of share, like you might see in a retail.

And I heard your comments, Jeff around how Kuban and pounds are somewhat disconnected, but.

I guess.

It sounds to me like you as you described the coupe and erosion dynamic it might be more price driven and share driven.

So you guys would seem to maybe have a little bit more control over the conversion dynamics and 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 and warehousing effect that might.

Jeffrey Robert Ajer: Prescription-driven product that goes generic, for example, and indeed, if you look at the drop in revenue in the fourth quarter of last year, for QVAN, relative to the fourth quarter of 2019, we were really right on top of our internal expectations.

It happened and the effects of the pandemic.

Wayne and sort of that timing.

Can you maybe give a little bit more color on that Jeff and you know in terms of and what you're seeing and in terms of warehousing.

Jeffrey Robert Ajer: If you then look further at the 2020 revenue, the midpoint of the guidance, that captures our expectations for the further erosion of that Kuban business in the United States. Now, let's turn to our expectations for Palantzik. And though both products are part of the same PKU franchise, their paths are now relatively disconnected, so our expectations for what happens with Palantzik are not high. Uh, tied to what happens with Kuvan now in the marketplace.

Is this something we should be asking about I guess as a as we think about the you know the infection rate and all the other measures and metrics of the pandemic change over time.

Thanks, Chris So good observation on your part maybe I'd start with saying that.

And without disclosing details that would constitute a.

And competitive.

Intelligence for one of our competitors it is true that our revenue from.

Jeffrey Robert Ajer: It is true that we have, um, we have a great base of business for Kuvan and a great deal of, uh, patient-level knowledge, particularly in the United States. And it is true that about 30% of our Palanzec patients have transitioned from PKU. So these would be patients that are not achieving a desired, uh, strength of, uh, clinical benefit from Kuvan and that are thus appropriate for a more powerful agent, uh, in Palanzec. 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.

Cube and loss of exclusivity is both a price and a volume mix.

So you're right on that point.

In terms of patient warehousing, that's it's a great question.

The rate limiting step for growth of <unk> and the United States has always been clinic capacity and that condition existed before.

The pandemic hit and when I say Clinton and capacity I mean, the ability and willingness of Shen.

Could be.

Prescribing pounds, Inc, and Inducting, patience, and titrated and them up on dose.

Jeffrey Robert Ajer: Thank you.

Philip M. Nadeau: Our next question is from Phil Nadeau with Cohen & Company. Your line is open.

Either one patient and a time or maybe small and multiples of patients at a time.

And so as.

Philip M. Nadeau: Good afternoon, thanks for taking my question. Hank, your comments on procedural benefits on the Ractavian refiling were intriguing to me, and I guess I'm trying to think through in my head what would be more advantageous for Biomarin or the FDA, filing early versus following after you have the phase two data. I guess what strikes me is from a Biomarin perspective, if they're gonna 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.

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 and that's the rate limiting step to growth of our business.

And if so how does that point to a warehousing effect certainly there will be patients that are wanting access to <unk> and and waiting for their clinics to either have the capacity or to be back and operation to be able to help them on <unk>.

Philip M. Nadeau: But conversely, I guess if you're the FDA, maybe it gives them more time to contemplate the full range of the data, both the one-year and two-year. So, I guess, how are you thinking what would be most advantageous to you based on where you think the FDA needs questions? Maybe concerns are about the data package.

Inc.

Get a prescription and dust.

Take rate and get to a maintenance phase certainly that'll be the case, we'll still be dealing with overall clinic capacity during this year.

Henry J. Fuchs: The thing I focus on is when we think we're going to finish. Because that's obviously the point in time when patients have a different choice available to them. And, you know, you could do the game theory in both directions, like you just said.

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 and the U S and particular and meeting the demand from patients that may be and that kind of warehouse category.

Henry J. Fuchs: 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 did they leave the complete response letter off in the U.S.? You know, we still have inspections to do. How do they see the management of the workload?

Free.

Thank you.

Our next question is from Jeff you can with Bank of America and your line is open.

Hey, guys. Thanks for the question.

Henry J. Fuchs: 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, you know, getting the decision on the one hand in the most expeditious way possible and, on the other hand, ensuring 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.

And also wanted to focus a bit on guidance.

And what we're not when I look at other commercial biotechs for farmers I didn't hear a lot about.

And the continued COVID-19 impact or headwind for this year, so I wanted to dig in.

To the guidance for the whole portfolio and not not just PKU is is it more of the geographic mix is it the orphan nature of the business that you're still seeing and Covid impact I didn't hear from you that there are headwinds on new starts.

Henry J. Fuchs: I think there's a lot of work that can be done before the two-year data, but they may choose 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.

Compliance and so I'm just trying to figure out the delta here. Thank you.

Jeff.

Yeah. Thanks, Jeff for the question. So we did try to.

The address some of the.

Dynamics of how the.

The pandemic is affecting our business in the guidance and so one of the things that we said was.

Henry J. Fuchs: 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, which sound like they're ongoing now?

We're exiting 'twenty and 'twenty, having at least for now.

Henry J. Fuchs: I think that we will be in a much better position to provide information after we've had a couple more conversations with them as to definitive, that's always a hard thing with the FDA, you know. It's sort of a step at a time, you submit, they file. So a bit of a stay tuned on the US regulatory status.

Pretty much solved the patient compliance problems that we experienced early last year.

So things 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 and in the script is.

Philip M. Nadeau: Perfect. Thanks for taking my questions. Mm-hmm.

Christopher Joseph Raymond: 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 PK.

Is the rate of new patient identification and new patient starts. So last year. We did in fact have material new patients for four and <unk>, 5% patient growth vimizim, 9% patient growth and.

Christopher Joseph Raymond: P.K.U. Commercial Dynamic

Jeffrey Robert Ajer: I heard your comments, Jeff, around how Kuhn and Palazic 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, as I see it, it seems like you'd have a pretty decent sense of any kind of patient warehousing effect that might happen as the effects of the pandemic wane in sort of that timing.

And talent Z you can read that from the revenue and growth.

But as I described.

Just a moment ago the rate of new patient starts for <unk> was severely impacted by.

COVID-19 last year.

And we 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 gating factor for the enzymes.

Jeffrey Robert Ajer: Can you maybe give a little bit more color around that, Jeff, 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?

We're expecting that the new patient starts will continue to be slower than we would have expected had theyre not them and the COVID-19 pandemic. So it's kind of that new business. The results from patient identification and patient and starts for our LSD Brad.

Jeffrey Robert Ajer: Thanks, Chris. So, good observations on your part. Maybe I'd start by saying that, you know, without disclosing details that would constitute, you know, competitive intelligence for one of our competitors, it is true that our revenue from QVAN's loss of exclusivity is both a price and a volume mix. So you're right on that point.

And that are affected there and it and you're right and maybe these dynamics may be unique to biomarin and enzyme replacement therapy and PKU business.

Globally relative to some of the other companies you are covering.

Jeffrey Robert Ajer: In terms of patient warehousing, that's a great question. The rate-limiting step for growth of palindzic 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 Palenzik 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 then if I may add Jeff regarding specific would be volume.

And as Dick.

The issue here is that as you might remember Bobby and <unk> revenues really start kicking in four months or so after.

Initiation of treatment because of the titration period and in the first.

First and foremost are so the revenue is generated per patients are pretty limited and and consequent to here.

And since we had the peak of your kidneys were closed for most of 'twenty and 'twenty, and then see where starting to reopen and then when that's taken away at it and the winter studying and November they closed again and and.

And until January they're starting to reopen now so and just as we've missed a lot of new patient starts even in Q4.

Jeffrey Robert Ajer: 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 capacity for dealing with new patients that's the great limiting step to the growth of our business. So how does that point to a warehousing effect?

And last year, which are impacting the revenue this year.

But again the good news is that you do with the vaccinations and the pandemic hopefully going away those clinics are going to reopen and.

And that's going to allow us to accelerate their growth.

And so again.

Gotcha, Okay. Thanks, guys, yes.

Jeff Sorry, this is Brian Mueller that I just yet.

And and clarified.

And to clarify that the headwinds the COVID-19 headwind is still there, but the assumption and our guidance is that it won't worse and so even during 2020, we were able to add new patients, albeit at a slower rate due to the pandemic.

Jeffrey Robert Ajer: Certainly, there will be patients that are wanting access to Palanzec and waiting for their clinics to either have the capacity or to be back in operation to be able to help them on Palanzec get a prescription.

And some disruption and weekly infusion, which we were largely able to recover so we're assuming we're going to be able to maintain the current level and.

And 2021.

Okay. Thanks for clarification guys.

Okay.

Jeffrey Robert Ajer: Our next question is from Jeff Meacham with Bank of America. Your line is open.

Our next question is from Paul.

And with Stifel. Your line is open.

Jeffrey Robert Ajer: Hey guys, thanks for the question. Also wanted to focus a bit on guidance. You know, when I look at other commercial biotechs or pharmas, I didn't hear a lot about the continued COVID impact or headwind for this year. So I want to dig into the guidance, not for the whole portfolio, not

Hi, Thanks for taking the question and this is Thor on for Paul.

Quick question on H, a given kind of like the evolving competitive landscape, what do you kind of assuming and what are you expecting to need to hit.

And with the gene therapy to be competitive in that space.

And I think one simple way of looking at.

Therapies for which there are <unk>.

Jeffrey Robert Ajer: Not just PKU, is it?

Conditions for which there are therapies is the extent to which the available therapies carry their own burden.

Jeffrey Robert Ajer: Is it more the geographic mix? Is it the orphan nature of the business?

Unknown Executive: Thank you all for joining us. (inaudible)

Jeffrey Robert Ajer: Yeah, thanks, Jeff, for the question. So we did try to address some of the dynamics of how the pandemic is affecting our business in the guidance. And so one of the things that we said was, you know, 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.

And then the condition and clearly that's the case and hemophilia a clearly that's the case and.

And PKU and similarly, and H a G U can get reasonably low attack rates, but it requires a high degree of compliance which is not easy.

Easily maintained.

And patients are looking for the opportunity essentially to be a tax free and prophylaxis free.

And as we've shown with productivity and I think from Teva and they've had.

Of the 134 patients I think to have returned to prophylactic factor replacement therapy, and and our long term studies of three and four years Nobody's return of prophylactic factor therapy.

And bleed rates are very low so.

Jeffrey Robert Ajer: The bigger issue that we pointed to in the script is the rate of new patient identification and new patient starts. So last year, we did, in fact, have material new patients for Naglezine, five percent patient growth. Vemizem, nine percent patient growth. And Palanzic, you can read that from its revenue growth. But as I described just a moment ago, the rate of new patient starts for Palanzic 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 normally pre-pandemic.

And HED population I think we'd 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 and important therapeutic advance for some of these patients.

Great. Thanks.

And.

Our next question is from a cost story with Wolfe Research. Your line is open.

Thanks, a lot so it looks like consensus models.

Operating margins approaching 25% by next year and 42% by 2024.

And the delays and <unk> do you feel like those figures are capable organically and has there been any discussions internally about how to improve the cost structure beyond just cogs, but maybe to R&D and SG&A and do we know broad strokes, what and for 'twenty and 'twenty, one R&D spend purpose or tied and valor.

Jeffrey Robert Ajer: And even then, we've got the clinic capacity issues and the overall gating factor. For the enzymes, we're expecting that 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 Biomarin's enzyme replacement therapy and PKU business globally relative to some of the other companies you're covering.

Okay.

And you wanted to take this one.

Thank you.

Thanks for the question and you touched on what are the key elements.

Since we view and our value proposition, which is both margin growth and <unk>.

Profitability growth with the potential of the <unk> tied and rock paid and so so while we haven't give given long term guidance, we've talked about the <unk>.

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.

Jeffrey Robert Ajer: And if I may add, Jeff, regarding specifically Palenzik... The issue here is that, as you might remember, Polyazinc revenues really start coming in four months or so after initiation of treatment because of the titration period. 3-4 months or so, the revenues generated per patient 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 the infrastructure, we built whether it be sales and marketing or R&D support and G&A support.

And that we've got in place today to support that.

The $2 billion.

Of revenue.

And non-GAAP income and.

And a positive level, which you can approximate the operating profit is that same infrastructure that we plan to use to launch <unk> and <unk>.

While theres going to be some incremental investments for both of those products. We expect a lot of those revenue to drive to our profit margin and.

And as I noted, we also expect lower cost of goods sold from those two products. So so while we're not giving specific numbers for the future. That's how you can think about the trajectory of the P&L and on R&D, We do want to increase the investment and R&D, We've got and exciting early stage pipeline and research engine that we wanted to continue to fund, but we believe we can do there.

Jeffrey Robert Ajer: And then when the second wave hit in the winter, starting in November, they closed again, and until January, they're now starting to reopen now. So in a sense, we've missed a lot of new patient starts, even in Q4 of last year, which is impacting 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 that's going to allow us to accelerate the growth of Paramedic again.

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 <unk>.

And we're tight and rock kv and R&D, specifically and we don't give specific product level R&D guidance, but with with both of those products still being and registration and requiring a lot of our internal efforts.

Jeffrey Robert Ajer: Gotcha. Okay.

JJ Bien-Aime: Okay.

Brian R. Mueller: Jeff, sorry, this is Brian Mueller. I thought I'd just chime in and clarify. We were trying.

And you'll see that we do disclose historical R&D by program and our 10-K, so you'll see that when we file. The K you can expect similar levels of rock teething and resort tight R&D this year.

Yeah.

Yeah.

Brian R. Mueller: [inaudible]

Yeah. Thanks, so much.

Brian R. Mueller: 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 level through 2021.

Thanks.

Your next question comes from the line of Keenan Mckay with RBC capital markets. Your line is open.

Alright, Thanks for taking my question and.

Congrats on wrapping up 2020 on a phone and maybe just another question on coupons.

Paul Andrew Matteis: Okay, thanks for clarifying guys. Our next question is from Paul Matteis with Seesaw. Your line is open. Hi, thanks for taking the question. This is Thoron for Paul. Quick question on HAE.

Love to understand a little bit more just what the assumptions are around built into the guidance around additional jeanette.

Henry J. Fuchs: Given kind of the evolving competitive landscape, what are you kind of assuming and what are you expecting to need to hit with gene therapy to be competitive in that space?

Generic entrant in the market if that's something again after about six.

Six months.

With Liberty period.

And sort of built into guidance or again just.

Henry J. Fuchs: I think one simple way of looking at conditions for which there are therapies is the extent to which the available therapies carry their own burden of the condition. And clearly, that's the case in hemophilia A, and clearly, that's the case in PKU.

And sort of what is built into the guidance there. Thank you again.

I'll start and then maybe Jeff or Brian.

Brian you can comment.

At this time, we don't anticipate any and all of you anticipate one additional generics.

Henry J. Fuchs: 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 Roktavian, I think with Roktavian, 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 has returned to prophylactic factor therapy.

This year because.

I think there is no other there's no third generic so far that asphalt.

For non peak and a day application in the U S.

So and so we do assume that the sick and generics and generic would be launching this year.

Jeff O'brien.

And this.

Yeah.

And as our comps and J&J.

Thanks, Jeff.

Yes.

And so they're taking a generic.

Yeah, just very briefly so.

We were aware and expecting to generic entries, we havent seen as JJ said, a third generic entry and.

Henry J. Fuchs: And bleed rates are very low. 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.

And relative to our expectation that we can retain some shit meaningful share of Kuban business in 'twenty and 'twenty one.

Our modeling suggests that it's exactly when you see a third fourth fifth generic entered the market that it becomes difficult to retain that share. So our assumption right now is to generics, we can retain meaningful share in the U S.

Akash Tewari: Thanks. Our next question is from Akash Tewari with Wolf Research. Your line is open. Thanks a lot.

Brian R. Mueller: So it looks like the consensus model, have operating margins approaching 25% by next year and 42% by 2024. Given the delays in basorotide and Valrox, do you feel like those papers are fittable organically? And has there been any internal discussions about how to improve the cost structure beyond just COGS but maybe to R&D and SG&A? And do we know, broadly speaking, what's baked in for the 2021 R&D spend for basorotide and Valrox? Thanks.

Yeah.

Yeah.

Next question please operator.

Yes, Ma'am. Your next question is from Gena Wang of Barclays. Your line is open.

Thank you for taking my questions just two very quick regarding their gene therapy, especially as you look tavy and Hum.

And you correctly from EMEA approval.

Italy given.

And given the timeline be likely also will see the two year data and if that's the case would that be any requirement for approval.

Brian R. Mueller: Brian, do you want to take this one?

Brian R. Mueller: I can take that, JJ. Thanks, yeah.

Regarding the two year data.

Brian R. Mueller: Thanks for the question. You touched on one of the key elements we view in our value proposition, which is both margin growth and profitability growth with the potential of Visorotide and Roctavian. So 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 $2 billion of revenue and non-gap 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 Roctavian.

And my second question is regarding the <unk> gene therapy.

So if I recall correctly, the first dose and the true researching and what kind of a factor or data.

From the initial dose.

Friday to choose 60 and stuff.

Second dose.

Hi, Judy.

The second one first.

And we use the 2014 doses the 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.

Brian R. Mueller: 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 a side note: we also expect lower cost of goods sold from those two products. So while we're not giving specific numbers for the future, that's how you can think about the trajectory, the P&L. And on R&D, we do want to increase the investment in R&D.

Dose intervals would proceed and half log meaning.

Meaning we would go from two to six.

And <unk>.

And.

We're not anywhere close to his concerns about the potential for over expression with then Alan and hydroxylase, as we werent and consideration of it for block cave and.

Because we've shown that you can't really get a feel of you cant get really sick from a low fee.

Brian R. Mueller: 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 and and the enzyme is such that it shouldn't cause low peak so.

We skipped before E step if you will and went through the <unk> stuff as originally planned and given the steep dose response curve that we and serve as Octavian and the initial signs of efficacy that we've seen.

Both in terms of fee lower and but also.

Relatively low and no evidence of liver dysfunction from the train Jean.

Akash Tewari: Yeah, thanks so much. Thank you very much.

We're encouraged to take the next step at $6 13.

Keenan McKay: 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 coupons I would love to

And then as far as your question about the EMEA I think it's important to understand that these procedures with the health I'll just take some time.

And that when you talk about what we have the one year data and then the two year data are available one year later.

And it may that's a that's almost the length of our review cycle. So you have to imagine that theyre going to have to go through the intellectual process of thinking through where do they want that data and what time point and what role will it play and the decisions and as I've said before the Europeans were less focused on the two year data and the FDA were.

JJ Bien-Aime: 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 third generic so far that has filed for an application in the US. So we do assume that the second generic could be launching this year. Jeff O'Brien, I'm going to add something.

So again these are discussions with the health authorities that we have to have about their procedures, they're tightening their considerations what they think they need in terms of ensuring effective adequate time to review.

Jeffrey Robert Ajer: That is our assumption, JJ.

JJ Bien-Aime: This is JJ.

Jeffrey Robert Ajer: Jeff? Yep, maybe he's keen on the app.

Huidong Wang: Yeah, just very briefly. We were aware of and were expecting two generic entries. We haven't seen, as they said, a third generic entry. And, relative to our expectation that we can retain some meaningful share of Kuvan business in 2021. You know, 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 that with two generics, we can retain a meaningful share in the US.

It will be and discussion about that we have not received anything from the EMA and it says anything different than we've represented to you before that is we believe that the one and your data are very important to them and we're just acknowledging that.

And that reviews will not conclude until the two year data are available.

Did you get any feedback regarding minimum CEB Aussie and will be lumpy.

And for them.

<unk>.

What do you.

No.

But but but what is clear is you know like I said you.

And even the hard even hard edge reviewers and view, our reduction and the annualized bleeding rate from four eight to less than one.

Henry J. Fuchs: Question, please, operator. Yes, ma'am. Your next question is from Jenna Wang of Barclays. Your line is open.

Gina Nguyen: Thank you for taking my questions. Just two very quick ones regarding gene therapy. First is Octavian, and did I hear you correctly about 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 PTU gene therapy. If I recall correctly, the first dose is 2E13, and what kind of factor or data from the initial dose makes you decide to choose 6E13 as the second dose?

And it's been less and one more or less everywhere, we look.

The second year after gene transfer with the phase III and material.

And third year after gene transfer with $4 13, and the fourth year after gene transfer with 613 by and large these are very low annualized bleeding rates and so.

I don't think Theres any real corner with the magnitude of these activity on the clinical endpoint.

Issue of the CRM as we've talked about is the ability to predict the future trajectory, so factory and expression and with two years of data on and of 134, we have to weigh the issue to 90, not rasp and at least know how to characterize it and product label and a bed.

Henry J. Fuchs: Hi Gina, I'll do the second one first. We used the 2E13 dose as the starting dose, which 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. 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 this decision.

Great. Thank you.

Mhm.

Your next question is from Matthew Harrison of Morgan Stanley. Your line is open.

Hello, everyone and this has caused us on for Matthew One quick question on the Saudi side can you provide some color around the launch preparation and Europe, and Colorado, you're thinking about pricing and.

Ooh.

Henry J. Fuchs: And the enzyme is such that it shouldn't cause a low fee. So we're, 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 6E13.

Jeff you want to cover that.

Yeah happy to.

So.

Back to some of the things we said in the prepared remarks, one is Europe represents a very very large patient and opportunity for us over time.

And in Europe, but it takes a little time to go market by market and navigate pricing and reimbursement approvals gets get patients started and generating.

Revenue, but we really expect Europe to be the long term.

Henry J. Fuchs: And as far as your question about the EMA is concerned, I think it's important to understand that these procedures with the health authorities take some time. And 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 they want that data, at what time point, and what role will it play in the decision.

<unk> revenue for four of the sort of tied in terms of pricing we've done a fair amount of pricing research and the U S and in Europe and.

Yeah.

<unk>.

As is typical for a practice, we won't set a price until we've gotten approval we've got a label.

And that sort of thing, but we think that.

Pricing corridor between our initial European markets call that France, Germany, Italy for example, and the United States will be relatively similar.

List pricing in particular.

And as we've as we've guided to previously based on the size of the patient population will probably not thinking about E. Our key types of pricing.

Henry J. Fuchs: As I said before, the Europeans were less focused on the two-year data than the FDA was. So, again, these are discussions with the health authorities that we have to have about their procedures, their timing, their considerations, and 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.

And maybe something more similar to <unk>.

Power and the type of pricing for for the sort of tied.

And then in terms of launch preparations.

A contemplation of patients or we.

We don't need to go through the.

And.

Disease awareness and screening and patient identification and all.

All of the achondroplasia patients are are essentially known as having achondroplasia from or shortly after birth. So that's an important step that we.

Henry J. Fuchs: Did you get any feedback regarding the minimum CABR rate they will be looking for, just directionally? for two years.

We can skip and it's a powerful steps to skip what we do have to do is we have two upon launch.

Henry J. Fuchs: Uh, no. But what is clear is, like I said, even hard-edge reviewers view our reduction in the annualized bleeding rate from 4.8 to less than one. And it's been less than one more or less everywhere we've looked.

And the track down and Corral, those achondroplasia patients and get them to and appropriate treatment at home.

And that treatment home and some cases might be geneticists and genetic clinics that were already connected with where it might be and 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.

Henry J. Fuchs: The second year after gene transfer with the Phase III material, the third year after gene transfer with 4013, and the fourth year after gene transfer with 6813, 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 factory expression. And with two years of data and N of 134, we have to weigh the issue to maybe not risk, but at least know how to characterize it on a product label and a benefit-risk decision.

There's not been a treatment for achondroplasia pharmacologic treatment.

To date. So those are the kind of thing big things that we're focused on finding.

Achondroplasia patients where they exist today.

Lining up and appropriate treatment at home from that for them and homing in on our final pricing strategy.

Very helpful. Thank you.

Your next question is from and we'll get the mantra of Citigroup. Your line is open.

Henry J. Fuchs: Great, thank you. Your next question is from Matthew Harrison of Morgan Stanley. Your line is open. Hello everyone, this is Costas Son on behalf of Matthew. One quick question on Vosorityte.

Hi, guys. This is James on for Mohit.

Just had a question since presenting the one year data in early January from Octavian, where you're able to engage and any discussions with the physicians or payers.

I would love to get any feedback on Oh and color on feedback there.

Liana Masatos: Can you provide some color around the launch preparation in Europe? And how are you thinking about pricing? Jeff, do you want to cover that?

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 and kind of like an NFPA Ed comes so it included both of those.

Jeffrey Robert Ajer: Yeah, happy to. So, you know, I'll go back to some of the things we said in our 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, negotiate price and reimbursement approvals, get patients started, and generate revenues. 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 risk pricing in particular, maybe something more similar to the Palin-Zeke type of pricing for Soratide and then in terms of launch preparation.

Guild and the practice of hemophilia, a treatment, who gave voice to the importance of having a treatment option and are.

The importance of both ADR and factory and considerations for choosing Ralph gave you and 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 internationally for the past couple of decades. So we had.

And.

And as I said it was one of my colleagues came away with making the cut and one of our colleagues Kimberly and making the comment and.

And this person has an extremely high bar and I'm, saying this is an impressive data package.

Jeffrey Robert Ajer: You know, achondroplasia patients are, you know, we don't need to go through the disease awareness and screening and patient identification processes. 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, upon launch, kind of track down and corral those achondroplasia patients and get them to an appropriate treatment home.

So.

And the basis of all that we look forward to the two year evidence package holding up and if that's the case and we should be able to make available a choice for patients and Jeff do you want to speak anything about payers and response to when you do that.

Yeah happy to Great question James.

Really happy with the way the one you're Octavian data came out we have not had a chance to go back explicitly with Payors and.

And refresh our payer research with them and.

Jeffrey Robert Ajer: That treatment home, in some cases, might be geneticists and genetic clinics that we're already connected to. 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 about achondroplasia because there's not been any pharmacologic treatment for achondroplasia 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.

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're putting in front of payers both in the United States and in Europe last year. So.

I concluded.

One thing the one year data, but the kind of the feedback that we've gotten from payers today.

<unk> is probably going to be consistent with the feedback we will get from payers. After we've explicitly stepped through that one year data.

I appreciate it guys. Thank you so much.

Yes.

Your next question is from Liana <unk> of Wedbush Securities. Your line is open.

Mohit Bansal: Your next question is from Mohit Bansal of Citigroups. Your line is open. Hi guys, this is James on behalf of Mohit. Just got a question. Since presenting the one-year data in early January for Roktavian, were you able to engage in any discussions with physicians or payers? We'd love to get any feedback on, or call on feedback there.

Thank you.

30% of Cowen and see patients came from Cuba, and what percent of Tucson, and patients are going to talent and seek versus the generic.

Okay.

Okay. So let.

Let me see if I understand the question you said.

Henry J. Fuchs: 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 FBA adcom. 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 Raftavian or an alternative therapy.

What percent of Kuban patients are moving over to the generic product and and I think that's independent of your observation that 30% of power and the patients are.

Transitioning from Covid and so.

Once we have that data.

It's important and valuable data, but we consider competitive intelligence that we don't want to give too of the generic competitors.

Henry J. Fuchs: 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 internationally. And as I said, it was one of my colleagues who came away with making the comment. One of our colleagues came away making the comment, and this person has an extremely high bar for 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 that choice available for patients. And Jeff, do you want to speak anything about payers in response to when you do that?

And so I would guide to say if you follow the the revenue erosion for the quarter and the revenue erosion that.

And that we projected for 2021 I've already commented that the revenue is a mix of volume and price erosion and.

And I'm afraid you'll have to excuse those percentages that you're in.

I mean, if I may and beyond.

So the other dynamic is that no.

And he is the only approved in the U S. Oh, sorry, how do you think it'll be approved and the U S for adults.

Jeffrey Robert Ajer: Yeah, happy to. Great question, James.

Jeffrey Robert Ajer: 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, but we will during the course of this year. What I would say is that the one-year data was highly consistent with the product profiles that we put in front of payers, both in the United States and in Europe last year. So, upon seeing the one-year data, 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 sped through that one-year I appreciate it guys, thank you so much.

And there are a lot of.

There were a lot of kids and Cooper and obviously they cannot be switched to a you probably think of it this time or in Chile.

Hey, J T.

Okay. Thank you.

Your next question is from Michelle Gilson with Canaccord Genuity. Your line is open.

Hi, Thank you for taking my question.

I'm, just wondering and PKU gene therapy, you mentioned, you're you're escalating the dose to 60 13, I guess compared to what you're trying to eat 13. What are you looking forward to seeing that next dose that and you know what gives you confidence that he is going to speed the dose.

JJ Bien-Aime: Your next question is from Liana Masatos of Web Bush Securities. Your line is open. Thank you. If 30% of Palanzec patients come from Kuvan, what percent of Kuvan patients are going to Palanzec versus the generic?

And then just kind of if I can.

Besides question here.

Is there any indication that you see and the data so far a day and modify steroid regimen is.

Jeffrey Robert Ajer: 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, and I think that's independent of your observation that 30% of Palantik patients are transitioning from Kuvan. So we have that data. I've already commented that revenue is a mix of volume and price erosion, and I'm afraid you'll have to deduce.

Is that gets better than than what was used and to generate studies.

Yeah, it's too early to comment on steroids just yet.

And.

And what gives us confidence the six Inc. Dose group is going to do it.

The preclinical data.

And that we have a.

Reasonably predicted actually what we would see and the starting dose level and as I mentioned, both from the preclinical data for <unk>, Octavian and clinical data and let's say, even and preclinical data on three of seven.

JJ Bien-Aime: Kulani is only approved in the U.S., oh, sorry, Palenik is only approved in the U.S. for adults, and there are a lot of kids, there were a lot of kids in Cuba, and obviously, they cannot be switched to Palentik at this time or until they reach age 18.

Do observe there to be a steep dose response curve.

So that's.

Amalgam of ethics and business confidence with 60 13 dose, we'll do it and when I say it you asked what are we looking for I think the dream of everybody with phenylketonuria and it's normal to normal diet and I don't have to take anything for it.

Michelle Gilson: Okay, thank you. Your next question is from Michelle Gilson of Canongirg Dinuwiki. Your line is open.

And I do think that and again when you go back to what Rob Teva and offers.

Henry J. Fuchs: Hi, thank you for taking my question. I'm just wondering, on TKU 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, you know, what gives you confidence that 6E is going to be the right 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, I guess, better than what was used in the GENERATE studies?

And we reduced factory and infusions from 136 per patient per year to two per patient per year.

And that would represent a very substantial reduction and the burden of care for patients with phenylketonuria and those patients also experienced fewer than one bleeding event and an ear, which would kind of you lay that over to the PKU arena that would be like no fond of and no confusion.

Snow mental cloudiness events.

So if and we're looking forward to PKU gene therapy, as normal and normal by it.

Henry J. Fuchs: It's too early to comment on steroids just yet, and what gives us confidence that the 60-dose group is going to do it? You know, the preclinical data that we have reasonably predicted, actually, what we would see at the starting dose level, and as I mentioned, both on the preclinical data for Roctavian, clinical data on Roctavian, and preclinical data on 307, we do observe there to be a steep dose response curve. So that's, it's an amalgam of that because there's confidence that the 6013 dose will do it. And when I say it, you ask, what are we looking for?

Okay.

Your next question is from Kimberly That's William Blair. Your line is open.

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

Okay.

Okay.

I mean, he can come from the Jeff and I think we've covered that and still keep.

Give me a call probably Jeff do you have anything to do out here.

Well the only thing I'd add here is we think that the generics are essentially a spa.

Henry J. Fuchs: I think the dream of everybody with spinal ketoneuria is normal feeding, a 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 Roktavian offers, 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, 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 if that we're looking for with PKU gene therapy is normal C, normal diet.

Specialty pharmacy substitution.

Type of activity, we don't think that the generics are promoting like and branded generic fashion to our physicians and one thing that we have going in our favor is I think physicians and patients have been <unk>.

And then and are continuing to be sensitive to the ranges of services that biomarin and provides around around our drugs, including Kuban and and the value of those services and and so that's a good thing for us.

Timothy Francis Lugo: Your next question is from Tim Lugo of William Blair. Your line is open. Hi guys, this is John on behalf of Tim. 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 Kuvan and how that might be affecting your expectations for erosion over the near and medium term. Thanks.

Alright, thanks, so much.

And.

And there's no further questions I would like to turn it back to you J J P and in May for closing remarks.

Thank you operator.

So I would say that again despite the.

And just that were caused by the COVID-19 epidemic is here are the demand for bandwidth medicine drove some strong results from 'twenty and 'twenty and they are expected to grow 9% in 'twenty and 'twenty, one including contributions from some of that.

Jeffrey Robert Ajer: I mean, you can cover that, Jeff, but I think we've covered that, you know, in terms of the call. That's probably it, Jeff. Do you have anything new out of here?

Our strong revenue base driving positive operating cash flows and you can get and that's advancement of our neck and neck.

JJ Bien-Aime: The only thing I'd add here is that we think that generics are essentially a specialty pharmacy substitution type of activity. We don't think that generics are being promoted 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 and are continuing to be sensitive to the ranges of services that Biomarin provides around our drugs, including Cuban, and the value of those services. And so that's a good thing for us.

He can product opportunities, we are well positioned for substantial growth over the coming quarters.

And importantly, it was the only chat and rotate and are approved and launched as you'd expect.

Commercial and market opportunities for both of those products.

Potential products significantly exceed the market sizes of our current products. These large large day large stage opportunities combined with our established base business create a compelling value proposition.

JJ Bien-Aime: All right, thanks so much, and there are no further questions. I would like to turn it back to JJ Bien-Aimé for closing remarks.

JJ Bien-Aime: 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 balm with medicine drove some strong results in 2020, and they are expected to grow 9% in 2021, including contributions from Cubans. So we are strong revenues-based, driving positive operating pressures, enabling the advancement of our next... We are well positioned for substantial growth over the coming quarters. Importantly, Doi Tat and Roktavion are approved and launched as we expect commercial market opportunities for both of these products.

And will enable the continued growth and expansion of our innovative research programs, what do you think.

For your continuous support and stay safe.

Thank you you may now disconnect.

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JJ Bien-Aime: Potential products significantly exceed the market sizes of our current products. These large-stage opportunities, combined with our established 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.

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