Q3 2021 Biomarin Pharmaceutical Inc Earnings Call

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Operator: Welcome to Biomarin's 3rd Quarter 2021 Financial Results Conference Call. Hosting the conference call today from Biomarin is Traci McCarty, Vice President of Investor Relations. Please go ahead, Traci.

Welcome to Biomarin.

Third quarter 2021 financial results conference call.

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

Traci McCarty: Thank you, Grace. Thank you, everyone, for joining us today.

Thank you great. Thank you everyone for joining us today to remind you. This non confidential presentation contains forward looking statements about the business prospects of Biomarin pharmaceutical, Inc, including expectations regarding Biomarin <unk> financial performance commercial products and potential future products in different areas of therapeutic research and development.

Traci McCarty: To remind you, this non-confidential presentation contains forward-looking statements about the business prospects of Biomarin Pharmaceutical Inc., including expectations regarding Biomarin's financial performance, commercial products, and potential future products in different areas of therapeutic research and development. Results may differ materially depending on the progress of Biomarin's product programs, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical market, and developments by competitors. And those factors detailed in Biomarin's filings with the Securities and Exchange Commission, such as 10Q, 10K, and 8K reports.

Results may differ materially depending on the progress with Biomarin <unk> product programs actions of regulatory authorities availability of capital future actions in the pharmaceutical market and developments by competitors and those factors detailed in Biomarin filings with the Securities and Exchange Commission, such as 10-Q, 10-K and 8-K report.

Traci McCarty: On the call today from Biomarin Management are J.J. Brinman, Chairman and Chief Executive Officer, Jeff Ager, Executive Vice President, Chief Commercial Officer, Hank Fuchs, President, Worldwide Research and Development, Greg Geyer, Executive Vice President, Chief Technical Officer, and Brian Mueller, Executive Vice President, Chief Financial Officer. We hope to keep this call to an hour, so respectfully request that you limit yourself to one question during the Q&A portion of Thank you so much. I will now turn the call over to Biomarin's Chairman and CEO, J.J. Bianamante.

On the call today from Biomarin management are J C. Penney, Chairman and Chief Executive Officer, Jeff <unk> Executive Vice President and Chief Commercial Officer Fuchs, President worldwide Research and development, Greg Guyer Executive Vice President Chief Technical Officer, and Brian Mueller Executive Vice President Chief Financial Officer.

Hope to keep this call to an hour. So respectfully request that you limit yourself to one question during the Q&A portion of the call. Thank you. So much I will now turn the call over to Biomarin as chairman and CEO J J P enemy.

Thank you Tracy and good afternoon, everyone. Thank.

J.J. Bianamante: Thank you, Traci, and good afternoon, everyone.

Thank you for all for joining us today.

J.J. Bianamante: Thank you all for joining us today. Biomarin's commercial organization is excited to be launching our seventh commercial product following the August

Bob brings a commercial organization is excited to be launching our seventh commercial product. Following the August approval in Europe of OXXO go for the treatment of Achondroplasia for children ages, two use that up.

J.J. Bianamante: Approval in Europe of VOXERGO for the treatment of echolealplasia for children ages 2 years and up. I would say that the level of initial prescription demand for patients seeking Vox Logo treatment is high.

I would say that the level of initial prescription demand for patients seeking box OCA treatment in Europe has exceeded our expectations.

J.J. Bianamante: Thank you for watching. Boxogo's revenues this year will come from France and Germany, where there are a number of children already on...

Box will go revenues this year would come from France, and Germany, where there were a number of a number of children are already on therapy.

J.J. Bianamante: Children already on therapy, as well as a number of select early access countries in Europe, the Middle East, and Africa, and actually also Latin America.

Well as a number of select early access countries.

In Europe, Middle East and Africa.

He also Latin America.

J.J. Bianamante: As the first and only approved medicine that targets the underlying cause of achondroplasia and improves bone growth in children, we are very pleased with early indicators of product demand. In the U.S., we are in late-stage labeling and post-marketing requirements discussions with the FDA.

As the first and only approved medicine that targets the underlying cause of achondroplasia unimproved bone growth in children.

We are very pleased with early indicators of product demand.

In the U S. We are in late stage labeling and post marketing requirements discussions with the FDA. So.

J.J. Bianamante: So we remain encouraged about the potential positive FDA pedofilaction outcome in less than a month now.

So we remain encouraged about the potential positive FDA Purdue faction outcome.

J.J. Bianamante: I think U.S. approval will pave the way for our largest global product launch to date.

Most of them.

I think the U S approval that would pave the way for our allergic largest global product launch to date.

J.J. Bianamante: and set the stage for significant revenue growth starting in 2022. Turning to the 2021 financials, it is important to understand the dynamics

And set the stage with significant revenue growth starting in 2022.

Turning to 2021 financials. It is important to understand the dynamics of our global business to appreciate the underlying strength. Despite the impact from anticipated uneven ordering in the first half of the year as compared to what we what is expected in the second half of the year. We are pleased to be improving full year topping.

J.J. Bianamante: Dynamics of our Global Business to appreciate the underlying strength. Despite the impact of anticipated uneven ordering in the first half of the year as compared to what is expected in the second half of the year, we are pleased to be improving your top and bottom line.

I'm tryin' guidance.

J.J. Bianamante: And this despite Kuvan having faced generic competition since the fourth quarter of last year. We actually, despite this, we anticipate generating full year 21 revenues mostly in line with our 2020 revenues.

And this is despite a.

Cougar and having faced generic competition since the fourth quarter of last year.

We actually despite this we anticipate generating full year 'twenty, one revenues, mostly in line with our 'twenty 'twenty revenues, which illustrates the strength of our base business.

J.J. Bianamante: which illustrates the strength of our base system. This is a result of underlying growth in net product revenues from products marketed by Biomarin, excluding Kuvan, and also continued expense management. The number of patients treated with Biomarine therapies has increased this quarter for all our products.

This is a result of underlying growth in net product revenues from products marketed by Biomarin, excluding coupon and also continued expense management.

Number the number of patients treated with bombings therapies.

He has increased this quarter for all our products.

J.J. Bianamante: All of them are at KUVAN, of course.

Then the cool down of course and has reached record levels, we expect revenues to rebound in the fourth quarter as compared to the third quarter. So as to end up with a strong finish in 2020 one.

J.J. Bianamante: and has reached a record level. We expect revenues to rebound in the fourth quarter as compared to the third quarter so as to end up with a strong finish in 2021. With the addition of Vox in Europe and the anticipated US approval, we expect a significant step up in revenues beginning next year in 2022.

With the addition of box over in Europe, and the anticipated U S approval, we expect a significant step up in revenues beginning next year in 2022.

J.J. Bianamante: leading to anticipate a sustainable positive gap income for the full year starting next year. We will provide food year 2022 guidance as usual during our fourth quarter quality calls.

Leading to anticipate that sustainable positive GAAP income for full year, starting next year.

We will provide full year 2022 guidance as usual during our fourth quarter.

Quality calls on next February.

J.J. Bianamante: Calls on the next February.

J.J. Bianamante: Suffice it to say that our strategy to layer on Voxpho and potentially Octavian to our strong base business...

Suffice it to say that our strategy to layer on Voc, so when potentially evoked have gone to our strong base business.

J.J. Bianamante: Leveraging our global infrastructure and manufacturing capabilities to drive meaningful profitability is rolling out as planned. In support of that plan, cash flows from operating activities increased to nearly $300 million year-to-date and are driving the expansion of Biomarin's earlier Stage 5 plan. With six early stage products on the agenda for our upcoming R&D day, we expect to initiate clinical trials for multiple new products over the coming years. Harnessing genetic technologies to speed our discovery capabilities has resulted in an exponential growth in our preclinical assets.

Leveraging our global infrastructure and manufacturing capabilities to drive meaningful profitability. He is rolling out as planned.

In support of that plan cash flows from operating activities increased to nearly $300 million year to date.

Driving the expansion Obama in earlier stage pipeline with.

With six early stage products on the agenda for our upcoming R&D day, we expect to initiate clinical trials for multiple new products over the coming years.

How are you seeing generic technologies to speed our discovery capabilities has resulted in an exponential growth in our preclinical assets.

J.J. Bianamante: and we are very excited to share our progress with you on November 30th.

And we are very excited to share our progress with you on November 30th.

J.J. Bianamante: So the past 18 months have been challenging for many reasons, the global pandemic, and regulatory setbacks.

So the past 18 months have been challenging for many reasons.

Global pandemic regulatory setbacks etcetera.

J.J. Bianamante: But we have remained focused.

J.J. Bianamante: on our mission and goals. Biomarin has never been better positioned to achieve the next level of growth

But we have remained focused on our mission and goals Biomarin has never been better positioned to achieve the next level of growth and we plan to capitalize on the many opportunities that are before us.

J.J. Bianamante: We plan to capitalize on the many opportunities that are before us. I want to thank our Biomarin colleagues.

Our biomarin colleagues and associates for their continued commitment to developing the essential medicines that help so many so.

J.J. Bianamante: So, thank you all for your continued support. I will now turn the call over to Jeff to discuss the

So thank you all for your continued support that would now turn the call over to Jeff to discuss the commercial business update Jeff.

Jeffrey Robert Ajer: The Commercial Business Update

Jeffrey Robert Ajer: Thank you, JJ. I'm very pleased with the team's performance across all brands and all regions during the quarter. Not only are we improving top-line guidance for the year, but we are at the start of launching what may be our biggest brand-to-date, VoxOgo. As JJ already described, the impact of large, unevenly timed orders for our enzyme replacement therapy brands in the first half of the year, as well as the U.S. loss of Kuvan market exclusivity a year ago, was notable in the third quarter.

Thank you J J I'm very pleased with the team's performance across all brands and all regions during the quarter.

Not only are we improving topline guidance for the year, but we are at the start of launching what may be our biggest.

Brand to date walks yoga.

As J J I already described the impact of large unevenly time to orders for our enzyme replacement therapy brands in the first half of the year as well as the U S loss of Kuban market exclusivity a year ago was notable third quarter. Despite those dynamics, we achieved $409 million in tow.

Jeffrey Robert Ajer: Despite those dynamics, we achieved $409 million in total revenues, reflecting solid demand in the third quarter and year-over-year growth in net product revenues marketed by Biomarin, excluding Kuvan. Q3 revenues were consistent with our expectations around order timing and the balance between first half and second half revenues communicated previously.

Revenues, reflecting solid demand in the third quarter and year over year growth in net product revenues marketed by Biomarin excluding Kuban.

Q3 revenues were consistent with our expectations around the order timing and the balance between first half and second half revenues communicated previously.

Jeffrey Robert Ajer: Keep in mind, patient demand remains a key indicator to gauge product demand. For both Naglozyme and Vimazem, patient numbers increased by more than 10%, respectively, year over year. For Bronura, in the third quarter, children on therapy increased by more than 20% year over year.

Keep in mind patient demand remains a key indicator to gauge product demand for both <unk> and vimizim patient numbers increased by more than 10%, respectively year over year or burner at in the third quarter children on therapy increased by more than 20% year over year.

Moving to Palin zinc with 32% year over year growth translated to $61 million of net product revenues in the third quarter, reflecting a combination of revenues for more patients achieving maintenance dosing as well as new patients initiating therapy.

Jeffrey Robert Ajer: Moving to Palanzec, where 32% year-over-year growth translated to $61 million in net product revenues in the third quarter, reflecting a combination of revenues for more patients achieving maintenance dosing, as well as new patients initiating therapy. This growth was achieved despite continued COVID impact, resulting in many peak AU clinics operating at partial capacity. Consistent with our commentary last quarter, it is important to note that PKU clinics in the U.S. have not opened up to new patient starts at the rate we anticipated. As expected, the U.S. was the main contributor of growth in the quarter, driven by U.S. patient increases of approximately 20% year-over-year.

This growth was achieved despite continued COVID-19 impact, resulting in many PKU clinics operating at partial capacity.

Insistent with our commentary last quarter. It is important to note the PKU clinics in the U S have not opened up to new patient starts at the rate we anticipated as expected. The U S was the main contributor of growth in the quarter driven by U S patient increases of approximately 20% year over year, while we remain optimistic.

About the growth prospects for Palin zinc for the balance of the year, we expect U S. PKU clinics to increased new patient starts at a slower pace than originally anticipated the.

The commercial launch of balance he can Biomarin is Europe middle East and Africa region continues to progress through individual country level pricing and reimbursement negotiations.

Continuing with the PKU franchise Kuban contributed $68 million in revenue in the third quarter, reflecting incremental erosion to generics in the U S revenues decreased by 45% year over year, primarily due to the U S loss of market exclusivity in October 2000.

Jeffrey Robert Ajer: While we remain optimistic about the growth prospects for Palanzec for the balance of the year, we expect U.S. PKU clinics to increase new patient starts at a slower pace than originally anticipated. The commercial launch of Balanzic and Biomarin in the Europe, Middle East, and Africa region continues to progress through individual country-level pricing and reimbursement negotiations. Continuing with the BKU franchise, Kuban contributed $68 million in revenue in the third quarter, reflecting incremental erosion to generics in the U.S.

'twenty as anticipated.

Moving onto box Zelle go our newest commercial opportunity and likely the largest launch to date, we've been very pleased with the level of prescription demand for patients seeking box. So good treatment since receiving European approval in August.

Mind, you that in Europe price and reimbursement processes are the primary gates to being able to treat patients and generate revenue and these processes can be lengthy.

Jeffrey Robert Ajer: Revenues decreased by 45% year-over-year, primarily due to the U.S. loss of market exclusivity in October 2020, as anticipated. Moving on to Voxelgo, our newest commercial opportunity and likely the largest launch to date. We've been very pleased with the level of prescription demand for patients seeking Voxelgo treatment since receiving European approval in August. A reminder that, in Europe, price and reimbursement processes are the primary gates to being able to treat patients and generate revenue, and these processes can be lengthy. Therefore, for revenue purposes, we are focused on the set of markets where we can quickly begin treating patients and generating revenues.

Therefore for revenue purposes, we are focused on the set of markets, where we can quickly began treating patients and generating revenues. These markets include France, Germany, and a number of other markets in which we are pursuing named patient sales importantly, we are seeing robust prescription demand already.

And we are optimistic about the prospects of being able to convert that demand to patient treatment and revenue.

The small revenue recorded for Q3 was from France and for the first patients they're starting treatment.

Already in Q4 additional patients have started therapy in France, and we have shipped box they'll go to Germany, and Switzerland to begin treating patients in these markets.

Jeffrey Robert Ajer: These markets include France, Germany, and a number of other markets in which we are pursuing named patient sales. Importantly, we are seeing robust prescription demand already, and we are optimistic about the prospects of being able to convert that demand into patient treatment and revenue. The small revenue recorded for Q3 was from France, and for the first patients there to start treatment.

Concurrent with the EMEA launch our U S. Commercial team is planning for the potential launch at the end of the year, assuming a positive proof of action outcome in November.

As has been our experience with prior launches in the U S. We do have the ability to quickly respond to prescription demand following approval while U S. Payers are numerous and diverse we have experienced navigating the medical exception process to facilitate early prescription demand while we worked.

Jeffrey Robert Ajer: Already in Q4, additional patients have started therapy in France, and we have shipped Voxogo to Germany and Switzerland to begin treating patients in these markets. Concurrent with the EMEA launch, our U.S. commercial team is planning for a potential launch at the end of the year, assuming a positive PDUFA action outcome in November. As has been our experience with prior launches in the U.S., we do have the ability to quickly respond to prescription demand following approval. Additionally, while U.S. payers are numerous and diverse, we have experience navigating the medical exception process to facilitate early prescription demand while we work through the process yielding payer coverage policies.

Through the process, yielding payer coverage policies.

As with the launch of previous Biomarin brands in the U S. This experienced team is in place and prepared for a potential approval.

We look forward to providing full year box so guidance for 2022, when we report fourth quarter results next February we would also like to set expectations for quarterly metrics that we will report on for the next six quarters for.

For the quarter being reported we will report net box they'll go product revenues.

Active markets with sales the total number of commercial patients at the end of the quarter and other color on the progress of the launch that will help you evaluate the commercial status of box. So go and inform your expectations.

In conclusion resulted in 2020 one for established brands are tracking to expectations for the improved topline guidance provided today raising the low end of the total revenue guidance by $30 million as well as the low end of the ranges for Vimizim, Kuban and Pelham Zeke <unk>.

Jeffrey Robert Ajer: As with the launch of previous Biomarin brands in the U.S., this experienced team is in place and prepared for potential approval. We look forward to providing full-year VoxOgo guidance for 2022 when we report fourth-quarter results next February. We would also like to set expectations for quarterly metrics that we will report on for the next six quarters. For the quarter being reported, we will report net Voxelgo product revenues.

For our essential medicines, and the 75 countries, where we do business is robust and growing the commercial team is energized to be launching our newest potentially largest product opportunity with box they'll go in the EMEA region, and we are eagerly preparing for the potential launch in the United States should we receive.

<unk> approval in November.

You for your attention and I will now turn the call over to Hank to provide an R&D update Hank.

Jeffrey Robert Ajer: Active Markets with Sales, the total number of commercial patients at the end of the quarter, and other color on the progress of the launch that will help you evaluate the commercial status of Boxogo and inform your expectations. In conclusion, results in 2021 for established brands are tracking to expectations for the improved top-line guidance provided today, raising the low end of the total revenue guidance by $30 million, as well as the low end of the ranges for Demizum, Kuvan, The commercial team is energized to be launching our newest and potentially largest product opportunity with Voxelgo in the EMEA region, and we are eagerly preparing for the potential launch in the United States should we receive approval in November.

Thanks, Jeff Similarly, the research and development organization echoes your enthusiasm for the European approval about Sogou.

Families have been waiting for a long time for a treatment option for their children and we believe that targeted mechanism about sogo, which promotes ended chondral bone growth. During the time period when growth plates are open can have a meaningful and potentially lifelong effect on children with achondroplasia.

We're so pleased that this important medicine is now available in Europe, and we look forward to hearing real world treatment experiences a fan as families access much I'll go over the coming months and years.

European approval about set up for children ages, two and up further demonstrates the importance of beginning treatment as early as possible to provide maximum clinical benefit while growth plates aren't amenable to treatment.

Look forward to the readout of our 52 week placebo controlled study in children newborn through five years of age around the middle of next year. That's the next potential steps toward expanding access to <unk>. So that should those data would be supportive.

In the United States, we look forward to the stupid target action date of next month, we believe the robust dossier of data under review and provides clear signals of clinical benefit so lots of good treatment.

Jeffrey Robert Ajer: Thank you for your attention, and I will now turn the call over to Hank to provide an R&D update. Thanks, Jeff. Similarly, the Research and Development Organization echoes your enthusiasm for the European approval of Oxogo. Families have been waiting for a long time for a treatment option for their children, and we believe the targeted mechanism of VOXO will help. Promotes endochondral bone growth during the time period when growth plates are open, and has a meaningful and potentially lifelong impact on children with achondroplasia.

I also want to take the opportunity for everyone to thank everyone, who contributed to this important milestone on behalf of families seeking a treatment option for achondroplasia. Thank you very much.

Under Octavian regulatory regulatory milestones are tracking the plan at the end of November.

2021 we'll reach the two year Mark for the Phase III study and the two year follow up observation period, we continue to expect Resubmission of the U S. Biologic application for Octavian in the second quarter of 2022, assuming supported two year data.

Led by an expected six months review procedure for the United States in.

Henry J. Fuchs: We're so pleased that this important medicine is now available in Europe, and we look forward to hearing of real-world treatment experiences as families access Pipe Sogo over the coming months and years. The European approval of Oxido for Children Ages 2 and up further demonstrates the importance of beginning treatment as early as possible to Provide Maximum Clinical Benefit While Growth Plates Are Amenable to Treatment. We look forward to the readout of our 52-week placebo-controlled study in children newborn through five years of age around the middle of this year. What is the next potential step toward expanding access to VoxOvo should those data be supported?

In Europe with the marketing authorization application validated and under review, we continue to expect C. H M. P opinion in the first half of next year, assuming supportive to your data, which will be shared with EMEA. When it is available we remain confident in <unk> potential to be an important treatment option for those with Citi.

Their hemophilia a based on the clinical evidence observed today, demonstrating dramatic reductions in bleeding rates factory utilization and factor eight infusions following treatment.

Turning to B M N three O seven therapy gene therapy for phenylketonuria. Following the clinical hold placed on that phase once you've studied by the food and drug administration. We've now received communication from the agency with guidance on next steps. We are in the process of addressing the agency's request for additional information. So we do not have an update on when the <unk>.

Henry J. Fuchs: In the United States, we look forward to the Padova target action date of next month. We believe the robust dossier of data under review provides clear signals of clinical benefits from Hoxhago treatment. I also want to take the opportunity to thank everyone who contributed to this important milestone on behalf of families seeking a treatment option for achondroplasia. Thank you very much.

Might be lifted the hold on our PKU gene therapy study was based on recently identified safety findings from a non clinical non G. L. P. Pharmacology studies immuno deficient mice.

Scientist striving to serve patients' needs, we're committed to understanding these fines findings as we've shared previously and it was corroborated during the FDA panel discussion on Hayden saved in September it remains uncertain and in our view unlikely that these specific findings with B M 307 will translate to a safety issue with this or other AAV gene.

It'd be treatments.

Henry J. Fuchs: Briefly, on Roctavian, regulatory milestones are tracking the plan. At the end of November 2021, we will reach the two-year mark for the Phase 3 study and the two-year follow-up observation period. We continue to expect resubmission of the U.S. biologic application for Roctavian in the second quarter of 2022, assuming supportive two-year data, followed by an expected six-month review procedure in the United States. In Europe, with the marketing authorization application validated and under review, we continue to expect a CHMP opinion in the first half of next year, assuming your data is supportive, which will be shared with the EMA when it For those with severe hemophilia A, based on the clinical evidence observed to date demonstrating dramatic reductions in bleeding rates, factor VIII utilization, and factor VIII infusions following.

We're working through the process with the FDA and we'll keep you posted as we have relevant updates.

Turning to our R&D day event now planned for November 30th.

Look forward to sharing new data and new program updates with you.

The R&D organization has hit its stride melding, our own internal discovery capabilities with genetic tools to understand underlying mechanisms of disease in order to develop targeted medicines. We're excited to share. These advances with you in greater detail and describe the many assets under development in your earlier stage pipeline. We hope you all tune in.

Thank you so much for your support and I'll now turn the call over to Brian to update financial results in the quarter Brian.

Thank you Henk. Please refer to today's press release summarizing our financial results for full details on the third quarter of 2021 as usual our comprehensive report on the quarter will be available on our upcoming Form 10-Q, which are on track to file over the next few days as.

As J J and Jeff mentioned, the previously anticipated order timing in 2020. One has created a meaningfully uneven revenue flow between the first and second halves of the year.

Illustrate the impact of select individual country order timing in Q3, 2021 last quarter Q2, 'twenty 'twenty. One there was approximately $90 million more revenue, excluding Kuban from Brazil, Russia, and the middle East that did not recur in the third quarter substantially accounting for the quarter over.

Henry J. Fuchs: Turning to BMN 307 therapy, gene therapy for phenylketonuria. Following the clinical whole placement in that phase, once your study is approved by the Food and Drug Administration, you've now received communication from the Agency with guidance on next steps. We are in the process of addressing the agency's request for additional information, so we do not have an update on when the hold might be lifted. The hold on our PKU gene therapy study was based on recently identified safety findings from a non-clinical, non-GLP pharmacology study in immunodeficient mice.

Prior quarter total revenue fluctuation.

Importantly, however, as Jeff mentioned, the key underlying business driver of patient demand continues to increase for all of our products can't accept converted in the United States.

Based on these timing dynamics, we anticipate to emphasize our full year guidance as the best metrics to measure our top line financial performance.

At that point the strong start in the first half of the year drove a previous upward revision of full year 2020, one revenue guidance back in July including Vimizim in pounds, each as well as improved GAAP and non-GAAP bottom line guidance.

Henry J. Fuchs: As scientists striving to serve patients' needs, we are committed to understanding these findings. However, as we have shared previously, and it was corroborated during the FDA panel discussion on AAV safety in September, it remains uncertain, and in our view unlikely, that these specific findings with BMN-307 will translate to a safety issue with this or any other AAV gene therapy. We're working through the process with the FDA, and we'll keep you posted as we have relevant...

We're pleased to announce today that we are again, improving total revenue guidance, including both Vimizim and <unk> Zeke.

By lowering by raising the lower end of our guidance for the full year 2021 as noted by Jay Jay Despite the impact of a full year of two van generic competition in the United States and a continued COVID-19 impact on our growth total revenue for 'twenty 'twenty. One is expected to be mostly in line with total revenues in 2020, which is better than our.

Expectations at the beginning of this year moved.

Moving to operating expenses R&D expense for the third quarter was $158 million, which was $11 million higher than the R&D expense of $147 million for the third quarter of 2020, which reflects increases in our early research.

Henry J. Fuchs: Turning to our R&D Day event now planned for November 30th, we look forward to sharing new data and new program updates. The R&D organization has hit its stride melding our own internal discovery capabilities with genetic tools to understand underlying mechanisms of disease in order to develop targeted, We're excited to share these advances with you in greater detail and describe the many assets under development in the earliest stage pipeline. We hope you will all tune in. Thank you so much for your support, and I'll now turn the call over to Brian to update financial results for the quarter. Brian?

Early stage research and development.

Based on our R&D expense trends through Q3, 21 and expectations for the fourth quarter, we're lowering the range for R&D expense guidance by $10 million for the full year.

Next with respect to SG&A expense Q3, 2021, SG&A totaled $183 million, which was essentially flat compared to third quarter of 2020.

Watching box they'll go in the EMEA region and preparing for the launch in the United States as G&A expenses in 2021 are weighted towards the fourth quarter of the year.

Turning to bottom line results, we reported a GAAP net loss of $37 million in the third quarter of 2021 compared to GAAP net income of $785 million in the third quarter of 2020. Please recall that GAAP net income in the third quarter of last year included a large tax benefit totaling 800.

Brian R. Mueller: Thank you, Hank. Please refer to today's press release summarizing our financial results for full details on the third quarter of 2021. As usual, our comprehensive report on the quarter will be available on our upcoming Form 10-Q, which we're on track to file over the next few days. As JJ and Jeff mentioned, the previously anticipated order timing in 2021 has created a meaningfully uneven revenue flow between the first and second halves of the year.

$35 million related to the transfer of certain intellectual property rights between Biomarin entities, which drove the significant level of GAAP net income last year.

Non-GAAP income of $34 million in the third quarter of 2021 was lower than non-GAAP income of $99 million in Q3, 2020, primarily due to the lower revenues this quarter as a result of the previously discussed timing.

We're very pleased with the Companys GAAP and non-GAAP bottom line performance through the first three quarters of 2021 and based on our expectations for the fourth quarter, we have improved full year GAAP and non-GAAP item line guidance, we've reduced the full year 2021 GAAP net loss guidance to between $85 million and $45 million.

Brian R. Mueller: To illustrate the impact of select individual country order timing on Q3 2021, last quarter, Q2 2021, there was approximately $90 million more revenue, excluding QVAN, from Brazil, Russia, and the Middle East that did not recur in the third quarter, substantially accounting for the quarter over prior quarter total revenue fluctuation. Importantly, however, as Jeff mentioned, the key underlying business driver of patient demand continues to increase for all of our products, again, except in the United States.

And an increased non-GAAP income guidance to between $215 million and $255 million, representing an increase of $20 million at the midpoint of the range.

That substantial level of non-GAAP income helped generate a continued increase in our total cash and investments as we ended the third quarter of 2021 with $1.55 billion compared to $1.35 billion at the end of 2020.

Set a goal of generating positive operating cash flow in 2021 and the business has delivered nearly $300 million of positive operating cash flows year to date.

Brief comment is that the previously discussed timing of revenue and expenses in 'twenty 'twenty. One also impacts our cash flows which we observe are also weighted to the first half of the year.

Brian R. Mueller: Based on these timing dynamics, we anticipate emphasizing our full-year guidance as the best metric to measure our top-line financial performance. To that point, the strong start in the first half of the year drove a previous upward revision of full-year 2021 revenue guidance back in July, including VIMISIM and Pallanzig, as well as improved GAAP and non-GAAP bottom-line guidance. And we're pleased to announce today that we are again improving total revenue guidance, including both VIMISIM and Pallan-Z, by raising the lower end of our guidance for the full year 2021.

This solid cash position, coupled with our strong operating performance through the first three quarters of 2021 is a strong foundation from which to look forward to the continued European launch of box sogo the potential U S launch at the end of the year.

Potentially rocked PV in next year and the progress of our early stage pipeline that is leveraging the same R&D organization that developed our portfolio of now seven approved products and two large market late stage programs is an exciting next chapter in Biomarin as potential future growth story. Thank you for your support and we will now open up.

Brian R. Mueller: As noted by JJ, despite the impact of a full year of generic competition in the United States and a continued COVID-19 impact on our growth, total revenue for 2021 is expected to be mostly in line with total revenues in 2020, which is better than our expectations at the beginning of this year. Moving to operating expenses, R&D expense for the third quarter was $158 million, which was $11 million higher than R&D expense of $147 million for the third quarter of 2020, which reflects increases in our early stage research and development.

The call to your questions operator.

Thank you Sir at this time, we will begin our question and answer session.

A question you would need to press star one on your telephone.

All your questions.

T.

Please standby, while we compile the Q&A roster.

And speakers our first question from.

Corey.

<unk> of J P. Morgan you May ask your question.

Great. Thanks, Good afternoon, guys. Thanks for taking the question. So the box yoga label in Europe is obviously pretty broad covering patients as young as two years old I'm wondering if there's any pushback from either an early access point of view, our physician comfort potentially treating patients under five and do you have expectations for the F. D. A label could be equally broad.

Brian R. Mueller: Based on our R&D expense trends through Q3'21 and expectations for the fourth quarter, we're lowering the range for R&D expense guidance by $10 million for the full year. Next, with respect to SG&A expense, in Q3 2021, SG&A totaled $183 million, which was essentially flat compared to the third quarter of 2020. As we are launching VoxOgo in the EMEA region and preparing for the launch in the United States, SG&A expenses in 2021 are weighted towards the fourth quarter of the year.

If approved of course, thank you.

Jeff do you want to answer the first part of the question and the second part.

Yeah happy to so.

One we're really happy with the broad and open label as you described it including for patients to.

Two years in up in in Europe.

And we believe that in Europe, the endorsement of the.

C H M b on a safe and effective use for ages two years in App is a powerful statement to both payers and prescribers, it's too early for us to provide specific color in Europe.

Brian R. Mueller: Turning to bottom-line results, we reported a gap net loss of $37 million in the third quarter of 2021, compared to a gap net income of $785 million in the third quarter of 2020. Please recall that gap net income in the third quarter of last year included a large tax benefit totaling $835 million related to the transfer of certain intellectual property rights between Biomarin entities, which drove a significant level of gap net income last year.

But we're not anticipating.

Pushback from payers or prescribers on two to five year old pace.

Patients and maybe I'd turn it over to Hank for the the.

The second part of the question.

Yes.

Yes, you know there's no direct connection between the FDA and the EMEA and they they tend to operate independently. We're really encouraged that the EMEA understood. The context of the condition and we're scientifically rigorous in consideration of the label and I did encourage you to come to R&D day, where we're going to share some of that information.

Brian R. Mueller: Non-GAAP income of $34 million in the third quarter of 2021 was lower than non-GAAP income of $99 million in Q3 2020, primarily due to lower revenues this quarter as a result of the previously discussed timing. We're very pleased with the company's GAAP and non-GAAP bottom line performance through the first three quarters of 2021. And based on our expectations for the fourth quarter, we have improved full-year GAAP and non-GAAP bottom line guidance.

Obviously, we're hopeful that the FDA may be similarly, an influence, but as you know the FDA is a little bit more conservative.

And so we'll just have to sort of muscle through the next month to see where it lands.

Okay, great. Thanks, guys.

And speakers.

Our next question from a field of Cowen and company you May ask your question.

Good afternoon. Thanks for taking our question another one on Voc. So go perhaps one of the more contrary controversial aspects of.

Brian R. Mueller: We've reduced the full year 2021 GAAP net loss guidance to between $85 million and $45 million and have increased non-GAAP income guidance to between $215 million and $255 million, representing an increase of $20 million at the midpoint of the range. That substantial level of non-GAAP income helped generate a continued increase in our total cash and investments, as we ended the third quarter of 2021 with $1.55 billion, compared to $1.35 billion at the end of 2020.

Like Chicago as the language that was in PMT acceptance letter discussing the need for two year placebo controlled data.

Now that you're in late stage negotiations could you give us some information or some idea of how the FDA reviewers have.

Dealt with the advisory committees commentary around two year placebo controlled data in.

Whether it's safe for us to assume that centurylink discussions that won't be necessary.

For approval of OXXO go this time around.

Yeah. Thanks, Phil for the question, we're really in the throes of it so I can't really give you too much of the exact sucks, making of discussion, but what I would say is that we've been fairly transparent from the get go is you just reminded about where the FDA was and you know at the time and I've continued to say that.

Brian R. Mueller: We set a goal of generating positive operating cash flow in 2021, and the business has delivered nearly $300 million of positive operating cash flows year-to-date. One brief comment is that the previously discussed timing of revenue and expenses in 2021 also impacts our cash flows, which we observe are also weighted to the first half of the year. This solid cash position, coupled with our strong operating performance through the first three quarters of 2021, is a strong foundation from which to look forward to the continued European launch of Voxogo, and the progress of our early-stage pipeline that is leveraging the same R&D organization that developed our portfolio of now seven approved products and two large-market late-stage programs is an exciting next chapter in Biomarin's potential future growth story. Thank you for your support, Operator? At this time, we will begin our

The agencies the U S agencies focuses on or interest I should say is durability and we've provided them what amounts to a two year placebo controlled study, it's a little bit unorthodox and its design, but it's essentially two years' worth of data and we supplemented that with five years of open label.

And data in comparison to some pretty good natural history sources of data. So we feel pretty good about the durability of the afore.

On linear growth.

A related question is going to be.

As it is.

A one or two year growth.

Does that constitute a substantial evidence of a clinical benefit.

Or is that a benefit that is reasonably likely to predict clinical benefit and there I would just say that you should be aware that in the gross field that.

Operator: Thank you, sir. At this time, we will begin our question-and-answer session. To ask a question, you will need to press Star 1 on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. And speakers, our first question from Corey Kasanov of JPMorgan. You may now ask your question.

The pace of growth hormone administration to non growth hormone deficient disorders, a lot of the language has been around final adult height.

And this suggests to us that the FDA is also very concerned about final adult height. So I think their decision, making about durability is going to be.

It's going to be related to ultimately not the two year sort of story, but what does that say about what can be expected.

Corey Kasimov: Great. Thanks. Good afternoon, guys.

Corey Kasimov: Thanks for taking the question. So the VoxOgo label in Europe is obviously pretty broad, covering patients as young as two years old. I'm wondering if there's any pushback from either an early access point of view or physician comfort about potentially treating patients under five. And do you have expectations for the FDA label to be equally broad, if approved? Thank you.

Final adult height all of this I think will come to some form of resolution in the next few weeks so stay tuned.

Perfect. That's very helpful. Thanks, again for taking our question.

Yep.

And our next question speakers from Chris Raymond.

You May ask your question.

I wonder if I could add.

Ask maybe a pipeline question on specifically three O seven so so I think I'm wondering if you can comment on what kind of.

J.J. Bianamante: Jeff, do you want to answer the first part of the question and Hank the second part?

No you said it sounds like you've met with FDA and you don't have a sense as to when the clinical hold will be lifted but.

Jeffrey Robert Ajer: Yeah, happy to. One, we're really happy with the broad and open label as you described it, including for patients two years and up in Europe, and we believe that in Europe, the endorsement of the CHMP on safe and effective use for ages two years and up is a powerful statement to both payers and prescribers. It's too early for us to provide specific color in Europe, but we're not anticipating pushback from payers or prescribers on two- to five-year-old patients. And maybe I'd turn it over to Hank for the second part of the question.

Can you comment on what additional experiments earn out analyses maybe the agency has requested.

And is this something that could be addressed in the near term or is this a maybe longer term experiments.

And maybe can you share what you did provide to the FDA. When you met with them I think you were going to meet with them this month to get the.

You felt might give comfort on that.

This was an issue related only to mice and then if I could just like.

Maybe a quick Buck Sogo question I'm not sure if you're willing to answer this but Ah patients that have started in Europe, what's the average age.

Thanks.

I will take the first part of your question, Chris well just plus the second part of your question.

Henry J. Fuchs: Yeah, Corey, as you know, there's no direct connection between the FDA and the EMA, and they tend to operate independently. You know, we're really encouraged that the EMA understood the context of the condition, and we were scientifically rigorous in consideration of the label. And I'd encourage you to come to R&D Day, where we're going to share some of that information. We obviously hope that the FDA will be similarly influenced. But, as you know, the FDA is a little bit more conservative. And so we'll just have to sort of muscle through the next month to see where... Okay, great, thanks guys.

Meeting with the FDA, we've had correspondence with them, they're busy it's hard to get meetings with the agency nowadays.

And it was a pretty sort of tactical correspondence because what happened was we observed the finding he felt duty bound to reported.

It turned out that we were in a.

Those evaluation period from the.

The second cohort of patients.

Discuss that and and so we were not enrolling patients at that moment anyway. So.

We were transparent with the agency about this preclinical finding as soon as we found it.

And as a consequence, they have not really seen all that much yet, but what they asked for of US is relatively straightforward and it can be wrapped up in a package and.

Philip M. Nadeau: And speakers, our next question is from Phil Nadeau of Cowen & Company. You may ask your question, too.

Philip M. Nadeau: Good afternoon. Thanks for taking our question. Another one on VoxOgo. Perhaps one of the more controversial aspects of VoxOgo is the language that was in the FDA acceptance letter discussing the need for two-year placebo-controlled data. Now that you're in late-stage labeling negotiations, could you give us some information or some idea of how the FDA reviewers have dealt with the advisory committees? Commentary around two-year placebo-controlled data in... Whether it's safe for us to assume that centering labeling discussions won't be necessary for approval of VOXOGO this time around.

They were pretty comprehensive and the kinds of things that they elsewhere, including.

How is this going to reflect an informed consent and protocol amendments and things like that so that's it.

It's obvious that they've seen these sorts of that you know that they've seen these sorts of things before and they have a pretty priest.

Prescribed list of the types of quest.

Questions and considerations.

I think that puts us in a bigger perspective and it goes back to your I think it's your question about the FDA Advisory Committee meeting.

The thing that's striking a lot of buzz about that was.

When the presentation came to integration in oncogenesis. The presentation was defined it into what did we know up through 2016, and what do we know from 2017 and beyond and I think the relevance of that is that.

Henry J. Fuchs: Yeah, thanks, Phil, for the question. You know,

Henry J. Fuchs: You know, we're really in the throes of it, so I can't really give you too much of the exact substance of the discussion. But what I would say is that we've been fairly transparent from the get-go, as you just reminded me about where the FDA was. And, you know, at the time, and I've continued to say, that the agency's, the U.S. agency's focus is on, or interest, I should say, is durability, and we've provided them with what amounts to a two-year placebo-controlled study. It's a little bit unorthodox in its design, but it's essentially two years' worth of data.

The agencies subsequently approved.

Subsequent to 2016, they improved loves terna and they approved Xeljanz xeljanz, but importantly for IV administration, and importantly, a lot of the vector goes to the liver.

And and in spite of the fact that in social oncogenesis was.

We're insertions were described in mice.

The agencies has approved.

Drug Xeljanz.

And in fact over 3000 patients have been treated with gene therapy and clinical trials for 200 patients have been treated with <unk>.

And so you know the agencies I think what that says is he interested on the one hand aware of the preclinical experiments that on the other hand.

He is thinking.

<unk> thinking about that as a.

Henry J. Fuchs: And we supplemented that with five years of open-label treatment data in comparison to some pretty good natural history sources of data. So we feel pretty good about the durability of the effect on linear growth. I think a related question is going to be, you know, in sort of a one- or a two-year growth, does that constitute substantial evidence of a clinical benefit? Or is that a benefit that's reasonably likely to predict a clinical benefit?

Not as a risk benefit issue because theres not a risk has not appeared yet, but it's a risk information for patients kind of an issue.

In that discussion I don't think that there was any real breakthrough in terms of what additional information to be providing I think rather there was maybe a little bit more of a challenge in the scientific community that aspire to understand what's going on mice and to ask the question are there any vulnerability for that to go on in humans, given that we haven't seen it.

Personal oncogenesis in humans to date, we fully expect to see insertion of vacancies.

Henry J. Fuchs: And there, I would just say that in the growth field, in the case of growth hormone administration to non-growth hormone deficient disorders, a lot of the language has been around final adult height. And this suggests to us that the FDA is also very concerned about final adult height. So I think their decision-making about durability is going to be, you know, ultimately related to not the two-year sort of story, but what does this say about what can be expected from final adult height? All of this, I think, will come to some form of resolution in the next few weeks. So stay tuned. Perfect, that's very helpful.

Whether that.

Cancer is that is it.

Speculation at this point.

So I think the field has been dealing with this issue for quite a while.

There are more experiments to do that.

That won't directly answer the question of how.

Does this translate to humans in terms of predicting the risk of oncogenicity in humans, but rather.

I would see more delineating technical details about how these experiments should be done and then interpret didn't give us comfort and to that point I just want to highlight one specific aspect of our findings and you're probably all aware of a study in dogs.

Clonal abundance of a specific set of mutations.

And they postulated that there was a cause and effect relationship between the fact that a lot of cells had the indicated insertion.

Philip M. Nadeau: Perfect, that's very helpful. Thanks again for taking our question.

Christopher Joseph Raymond: And our next question speaker is Chris Raymond of VibriSender. You may ask your question. Thanks.

And there versus insertion of a lot of self had to syndicate construction. However.

I think to keep in mind and we see this north Korea, a sentence that he is not every cell in the sample has that characteristic and so it raises the question of whether these findings are in fact causal in mice, where passengers in mice and I think we have a better idea about the answer to that question, we're not even going to get on first base in terms of.

Christopher Joseph Raymond: Hey, thanks. I wonder if I could ask you maybe a pipeline question on specifically 307. So, Hank, I'm wondering if you can comment on what kinds of – I know you said you – it sounds like you've met with FDA and you don't have a sense as to when the clinical hold will be lifted, but, you know, can you comment on what additional experiments or analyses maybe the agency's requested? And, you know, maybe you could share what you did provide to the FDA when you met with them?

The relevance to humans. So we are in the front row.

With us because we have a lot going on in gene therapy, and our scientists are awesome teasing apart problems and we look forward to providing you didn't see it.

That's restarted on the 311 trial shortly.

Christopher Joseph Raymond: I think you were going to meet with them this month to give, you know, This is an issue that we felt might give comfort on the, this is an issue related only to mice. If I could just like add maybe a quick Voxogo question, I'm not sure if you're willing to answer this, but of patients that have started in Europe, what's the average age?

And now let me pass it suggests to.

At the end of your question.

Thanks, Jack I'm still digesting all that you had to say, but with respect of OXXO go and Chris with the implementation of GDP, our privacy regulations in the EU. We don't have the same very specific data about our individual patient.

That we might.

Might historically have had.

So so I'm kind of rounding around your question as we get some data about product usage bye bye bye all strength will be able to make estimates.

Henry J. Fuchs: I will take the first part of your question, Chris, while Jeff deals with the second part of your question. You know, Chris, let's just, you know, meeting with the FDA. We've had correspondence with them. They're busy. It's hard to get meetings with the agency nowadays.

The size and thus the the age of the mix of patients that we've got on treatment, we don't have enough data yet to.

To work through that what what I might say is.

The early patient early ESP patients treated are coming from France under an H T. You early access program there that <unk> was approved separately or in parallel with the <unk>.

Henry J. Fuchs: And it was a sort of tactical correspondence because what happened was, you know, we observed the finding and felt duty bound to report it. But it turned out that we were in a dose evaluation period for the second cohort of patients, and so we were not enrolling patients at that moment anyway.

M a.

Negotiations that led to the label of two years and up so interesting enough. The Apu label label indication is for patients five years and up.

Henry J. Fuchs: So we were transparent with the agency about this preclinical finding as soon as we found it. And as a consequence, they've not really seen all that much yet. But what they asked of us is relatively straightforward and can be wrapped up in a package.

And so in France, the early experiences with patients in the range of let's say five to nine or 10 years old.

And we'll keep you posted with that kind of color.

Going forward as we get more data to evaluate.

Thanks, guys.

Yes.

And speakers.

From Sal <unk> of.

Henry J. Fuchs: And, you know, they were pretty comprehensive in the kinds of things that they asked for, including, you know, how is this going to reflect in informed consent and protocol minutes and things like that. So it's obvious that they've seen these sorts of things before, and they have a pretty prescribed list of the types of questions and considerations. I think, you know, to put this in a bigger perspective, and it goes back to your I think it's your question about the FDA's advisory committee meeting.

Goldman Sachs you May ask your question.

Afternoon, Thanks for taking my question.

On Fox.

You talked about the strong demand can you just give us some color there how we should think about not just France, Germany and the select early access countries in <unk> and how the launch so far it's exceeded our expectation.

Hi, Savi. Thanks for question, it's really a pleasure to answer this one.

And some of the color that I would add here it's.

Specifically from France, and Germany.

Henry J. Fuchs: You know, the thing that struck a lot of us about that was when the presentation came to integration and oncogenesis, the presentation was divided into what we knew up through 2016 and what we know from 2017 and beyond. And I think the relevance of that is that, you know, the agency subsequently approved that, after 2016. They approved Lufsterna, and they approved Zolgensva.

I would characterize as this in previous launches we've had patients come in generally one patient at a time one patient from clinic, a one patient from clinic B a little while later another patient from clinic C. Maybe sometime later a second patient.

From clinic, a what we're seeing this time around is we're still seeing some.

Prescriptions emerge from individual clinics with a patient and N of one but we're also seeing ends of fore ends of five coming.

Henry J. Fuchs: Zolgensva importantly is for IV administration and importantly, a lot of the vector goes to the liver, and in spite of the fact that insertion oncogenesis was or insertions were described in mice the agency's has approved Zolgensma and in fact over 3,000 patients have been treated with gene therapy in clinical trials, 1,400 patients have been treated with Zolgensma and so you know the agency I think what that says is the agency is on the one hand aware of the preclinical experiments and on the other hand is is thinking about that as a sort of not as a risk-benefit issue because there's not a risk has not appeared yet but it's a risk information for patients kind of an issue. In that discussion I don't think that there was any real breakthrough in terms of what additional information to be providing.

Straight through at once.

We've never really experienced that and that gives us.

That drives our comment about the strength of the prescription demand in part so those patients coming through and in clusters. In addition.

There's been a lot of prescription demand that has emerged from named patient sales markets. I mentioned that we have we have sales to Switzerland, which by the way is not in EMEA market. So, Switzerland is not covered by an MAA.

Provable and it is thus a named patient outside of registration.

Market, we've seen initial prescription demand.

From a <unk>.

<unk> markets in the Middle East as J, J mentioned and also in Latin America, and that we've seen and larger than one.

And that experience so that the combination of quick named patient sales prescription demand for markets and the clusters of groups of patients not one or two.

Henry J. Fuchs: I think there was maybe a little more of a challenge in the scientific community to aspire to understand what's going on in mice and to ask the question, is there any vulnerability for that to go on in humans given that we haven't seen insertional oncogenesis in humans to date? We fully expect to see insertions of AADs, whether that leads to cancer is speculation at this point. So I think the field has been dealing with this issue for quite some time.

What's really driving our our comment about prescription demand.

However, having the.

I mean, obviously the dollar the dollar sales in Q4 are going to be.

You know relatively limited compared to the.

The demand doesn't mean, he got the up because.

The patient is treated we only had been treated for like one or two months. So.

But it is really it bodes well for 2022 and.

Henry J. Fuchs: Do you think that there are more experiments to do that won't directly answer the question of how you know does this translate to humans in terms of predicting a risk of oncogenicity in humans, but rather, I would see more delineating technical details about how these experiments should be done and interpreted and give us comfort. And to that point, I just want to highlight one specific aspect of findings. You're probably all aware of a study in dogs that found clonal abundance of a specific set of mutations, and they postulated that there was a cause-and-effect relationship between the fact that a lot of cells had the indicated insertion and that there was this insertion, and a lot of cells had this indicated insertion.

And the significant growth in revenues in 2022, there's definitely a lot of interest.

It's interesting anecdotally is that we got we got.

Notice from the Russian.

The ratio of government that we got on there with other federal reimbursement.

For a buck so go in Russia, when we have not even filed.

Kind of an interesting anecdote okay.

Next question.

And speakers. Our next question from Akash Tiwari of Jefferies. You May now ask your question.

Hey, thanks, so much so one of the sore tight can you talk a bit about the use of technology for <unk> tightened. The 206 study how are they being used to kind of adjust the dosing for these younger patients and what have you seen from a safety perspective, so far in that population and this one is a bit more high level.

Henry J. Fuchs: However, the thing I think to keep in mind, and we see this in our 3.07 study, is that, and so it raises the question of whether these findings are, in fact, causal in mice or just passengers in mice.

That's been range bound for the last few years. Despite the fact that you guys are approaching your largest most important commercial launches is there a point in time, where you would more seriously explore strategic venues to unlock value, particularly if either a blockade and <unk> don't get FDA approval as planned. Thanks, so much.

Henry J. Fuchs: And I think we have a better idea about the answer to that question. But we're not even going to get on first base in terms of understanding the relevance to humans. So we are in the front row of all of this because we have a lot going on in gene therapy, and our scientists are awesome at teasing apart problems, and we look forward to providing the agency with the info it needs to get us restarted on the 307 trial. Now, let me pass this to Jeff to see if he can handle your question. Thanks, Hank. I'm still digesting all that you had to say.

Right.

I'll start with the first part of your question.

This study was put in the field before.

Before the phase three trial read out so you know the comprehensive evidence of safety and efficacy in older children wasn't available at the time of the studies. So in consultation with health authorities. The study was designed.

Jeffrey Robert Ajer: But with respect to Voxelgo and Chris, with the implementation of GDPR privacy regulations in the EU, we don't have the same very specific data about our individual patients that we might historically have had. So I'm kind of rounding around to your question. As we get some data about product usage by vial strength, we'll be able to make estimates of the size and, thus, the age of the mix of patients that we've got on treatment.

Two enrolled patients in three cohorts ages two to five.

Let's see it was it was 2%.

Three cohorts by age kind of top of my head I'm, having a brain in terms of ages six to two months and six months and the underlying the underlying reason for that was that there were hypotheses about differences.

The dose exposure and exposure response relationships.

Jeffrey Robert Ajer: We don't have enough data yet to work through that, but what I might say is the earliest patients treated are coming from France under an APU, early access program there. That APU was approved separately or in parallel with the EMA. Negotiations led to the label of two years and up. So, interestingly enough, the ATU label indication is for patients five years old and up. So, in France, the early experience is with patients in the range of, let's say, five to nine or ten years old. And we'll keep you posted on that kind of color going forward as we get more data to evaluate. Thanks, guys. And speakers, our next question comes from Salveen Richter of Goldman Sachs, and you may ask your question.

And.

So the concept was to enroll sentinels to evaluate PK PD.

And Bruce safety response to.

To that 15 microgram per kilo dose that we had been using an older children. Before then opening the rest of that cohort up to randomization to active medication that placebo.

And in the two to five year old cohort, we found that the 15 microgram dose with an appropriate dose that gave an appropriate exposure than appropriate PD response, and we'll actually review those data at R&D day, because that was the information that inform the European health authorities to move forward with the application.

Salveen Jaswal Richter: And speakers, our next question is from Salveen Richter of Goldman Sachs. You may ask your question, too.

We only had a limited amount of efficacy data in those small number of patients because there was no contemporaneous control and.

Jeffrey Robert Ajer: Hi Salveen, thanks for the question. It's really a pleasure to answer this one. And some of the color that I would add here, specifically from France and Germany, I would characterize as this.

I think that what that tells US is that the two to five year olds can be safely dose with the same dose as children are older than five now turning to the children are under two we did find a dose exposure relationship such that we had to increase the dose.

Jeffrey Robert Ajer: In previous launches, we've had patients come in, generally one patient at a time. One patient from Clinic A, one patient from Clinic B. A little while later, another patient from Clinic C. Maybe sometime later, a second patient from Clinic A.

And off the top of my head I think that we had to do that also for the.

Jeffrey Robert Ajer: What we're seeing this time around is that we're still seeing some prescriptions emerge from individual clinics with a patient N of 1, but we're also seeing N's of 4, N's of 5, coming straight through at once. We've never really experienced that, and that drives our comment about the strength of prescription demand, in part, so those patients coming through in clusters. In addition, there's been a lot of prescription demand that has emerged from named patient sales markets.

The infants that were enrolled in the study from zero to six months of age.

And I think what that means is that we're actually benefited by having relatively short acting drug in the sense that short acting drugs are easier to adjust and accommodate.

Dosing and exposure on the basis of response, then very long acting drugs, especially since although we did the trial from five to two to six months humans age and the other normal direction from six months to two years to five years and so it's going to be important to have all this dose exposure safety information.

Jeffrey Robert Ajer: I mentioned that we have sales to Switzerland, which, by the way, is not an EMA market, so Switzerland is not covered by an EMA approval, and it is thus a named patient outside of registration. We've seen initial prescription demand from markets in the Middle East, as JJ mentioned, and also in Latin America, and we've seen ends larger than one in that experience, so the combination of quick named patient sales, prescription demand from markets, and the clusters of groups of patients, not one or two, that's really driving our comment about prescription demand. However, Salveen, obviously, the dollar sales in Q4 are going to be relatively limited compared to the demand that's going to be out there.

From a safety perspective.

With the relatively.

Now well described safety profile about sogo, we haven't really seen much. Additionally in terms of of of significant clinical adverse responses.

And so I feel like we're in pretty good shape understanding the relationship of dose and therapeutic and safety response.

And you'll get a dose of you'll get your own dose of that in just under a month, we're just over a month I should say.

Let me pause there.

Yeah.

So I think you had a second part of your question Akash I was totally different.

No absolutely.

It looks like you forgot about it.

Oh hi.

No I mean, obviously I mean I think there was a recent survey I don't think you are.

These past.

Jeffrey Robert Ajer: An interesting anecdote is that we got notice from the Russian... Federation of Government that we were on federal reimbursement.

A few weeks ago, just last week or so that keeps us not on investment as a parent if you don't believe that.

October will be approved in the U S. So I think that's good news because it gets approved that should result in a significant move into stock and that's and that's advantage is only.

Jeffrey Robert Ajer: for VoxPogo in Russia when we have not even filed. That's going to be an interesting anecdote, okay?

About three weeks away. So, let's you know last week they thought the conversation again after after the <unk> date on box shuttle and then and then it'll still potential BD Europeans tier shipyard opinion in Q2 of next year.

Akash Tewari: And speakers, our next question is from Akash Tewari of Jeffrey's. He may now ask your question.

Akash Tewari: Hey, thanks so much. So one on the sore tide, can you talk a bit about the use of sentinels for the sore tide in the 206 study? How are they being used to kind of adjust the doses for these younger patients? And what have you seen from a safety perspective so far in that population? And this one's a bit more high level.

Yes.

Thank you so much.

Our next question from Gena Wang from Barclays. You May ask your question.

Thank you for taking my questions.

First is regarding rocket PV and just wondering what is the latest.

The interaction.

<unk> will PV and filing specifically on durability.

Then related question is that for the type of.

Akash Tewari: The stock's been range-bound for the last few years, despite the fact that you guys are approaching your largest, most important commercial launches. Is there a point in time when you would more seriously explore strategic venues to unlock value, particularly if either Rocked In or Besore Tide don't get FDA approval as planned? Thanks so much.

Any more detailed preclinical data that he is asking for the PKU program do you expect FTE also ask.

Enough for similar type of data for rock paintings.

Yeah.

Well, it's a little bit complicated, but let's let's.

Henry J. Fuchs: Hi Akash. I'll start with the first part of your question. The study was put in the field before the phase three trial read out. So, you know, comprehensive evidence on safety and efficacy in older children wasn't available at the time of the study. So in consultation with health authorities, the study was designed to enroll patients in three cohorts, ages two to five, three cohorts by age. Now, off the top of my head, I'm having a brain melt in terms of ages, six to two months and zero to six months.

Let's see if I can cut cut to the chase of it in terms of FDA interaction. There really is no news there in terms of.

Resetting or differing expectations, we said at the time, let's see our L. They want two years' worth of data and by gum and by Golly in spite of our trying really hard they want two years' worth of data.

We've had some lower level communications and correspondence about.

Things like statistical analyses, which reveal really nothing new other than that they wanted the two year data.

So we are interacting with the division and the review Division is very collegial and.

Henry J. Fuchs: And the underlying reason for that was that there were hypotheses about differences in the dose exposure and exposure response relationship. And so the concept was to enroll sentinels to evaluate PK, PD, and safety responses to that 15 microgram per kilo dose that we'd been using in older children before then opening the rest of that cohort up to randomization to active medication or placebo. And in the two- to five-year-old cohort, we found that the 15-microgram dose was a dose that gave an appropriate exposure and an appropriate PD response.

And very very much to the process of of discussion.

And you know based on what we've seen so far we believe and we've had experts in to tell us what they think the FDA might not be telling us but might be conveying and the experts have advised that.

This reads like a situation in which they asked for the two year data and they're going to make the decision on the basis of two year data.

And that's good for us and for patients because we're optimistic that hemostatic efficacy will be maintained out through two years. It was demonstrated in the first 17 patients that were treated in the phase three clinical trial have now been followed for an additional second year as we reported earlier. This year. So we are confident that the remaining 100 or so patients will be.

Henry J. Fuchs: And we'll actually review those data at R&D Day because that was the information that informed the European health authorities to move forward with the application. We only had a limited amount of efficacy data in those small numbers of patients because there was no contemporaneous control. And I think that what that tells us is that two- to five-year-olds can be safely dosed with the same dose as children who are older than five.

Adequately controlled from.

Some factory expression.

Through the second year.

Issue of durability in PKU is a little bit more difficult for the simple reason that in fact, the right expression you measure the actual transgene product itself, whereas within with PKU you measure indirectly.

Henry J. Fuchs: Now, turning to the children who are under two, we did find a dose-exposure relationship such that we had to increase the dose. And off the top of my head, I think that we also had to do that for the infants that were enrolled in the study from zero to six months of age. And I think what that means is that we're actually benefiting by having relatively short-acting drugs in the sense that short-acting drugs are easier to adjust and accommodate dose and exposure on the basis of response than very long-acting drugs, especially since although we did the trial from five to two to six months, humans age in the other normal direction from six months to two years to five years.

The.

Gene therapy product.

And.

And we we will want to see what the pattern of the control looks like before committing to a specific answer to that question.

But based on preclinical data, where we have seen maintenance of gene expression.

We believe that there's a stronger argument to be made around PKU and durability in one year supporting that than there was for rock Teva and just recall for rock came in.

Because of the nature of the immune response and nonhuman primates people don't typically do long term studies and when we surface a long term studies that we did do and others have done not a lot of them you can see the effect of the immune response and lower species to the human protein in in PKU been able to demonstrate sustained durability in preclinical.

Henry J. Fuchs: And so it's going to be important to have all this dose exposure safety information. From a safety perspective, with the relatively now well-described safety profile of Voxogo, we haven't really seen much in terms of significant clinical adverse responses. And so I feel like we're in pretty good shape understanding the relationship of dose and therapeutic and safety response. And you'll get your own dose of that in just under a month or just over a month, I should say.

Species, so we hope that argument.

Prevails upon the agency, but you know that that discussion has yet to be had in sufficient detail with actual data from patients two to inform the good news of all of this is that unlike with <unk>, where we change the material from phase one to phase III and we made a tweak to the trial and the steroid regimen, none of those things are happy.

And the in the.

<unk> hundred seven trials. So these earliest patients will provide relevant information for long term exposure.

Henry J. Fuchs: Sorry, I think you're

Henry J. Fuchs: I think part of your question, Akash, is totally different. No, absolutely not. No, no, no, no, no, no, no, no.

Sorry, I wasn't clear I was with farming for the PKU program. It was modest safety data with asking for additional preclinical data all animals like whatever data FDA.

J.J. Bianamante: I don't know. I think there was a recent survey. I don't know if I'll do another analysis, but in the past few weeks, the past week or so, 50% of investors apparently don't believe that Voxogo would be approved.

Asking do you expect you also asked a similar type of data sets.

Poor safety food.

The PBR program.

unknown: [inaudible]

So far they have not been requiring preclinical carcinogenicity studies I mean, if you look at the Zelle Jensen our label.

Gina Nguyen: Our next question is from Gina Nguyen from Berkeley, so you may ask your question.

Gina Nguyen: Thank you for taking my questions. So the first is regarding Roctavian; just wondering what the latest FDA interaction regarding Roctavian filing, specifically on durability? And then a related question is for the type of animal data or preclinical data that FDA is asking for under the PTU program, do you expect FDA will also ask for similar types of data for Roctavian?

There's there are no oncogenicity studies either in the.

Prior to submission studies, our post approval studies, so don't don't expect.

Prior to submissions and approvals, but again those are discussions to be had as well.

Thank you very much.

Yeah.

And our next question from the line of Bob.

Of Stifel you May ask your question.

Henry J. Fuchs: Well, it's a little bit complicated.

Thanks for taking the questions.

Henry J. Fuchs: I know this is a little complicated, but let's see if I can cut to the chase of it. In terms of FDA interaction, there really is no news there in terms of resetting or differing expectations. We said at the time of the CERL that they wanted two years' worth of data, and by gum and by golly, in spite of our trying really hard, they want two years' worth of data. We've had some lower-level communications and correspondence about things like statistical analyses, which reveal really nothing new other than that they want the two-year data. So we are interacting with the division and the review division. It's very collegial and contributes very much to the process of discussion.

Thank you if I heard you correctly when you talked about the issue of the two year placebo controlled study earlier it sounded as though you feel like at this point in our review this as a matter of either full approval or potentially accelerated approval I guess did I understand that right and if it is ultimately deem that this is an accelerated approval.

How do you think benefit would be confirm do you think you'd need to do a two year placebo controlled study as opposed to marketing requirement. Thanks, so much.

Well the approval pathway is specifically the agency's decision specifically yet.

As a tail end of the consideration decisions so.

Henry J. Fuchs: And based on what we've seen so far, we believe, and we've had experts in to tell us what they think the FDA might not be telling us but might be conveying. The experts advise that this reads like a situation in which they ask for the two-year data, and they're going to make their decision on the basis of the two-year data. And that's good for us and for patients because we're optimistic that hemostatic efficacy will be maintained through two years.

I don't want to read too much into anything other than.

Just what I was characterizing that the landscape issue was that in.

In the landscape of growth promoting products from an FDA perspective final adult height, it's more of a question.

Then integral growth velocities have been a question.

Studied already could constitute the nexus are the where.

Henry J. Fuchs: It was demonstrated in the first 17 patients that were treated in the Phase III clinical trial have now been followed for an additional second year, as we reported earlier this year. So we're confident that the remaining 100 or so patients will be adequately controlled from factor VIII expression through the second year. The issue of durability in PKU is a little bit more difficult for the simple reason that in factor VIII expression, you measure the actual transgene product itself, whereas with PKU, you measure the gene therapy product indirectly. And we will want to see what the pattern of V control looks like before committing to a specific answer to that question.

The main as I should say the main group for evaluation, we have provided.

Agency.

As you know we had I think five plus years of treatment data on the first patients treated in an open label several of whom were close to final adult height.

And the agency seems interested in.

Those patterns.

But for patients is not a lot of patients for them. So we're hopeful that whether it's a post approval commitment.

Two a conditional to an accelerated approval or whether it's a post marketing requirement for even a full approval that final adult height characterizations will come in when they come in and will be powerful to document the accumulated benefit of oxycodone. So at some level.

Henry J. Fuchs: But based on preclinical data where we have seen maintenance of gene expression, we believe that there's a stronger argument to be made around PKU and durability and one year supporting that than there was for Roctavian. Just recall that for Roctavian, you know, because of the nature of the immune response in nonhuman primates, people don't typically do long-term studies. And when we look at the long-term studies that we did and others have done, and not a lot of them, you can see the effect of the immune response in lower species to the human protein.

They are different.

Got it.

Anyway.

And speakers. Our next question from the line of Geoff Meacham of Bank of America, You May ask your question.

Hey, guys. Thanks for the question.

Guys I've talked in the past about PKU clinics.

Still not fully reopened just on the commercial business just wanted to maybe get an update on that have you started to see a recovery in <unk>.

In pounds new starts.

Henry J. Fuchs: In PKU, we've been able to demonstrate sustained durability in preclinical species. So we hope that argument prevails with the agency, but, you know, that discussion is yet to be had in sufficient detail with actual data from patients to inform it. The good news of all of this is that unlike with Roctavian where we changed the material from phase I to phase III and we made a tweak to the trial and the steroid regimen, none of those things are happening in the 307 trial. So these earliest patients will provide relevant information for long-term exposure.

That'd be kind of helpful and maybe how you think that's going to play out in 2022 and then.

Bigger picture for J J I mean on the on the BD side of things.

How are you thinking about.

New opportunities in light of what could potentially be a little bit more scrutiny on AAV.

<unk> technology is it is there something that you're looking for.

In terms of asset diversity by indication or technology diversity, or how you're thinking about that going forward. Thank you.

Jeff do you want to go over the PKU clinic and the problems. It can even start a question.

Sure I'd be happy to so as noted in our remarks, both this quarter and the previous quarter, what we're seeing is.

Henry J. Fuchs: I'm sorry, Hank, I wasn't clear. I was referring to the PQ program. It was more the safety data that FDA was asking for additional preclinical data or anything else like whatever data FDA is asking. Do you expect FDA will also ask for a similar type of data sets to support safety for the Roktavian program?

In Europe, but more importantly in the U S.

PKU clinics are continuing to operate at less than full capacity of course in the U S. There's 125 PKU clinics, so theres some variability across there, but theres a lot of clinics are operating virtually not live.

Henry J. Fuchs: So far, they have not been requiring pre-clinical carcinogenicity studies. I mean, if you look at the Zolgensma label, there are no oncogenicity studies either prior to submission studies or post-approval studies. So don't expect additional studies to be required from a safety perspective prior to submissions and approvals, but again, those are discussions to be had as well.

Hi.

There are staffing issues in PKU clinics as certain supporting staff in particular have been reassigned.

During the pandemic.

And frankly for for the the genetics clinics.

Paul Andrew Matteis: And our next question comes from the line of Paul Matteis of Steeples. He may ask your question.

While PKU usually is the largest group of patients that they're treating.

Paul Andrew Matteis: Thanks for taking the questions. Hank, if I heard you correctly, when you talked about the issue of the two-year placebo-controlled study earlier, it sounded as though you feel that at this point in the review, this is a matter of either full approval or potentially accelerated approval. I guess, did I understand that right? And if it is ultimately deemed that this is an accelerated approval, how do you think benefits would be confirmed? Do you think you'd need to do a two-year placebo-controlled study as a postmarketing requirement?

There are.

Needs for patients in those genetics clinics, and we've seen that those acute needs for.

Really terrible conditions for children.

Our first person line for priority for their capacity.

Having said that.

We are we are getting new patient referrals on a steady basis I would say steady through the pandemic and we're drawing the conclusion that.

If we've been we've been optimistic about PKU.

Clinics getting back to their previous pre pandemic capacity it hasnt happened and we've been working on other tactical solutions to facilitate.

Henry J. Fuchs: Thanks so much.

Paul Andrew Matteis: Well, you know, the approval pathway is specifically, the agency's decision is specifically, a tail end of the consideration decision. So I don't want to read too much into anything other than just what I was characterizing with the landscape issue was that, you know, in the landscape of growth-promoting products from an FDA perspective, final at all times is more of a question than interval growth velocities have been a question.

PKU patients to continue.

Access to therapy and for new patients.

To start and I think what we're trying to do is reset a little bit of expectations here that.

While we were optimistic.

At the beginning of the year, we're less optimistic about that capacity for the balance of the year now.

But we're continuing to see overall growth.

I might I might just comment as kind of a read through to what do we think about that four box they'll go.

Paul Andrew Matteis: If it were to come to pass that a confirmatory study would be required, we would hope that longer-term follow-up of the patients that we have studied already could constitute the nexus or the or the main, if I should say the main group for evaluation. So we're hopeful that whether it's a post approval commitment to a conditional to an accelerator approval or whether it's a post marketing requirement for even a full approval, final adult height characterizations will come in when they come in and will be powerful to document the accumulated benefit of a box. So on some level, Paul, we're in there. I got it. Thanks a lot.

In fact, other health care providers that we call on such as pediatric Orthopedists and pediatric endocrinologist, both of which are really relevant to box they'll go.

For the most part.

And with restrictions and protocols in place those specialties are there.

They're back in business. So the kind of capacity constraints, we're seeing in the PKU clinics I would say don't let that read through to your expectations about box sogo.

So Jacob.

Alright.

Regarding your BD question.

So.

Geoffrey Meacham: And speakers, our next question comes from the line of Geoff Meacham of Bank of America. You may ask your question. Hey guys!

I mean, that's a good question.

Just one.

A few comments.

As you know we.

Geoffrey Meacham: hey guys thanks for the question I just had a couple the main one you guys have talked in the past about you know PKU clinics still not fully reopened just on the commercial business just wanted to maybe get an update on that have you started to see a recovery in and pounds each new starts that'd be you know kind of helpful and maybe how you think that's going to play out in 2022 and you bigger picture you know for JJ I mean on the on the BB side of things you know how are you thinking about you know new opportunities in light of you know what could potentially be a little bit more scrutiny on AAV you know technology is it is there something that you're looking for In terms of, you know, asset diversity by indication or technology diversity or how are you thinking about that going forward? Thank you.

We have several but one of them called modalities within Valvoline, we started as a company mainly based on pushing therapeutics.

<unk> being a small molecule with an exception.

So.

If you look at our pipeline today, we have additional putting through a beauty because we have small molecules, we are moving into an ego.

<unk>.

To get back in the clinic with a second generation what are you gonna nucleotide and we have some options there beyond beyond DMD.

And.

So we are always going to go beyond one modality, so I would say gene therapy.

Very important for us and will continue to be in the future but.

But we have no intent on being a pure gene therapy company.

Jeffrey Robert Ajer: Jeff, do you want to go over the PK eukaryotic and the palliative new start question?

And if you will see at R&D day, what are we going to disclose.

Some new programs that I'm talking about all the programs we have in development.

Jeffrey Robert Ajer: Sure, I'd be happy to. So as noted in our remarks both this quarter and the previous quarter, what we're seeing is in Europe, but more importantly, in the US, PKU clinics are continuing to operate at less than full capacity. Of course, in the US, there are 125 PKU clinics, so there's some variability across them, but there's a lot of clinics that are operating virtually, not live.

Besides.

<unk>. Thank you would you say I T.

Itchy gene therapy, which is about to start the only new programming to the gene therapy potentially.

Can you go right now but to be the peak in about a year and a half two years hypertrophic.

Hypertrophic cardiomyopathy, so, but we have many many other programs that are not gene therapy programs.

And that will continue to be the case at the same time, we are not we are far from giving up on June 30, and I guess, we're not the only company doing so.

Jeffrey Robert Ajer: There are staffing issues in PKU clinics, as certain supporting staff, in particular, have been reassigned during the pandemic. And frankly, for the genetics clinics, while PKU usually is the largest group of patients that they're treating, there are acute needs for patients in those genetics clinics, and we've seen that those acute needs for really terrible conditions for children, you know, are first in line for priority for their capacity. Having said that, we are getting new patient referrals on a steady basis, I would say steady throughout the pandemic, and we're drawing the conclusion that if we had been optimistic about PKU clinics getting back to their previous pre-pandemic capacity, that hasn't happened.

We still believe it's got major potential.

And I.

I mean, it kind of reminds me.

I don't know I'm, losing track of time here with 25 to 30 years ago when some.

The first patient treated with monoclonal antibodies died and I would say somewhat based on that with you. All if that's the end of monoclonal antibodies we shouldnt.

Didn't go forward with those that would have been a huge mistake considering that I don't know the aggregate sales of monoclonal antibodies today is over $100 billion a year. So.

So here we are at the beginning of the adventure with gene therapy, We're learning a lot I think we are.

I think was just waiting yes, we can.

Continue to learn and lots we believe we are well ahead of.

Most other gene therapy.

Companies in this respect and our understanding of what happens in the sales after the genius, they're shown in what at least two expression.

Jeffrey Robert Ajer: And we've been working on other tactical solutions that facilitate PKU patients to continue access to therapy and for new patients to start, and I think what we're trying to do is reset a little bit of expectations here that while we were optimistic at the beginning of the year, we're less optimistic about that capacity for the balance of the year now. So we're going to see overall growth. And I might just comment as kind of a read-through to what we think about that for Voxelgo.

Durability.

Hum.

If somebody told me response or immune response. So we believe we can design better and better cost structure. We also got to look at re treatments, you'll hear about a little bit that R&D.

R&D day, when you look at the non viral gene therapy.

Judy. So this is basically the framework of what drives our internal research on what drives the kind of stuff when it counts. So we're looking at outside in terms of BD.

I hope that answers your question and maybe Hank can you guys give you some perspective here to the middle of this.

Jeffrey Robert Ajer: In fact, other healthcare providers that we call on, such as pediatric orthopedists and pediatric endocrinologists, both of which are really relevant to Voxelgo, and, for the most part, and with restrictions and protocols in place, those specialties are, you know, they're back in business. So the kind of capacity constraints we're seeing in the PKU clinics, I would say don't let that read through to your expectations about Regarding your BD question, I mean, I think that's a good question. I just want to make a few comments. As you know, we

Well I think I, just think that the genetic and genomic revolution is unearthing so many opportunities.

And it just really creates a target rich environment I mean, I'm always then we have this behind the seizure program.

For <unk>.

Screening children, who have essentially unexplained epilepsy.

And so we find ceiling to patients who are indicated for bring your treatment, but we also find increasingly numbers of mutations that then get associated with pedigrees, because we're starting because of the <unk> starting to accumulate large enough family.

J.J. Bianamante: We have several, what we call, modalities within Biomarin.

Trees that they can start to identify.

J.J. Bianamante: Kuvan, KUVAN was an exception. If you look at our pipeline today, we have additional protein therapeutics, we have small molecules, we are moving into oligos or about to get back in the clinic with the second generation oligonucleotides, and we have some options there beyond DMD.

Things that have genetic etiologies, where it used to be like well it sort of runs in families. But now there's actually concrete evidence and it's actually concretely linked to specific genes.

With specific limitation of medical history. So it's really an amazing time to be where we are and to be able to leverage the diverse technology base that we've invested in.

J.J. Bianamante: And so we are always going to go beyond one modality. So I would say...

We can do small molecules proteins peptides nucleic acids are complex nucleic acid mixtures.

J.J. Bianamante: Gene therapy is very important for us and will continue to be in the future, but we have no intention of being a pure gene therapy company.

It's really a nice coming together of the fundamental thing about biomarin in terms of our orientation to research and science and the therapeutic opportunities that are presenting itself.

J.J. Bianamante: and if you you will see at R&D Day when we're going to disclose some new programs and talk about all the programs we have in development besides Roktavia and PQ-GCIP and

That all the way of saying that we've been successful in academic and early partnerships.

And for the time being I think that that's.

J.J. Bianamante: H.A.G. Therapy, which is about to start, is the only new program in terms of...

Where we are.

Great.

Thanks, Nick.

J.J. Bianamante: Gene therapy is potentially in the preclinical stage right now, but it will be in the clinic in about a year and a half, two years for hypertrophic cardiomyopathy. But we have many, many other programs that are not gene therapy programs. And that will continue to be the case. But at the same time, we are far from giving up on gene therapy. And I guess we're not the only company doing so. But we still believe it has got major potential.

Oh, sorry, one more comment indirectly related to visa.

As you know and I'm not going to disclose any data out here, but we've got some at R&D day, we are going to give you our first step based on.

At a clinical trial going on with our with Fox Sogou is very tight.

Indications beyond achondroplasia.

This could open up a major additional opportunity for OXXO go so high.

I would highly recommend you you attend that part of.

The R&D day presentation.

Thanks.

J.J. Bianamante: It kind of reminds me, I don't know, I'm losing track of time, it was 20 or 30 years ago when some of the first patients treated with monoclonal antibodies died. And I would say, based on that, we would say, oh, that's the end of monoclonal antibodies. We shouldn't go forward with those. That would have been a huge mistake, considering that, I don't know, the aggregate sales of monoclonal antibodies.

Sure.

And our next question from Kennan Mackay from RSC.

RBC capital markets you May ask your question.

Squeezing me in.

Going back to some of the prior questions.

Rip concerned.

The concerns on <unk> three of seven might read through to <unk>, maybe can you address the levels of identify rural or <unk> associated viral integration.

J.J. Bianamante: So here we are at the beginning of the adventure with gene therapy, we're learning a lot, I think we are, as Hank was illustrating, we continue to learn a lot. We believe we are ahead of most other gene therapy companies in this respect in our understanding of what happens in the cells after the gene insertion and what leads to expression, and durability.

And the vectors used in Rockville and versus that of what was seen in P. M through a southern thank you.

Yeah.

It's not really sets out to do head to head kinds of things, but in general the <unk>.

J.J. Bianamante: I hope that answers your question, and maybe Hank can give his perspective here too.

Level of integration that can be found.

Cross species are relatively low.

Henry J. Fuchs: Well, I think, I just think that, you know, the genetic and genomic revolution is unearthing so many opportunities, and it just really creates a target-rich environment. I mean, I'm always stunned; we have this Behind the Seizures program for screening children who have essentially unexplained epilepsy.

And.

I don't think that.

Theres really a meaningful likelihood that activity is necessarily any more or any less integrating and anything else. You know the agency in their 2020 early got early 'twenty 'twenty guidance on gene therapy referred to AAV vectors.

Henry J. Fuchs: And so we find, you know, CLN2 patients who are indicated for Brunier treatment, but we also find increasing numbers of mutations that then get associated with pedigrees because we're starting, because vitae is starting to accumulate large enough family trees that they can start to identify things that have genetic etiologies where, you know, it used to be like, well, this sort of runs in families, but now there's actually concrete We have specific annotation of his medical history.

Vectors that have a low propensity to integration unless they are designed to otherwise to integrate and quite to the contrary we redesigned our we did not.

To integrate and in fact, we would move things that can be suspects suspected.

Facilitating integration so we've been fairly deliberate to stay on the low propensity integration side and believe that that is likely to be true for all our vectors and as you know we've done longer term studies for both the a J E vector already for a vector that is otherwise identical to react to anything other than its coding sequence.

Henry J. Fuchs: So it's really an amazing time to be where we are and to be able to leverage the, you know, diverse technology base that we've invested in. We can do small molecules, proteins, peptides, nucleic acids, and complex nucleic acid mixtures.

So we feel pretty good about the lack of read through from one bucket to another in fact, we feel pretty good about the lack of read through from nice to other species.

Henry J. Fuchs: So it's really a nice coming together of the fundamental things about Biomarin in terms of our orientation to research and science and the therapeutic opportunities that are presenting themselves. So that all is a way of saying... We've been successful in academic and early partnerships, and for the time being, I think that that's where we are. Great. Really helpful. Thanks. Sorry, one more comment, indirectly related to this, as you know, and I'm not going to disclose any data here, but at R&D Day, we're going to give you our first update on...

Thank you.

And speakers there are no further questions at this time you may now continue.

For the closing comments.

Yes, so thank you again for.

Joining us today. So we are I hope we could issue we are poised for significant growth next year as just described.

That's based on our foundational base business on the box over the launch in the EMEA region.

Anticipated in the U S next month.

unknown: [inaudible]

J.J. Bianamante: This could open up a major additional opportunity for Vox Togo, so I would highly recommend you attend that part of the R&D day presentation.

Kevin Gene therapy potential potentially later layered on top of that.

Cannon McKay: And our next question from Cannon McKay from RBC Capital Markets. You may ask your question, locking me in.

In mid to late 2022 as well as a deep early stage pipeline that we look forward to sharing with you in November on November 30th.

Cannon McKay: Thanks for joining us. It's not really facile to do, you know, head-to-head kinds of things, but in general, the levels of integration that can be found across species are relatively low, and so I don't think that there's really a meaningful likelihood that So we've been fairly deliberate to stay on the low-propensity integration side and believe that that's likely to be true for all our vectors, and as you know, we've done longer So we feel pretty good about the lack of read-through from one vector to another. In fact, we feel pretty good about the lack of read-through from mice to other species.

Virtual R&D day, so we are focused on.

Continuing the strong momentum as we achieve our next important catalysts.

Including the potential approval of <unk> in the U S. By the end of next month. So thank you for your attention today.

We look forward to speaking with you again soon.

[music].

Operator: And speakers, there are no further questions at this time. You may now continue changing the anime for the closing comments.

J.J. Bianamante: Yeah, so thank you again for joining us today.

J.J. Bianamante: today. So we are here.

J.J. Bianamante: I hope we can reach you. We are poised for significant growth next year, as just described, and that's based on our foundational base business from the Vox overlaunch.

Sure.

[music].

J.J. Bianamante: Oxford will launch in the EMEA region.

J.J. Bianamante: Uh... anticipated in the U.S. next month. Also, the Roquevengine 30 potential.

J.J. Bianamante: potentially layered on top of that in mid to late 2020.

J.J. Bianamante: Thank you all for joining us on November 30th during our virtual R&D day. We are focused on continuing this strong momentum as we achieve our next important catalyst.

Okay.

J.J. Bianamante: Thank you for your attention today, and we look forward to speaking with you again soon.

Yeah.

Yeah.

[music].

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