Q2 2021 Biomarin Pharmaceutical Inc Earnings Call

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Operator: Welcome to Biomarin's 2nd Quarter 2021 Financial Results Conference Call. Hosting this conference call today from Biomarin is Traci McCarty, Vice President of Investor Relations. Please go ahead, Traci. Thank you, Grace.

Welcome to the Biomarin second quarter 2021 financial results conference call hosting this conference call today from Biomarin is Traci Mccarty Vice President of Investor Relations. Please go ahead Traci.

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

Great. Thank you all for joining.

Yesterday to remind you. This non confidential presentation contains forward looking statements about the business prospects of Biomarin pharmaceutical, including expectations regarding Biomarin <unk> financial performance commercial products and potential future products in different areas of therapeutic research and development results may differ materially any other progress of Biomarin.

Traci McCarty: To remind you, this non-confidential presentation contains forward-looking statements about the business prospects of Biomarin Pharmaceuticals, 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 are detailed in Biomarin's filings with the Securities and Exchange Commission, such as 10Q, 10K, and 8Q reports. On the call today from Biomarin Management are J.J. Bien-Aimé, Chairman and Chief Executive Officer. Joseph Ajer, Executive Vice President, Chief Commercial Officer; Hank Fuchs, President, Worldwide Research and Development; Greg Geyer

<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-Q10-K and a report.

On the call today from Biomarin management are J J b enemy.

Chairman and Chief Executive Officer.

<unk> Executive Vice President and Chief Commercial Officer, Hank Fuchs, President worldwide Research and development, Greg Guyer Executive Vice President and Chief Clinical Officer, and Brian Miller, Executive Vice President and Chief Financial Officer.

Traci McCarty: Research and Development, Greg Geyer, Executive Vice President, Chief Technical Officer, and Brian Mueller.

Traci McCarty: President and Chief Financial Officer. We hope to keep the call today to one hour and give everyone a chance to ask a question, so we respectfully request that you limit yourself to one question during the Q&A portion of the call. Thank you for your understanding. I will now turn the call over to Biomarin's Chairman and CEO, JJ Pianamay.

Hope to keep the call today to 1 hour and give everyone a chance to ask.

That's a good question. So we respectfully request that you limit yourself to 1 question during the Q&A portion of the call. Thank you for your understanding I will now turn the call over to Biomarin, Chairman and CEO J J P enemy.

JJ Bien-Aime: Thank you, Traci, and good afternoon, everyone. We hope your families are enjoying the summer.

Thank you Traci and good afternoon, everyone. We hope you your families are enjoying the summer.

JJ Bien-Aime: So we had very strong results in the first half of this year, recording $988 million in total revenues in the first six months of the year and half a billion dollars in total revenues in the second quarter globally. Representing 17% top-line year-over-year growth, including Kuvan, and 38% year-over-year growth in Q2, excluding Kuvan, which, as you know, has been facing generic competition in the U.S. since October of last year. These results underscore our ability to execute despite the impact of a global pandemic and, more importantly, are a testament to the value our products represent to patients. Based on this strong performance, we are pleased to be raising our total revenue and bottom line guidance for the year, and Jeff and Brian will provide more details in a moment.

And so we had a very strong very strong results.

In the first half book this year.

A recording a $988 million in total revenues from the first 6 months of the year and half a billion dollars in total revenues in the second quarter alone representing a 17% top line year over year growth, including proven.

And.

And 38% year over year roof in Q2, excluding <unk>, which as you know has been facing generic competition in the U S. In October of last year.

These results underscore our ability to execute despite the impact of a global pandemic and more importantly are a testament to the value.

Our products are represented 2 patients.

Based on this strong performance, we are pleased to be raising our total revenue and bottom line guidance for the year and Jeff and Brian will provide more details in a moment.

JJ Bien-Aime: With the commercial business increasing steadily, we look to the next generation of biomarine products to drive transformational growth in the coming years. With our late-stage products, VoxPogo and Roktavion, currently under review by health authorities, the R&D organization achieved a number of key goals in the first half of the year. In this quarter, Hank and his team advance regulatory progress with both products. Setting up for four potential US and European approvals, beginning with Vox Togo in Europe in the next few weeks, hopefully by the end of next month, and actually we are going to start treating our first commercial box local patients in France imminently based on an early access program which was approved by the so-called ATU in France and Jeff will give some more details in a little while, uh so uh we expect um, U.S. approval to be followed by potential approval in the U.S. is based on the current PDUFA action date of November 21.

With the commercial business increasing steadily.

We look to the next generation of Biomarin products.

You have the review by health authorities.

R&D organization achieved a number of key goals in the first half of the year.

Is this quarter Hank and his team in advanced regulatory progress with both products.

Thank god for for potential U S or European approvals, beginning work with box struggle in Europe.

In next few weeks, so hopefully by the end of next month.

And actually we are going to start treating our first commercial book local patients in France imminently.

Based on early access program, which was approved the so called <unk> and from and Jeff will give some more detail so enough either.

Oh Wow.

So we expect.

<unk> approval to be followed by potential approval in the U S based on.

Karen do fashion day till November 'twenty, 1 and.

JJ Bien-Aime: Discussions with the FDA are moving forward. With Roktavien, the recent validation of the MAA and potential CSMP opinion in the first half of 2022 paves the way for a third potential measure of market approval in the next 12 months upon completion of the three-year observation from all 134 patients in our pivotal TNRA-1 study with Roktavien. We should see the data be supportive as we expect, and then anticipate a fourth major market approval, if possible, potentially in late 2022. The value proposition of Octavia increases with each additional year of being controlled, as demonstrated.

You have here moving forward.

With Rocky in the rest of the recent validation of the MBA from the.

Potential.

Here's a few appear in the first half of 2022 paves the way for you.

Third potential measure.

<unk> approval.

In our in the next 12 months upon completion.

The 2 year observation.

From call it 34 patients.

Pivotal generates 1 study with a Octavian this will be the basis of a potential BLA submission next year in the U S.

Should the data be.

Market is as we expect.

And and then anticipating a fourth major market approval is possible potentially in late 'twenty 'twenty 2.

The value proposition of Octavia increases with each additional year operating control is demonstrated.

JJ Bien-Aime: As we just shared at the recent ISDH meeting from our Pivotal Generate 1 study, over 90% of the 134 patients had an annualized beating rate of zero or lower. The baseline, after four weeks following treatment with Roctavial, this is just with one intubated infusion of Roctavial. Also at NIH, from our Phase 1-2 study, following a single infusion of rofibin through at least five years, we observed a 95% reduction in Mini-Iolized Bleeding Rays to Less than 1 Bleed Per Year. However, compared to the bleed rates from participants previously treated, we still don't have care-accurate prophylaxis. Again, we're not competing ourselves with placebo here. We're comparing ourselves to steal the cure instead of care. So we are recognizing that it has to be determined how long Procedio was demonstrating study efficacy.

As we just shared at the recent Ics.

Supports me.

From our pivotal generate 1 study over 90%.

Of the 134 dishes had.

And annualized bleeding rate on zero or lower.

Baseline after 4 weeks following treatment with relative if this is just with Ah.

1 intravenous infusion.

IC activity.

Also in I E cash from our phase 1.2 study following a single infusion over a billion.

Throughout these 5 years, we observed a 95% reduction.

In mean annualized bleeding rate to less than 1 billion per year.

Compared to the bleed rates from participant previously.

We set it up care activates profit actually so again, we're not comparing ourselves to proceed from here, we prepare ourself to steal the parent's done up there.

So we arent recognized than it has like a 90 day has to be determined how long from Kenya will demonstrate hemostatic efficacy, but we have reason to believe based on the.

JJ Bien-Aime: But we have reason to believe, based on the current data, that beating control may be sustained for at least five years and beyond, based on the current data. And while gene therapy is not curative in 70% of the life

Between the data the bidding patrol may be sustained for at least 5 years and beyond based on the current data.

And while gene therapy, not curious and $70 lifestyle apparel.

Lucky to be lifetime therapy at this time.

JJ Bien-Aime: The value proposition of Octavian represents to patients and payers. All instructions with each year of data we are accumulating.

And that even proposition of Octavian represents to patients and payers.

Only strengthened.

With each year of beta we are accumulating.

JJ Bien-Aime: To date, based on the five-year risk control from our Phase 1-2 study, at least $3.25 million dollars for patients has been spared for each patient in the clinical trial in the US. This is based on the fact that in the U.S., the Covenant Factor 8... profit, I consider to be close to $650,000 per year. So, as you can imagine, peers will understand this kind of a lot easier.

To date.

Based on the 5 year beat control from our phase 1.2 study.

At least $3.25 million.

Per patient has been spared from each patient in the people trial in New York.

Uh huh.

This.

Based on the fact that in the U S B Covenant factory.

Profit after tax cost of about $650000 per year.

So as you can imagine payers will understand its kind of a master easily.

JJ Bien-Aime: We are considering a value we recently learned from a review of insurance claims of patients taking Imlibra in the U.S., that many of them are still using recombinant factor VIII despite treating with Imlibra. This is based on a review of insurance claims for the year 2020. This not only highlights the ongoing infusion burdens within NIDRA but the tremendous cost of potential geothermic, in-labor, which is quite fancy and can cost over $700,000 per year for your patients, in addition to whatever medications the patients are taking.

The way considering value. We recently learned from also from a review.

Some interest claims of patient sticky libre in the U S.

Many of them or steel.

Using a recombinant factor weighted despite treating with increasingly become deeper and this is based on a review of interest claims in the year 2020.

This is a listen only highlight C.

[noise] ongoing infusion burdened with indeed, Rob at the tremendous cost of potential deal with that.

India, which as Chris said, Ian can cross over $700000 per year per patients. In addition to whatever effectively the pieces I've taken.

JJ Bien-Aime: The bottom line is that the sustained, durable hemostatic efficacy observed following treatment with Roctavian in the longest and largest gene therapy trial ever done in hemo-PIA, Physicians will give you a very attractive treatment option, both patients and payers, receiving approval in the US and in Europe. As we shared with you previously from a paper published by Courtauld in 2019.

The bottom line is that the sustain durable hemostatic efficacy observed following treatment.

Treatment with productivity in the longest and largest gene therapy trial ever done in hemophilia a.

<unk> it is very attractive very attractive treatment option.

To both patients and payers.

Moving approval in U S and in Europe.

As we shared with you previously.

Pay.

Properly sized for Tau in 2019.

JJ Bien-Aime: The Lifetime Cost, Factory Profit Act is the law, and not including other aspects of the disease management and surgeries that the patients have to undergo on a regular basis. So the lifetime cost of activated prophylactics alone is estimated in that paper and other papers to be between $28 million and $31 million. So obviously, if we price our product between $2.5 and $3 million, we're not pricing our product for a lifetime. That's more relevant to the value proposition for Octavian, specifically as noted in an ICER report last year. ICER determined that the value proposition for Octavio was around 2.5 million dollars.

And my son costs.

Activate profit actually sit alone.

And that's not including all of their aspects of the disease management and surgeries that suspicious to.

2 of them to go on a regular basis, so the lifetime cost of activated profit.

And from that piece alone.

Is it the minute in that paper to be in all the papers to be between $28 million and $31 million. So obviously, if we price our product to Dupont Dupont from a 3.

$3 million were not pricing our product as a lifetime to Europe.

More relevant to the value proposition for Octavian specifically, yes.

As noted in the nicer.

Reported last year.

<unk> determined that the value proposition brocade was around $2.5 million.

JJ Bien-Aime: And that was the cost-effective threshold for treatment with roctelian, and that was based only on three years of efficacy data. So we are thrilled with the dramatic b-control demonstrated in Octavian. And more than ever, we believe that it will be an important treatment choice based on efficacy for patients and cost savings for payers. As our next potential significant growth drivers, Roktavion and VoxNorco have been a key focus and we expect them to be transformational for Biomarin.

And that was a cost effective threshold for treatment with Nokia and that was based only on 3 years of efficacy data that we have value.

Sales with a dramatic decontrol demonstrated a octavian.

And more than ever we believe that it will be an important treatment choice based on efficacy for patients and cost savings for payers.

And our next potential significant growth drivers for <unk> as of October being a key focus and we expect.

So we will be transformational to biomarin.

Upon potential approval.

But it is our next generation of early stage pipeline products that we look forward to.

JJ Bien-Aime: It is our next generation of early-stage pipeline products that we look forward to unveiling in more details later this year. The biomarine value proposition reaches far beyond our strong-based business and our near-term opportunities in hemophilia and achondroplasia, and we're excited to share more details with you at our upcoming R&D day in November of this year. Thank you all for your continued support, and I would like to turn the call over to Jeff. We'll discuss the commercial business update in more detail. Thank you, JJ.

So investing in more details later this year.

The biomarin value proposition.

As far beyond our strong base business and our near term opportunities and he will.

B I N achondroplasia.

And we're excited to share more details with you.

Coming R&D day in November of this year.

So thank you all for your continued support and now I would like to turn the call over to Jeff <unk>.

The commercial business updates in more detail.

Thank you J J.

Jeffrey Robert Ajer: I'm very pleased with the team's performance across all brands and all regions during the first half of the year. In the second quarter, we achieved $502 million in total revenues, representing 17% growth in the second quarter of 2021 compared to the same period in 2020. Significant growth concentrated in markets where customers place bolus orders Specific to our enzyme replacement therapy brands, grow strong cells in the first half of the year. Specifically, in the first and second quarters of 2021, large orders for Maglazyme and Vimazim from such markets as Turkey, Brazil, Egypt, Russia, and Saudi Arabia are expected to partially satisfy demand for those products in those regions in the second half of 2021. As a result, we expect a step down in volume in the second half of 2021 in those markets.

Please.

With the team's performance across all brands and all regions during the first half of the year.

In the second quarter, we achieved $502 million in total revenues, representing 17% growth in the second quarter of 2021 compared to same period 2020.

Significant growth concentrates.

Pleased with end markets, where customers place bolus orders specific to our enzyme replacement therapy brands drove strong sales in the first half of the year.

Specifically in the first and second quarters of 2021.

Large orders for that goes on in Vimizim from such market says, Turkey, Brazil.

Trade, Egypt, Russia, and Saudi Arabia is expected to partially satisfy demand for those products in those regions in the second half of 2021.

As a result, we expect a step down in volume in the second half of 2021 in those markets.

Jeffrey Robert Ajer: Based on the strength of demand in the first half of the year and expectations for the remainder of 2021, we are raising full-year guidance on total revenues. Increasing Vemisim, Naglazyme, and Palindic guidance, raising the bottom end of the range for QVAN, and reaffirming previously provided bronero guidance. The detailed guidance updates are available on page four of today's press release. Beyond ordering dynamics, patient demand is another key indicator to pay attention to. For both naglozyme and bimazine, patient numbers increased more than 10% year over year, underscoring the essential nature of these important therapies. For Bronura, in the second quarter, patient drug therapy increased 33% year over year.

Based on.

I'll take the <unk>.

In the first half of year.

And expectations for the remainder of 2021, we are raising full year guidance until revenues.

Increasing vimizim that goes on in Pelham These guidance raising the bottom end of the range for Kuban and rehab.

The stemming previously provided <unk> guidance. The detailed guidance updates are available on page 4 of todays press release.

Beyond ordering dynamics patient demand is another key indicator to pay attention to.

For both <unk> and Vimizim patient numbers increased more than 10%.

<unk> year over year underscoring the essential nature of these important therapies for burner at in the second quarter of patients on therapy increased 33% year over year.

Jeffrey Robert Ajer: Moving to Palantir, where year over year growth of 45% translated to $59 million in second quarter revenue. Despite continued COVID impact and new patient starts, due to PKU clinics closed or not operating at full capacity. Building on that theme, 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. We are still experiencing that patient growth, noting that new patient starts in the U.S. in the second quarter were lower than we expected. Consistent with expectations, the US was the main contributor of growth in the quarter, driven by US patient increases of approximately 30% year over year.

Moving to balance sheet, where year over year growth of 45% translated into $59 million in second quarter.

Reaffirming despite continued COVID-19 impact to new patient starts.

Due to PKU clinics closed or not operating at full capacity.

Building on that theme. It is important to note that PKU clinics in the U S have not opened up to new patient starts at the rate we anticipate.

Revenues.

We are still experiencing net patient growth, noting that new patient starts in the U S. In the second quarter.

More than we expected.

Consistent with expectations. The U S was the main contributor of growth from the quarter driven by U S patient increases of approximately 30%.

Year over year, and while we remain optimistic about the growth prospects for <unk> for the balance of 2021, we expect U S. PKU clinics to increased new patient starts.

Jeffrey Robert Ajer: And while we remain optimistic about the growth prospects for Palantir for the balance of 2021, we expect US TKU clinics to increase new patient starts at a slower pace than originally anticipated. The pandemic impact of Palantik in the EMEA region remains in effect, where we have experienced delays in price, reimbursement approvals, and very little new patient activity. In spite of that, we are making incremental progress, and I continue to expect that we will see more material Palantik revenue from this region when PKU clinics have more freedom to operate and start additional patients. Continuing with the PKU franchise, Kuban contributed $79 million in revenues in the second quarter, an increase compared to the first quarter of this year and reflects two factors.

Slower pace than originally anticipated.

The pandemic impact on Palin seek in the EMEA region remains in effect.

Where we have experienced delays in price reimbursement approvals and very little new patient activity.

In spite of that we are making incremental progress and I continue to expect that we will see more material balance zinc revenue from this region when PKU clinics have more freedom to operate and start additional patients.

Continuing with the PKU franchise Kuban contributed $79 million from revenues in the second quarter, an increase compared to the first quarter of this year and reflects 2 factors first slower than expected erosion to generics and second a rebound from the seasonal dip in demand.

Jeffrey Robert Ajer: First, slower than expected erosion to generics, and second, a rebound from the seasonal difference in demand for QVAN and Q1 that we typically experience. QVAN net product revenue decreased by 36% year-over-year, primarily due to the U.S. loss of market exclusivity in October 2020, as anticipated. Despite the impact of these challenges, as I mentioned, we are raising the bottom of the range of full-year revenue guidance for QV

For <unk> in Q1 that we typically experience.

<unk> net product revenues decreased by 36% year over year, primarily due to the U S loss of market exclusivity in October 2020 as anticipated. Despite the impact of these challenges as I mentioned, we are raising the bottom.

With a range of full year revenue guidance for Covid.

Jeffrey Robert Ajer: And now turning to Boxoco, our next potential commercial opportunity and potentially the largest launch to date. As JJ said, we are so pleased to have received the positive CHMP opinion for treatment of children two years old through final adult life, given the importance of starting treatment early in achondroplasia. Additionally, receipt of authorization for use for the ATU early access program granted in France allows access to Voxogo for those seeking treatment in France. This will give us the ability to get patients started in France imminently. Consistent with our past practice, we will communicate the price for Boxogo once we have received approval.

And now turning to book Soco, our next potential commercial opportunity and potentially the largest launch to date.

As JJ said, we're so pleased to have received a positive <unk> opinion for treatment of children 2 years old.

Through final adult height, given the importance of starting treatment early in achondroplasia.

Additionally, in receipt of authorization for use for HEU.

Early access program granted in France allows access to box soda for those seeking treatment in France. This will give us the ability to get <unk>.

Patients started in France imminently.

Consistent with our past practice, we will communicate the price per box sogo once we have an approval.

Jeffrey Robert Ajer: Assuming the upcoming EU decision aligns with the CHMP opinion, which is typically the case, we look forward to potential launch in the third quarter in Europe. Upon that approval, we expect to launch in Germany first, begin the reimbursement process in other large markets, and take advantage of named patient sales opportunities in markets where they exist. As we have shared previously when asked for health modeling FOXOGO revenue, we are targeting annual net per patient revenue that is more like Palanzik than enzyme replacement therapy.

Assuming the upcoming EU decision aligns with the <unk> opinion, which is typically the case, we look forward to a potential launch in the third quarter in Europe.

Upon that approval, we expect to launch in Germany first begin the reimbursement process and other large markets and take advantage of named patient sales opportunities in markets, where they exist.

As we have shared previously when asked for help modeling Fox Sogo revenue, we are targeting annual.

Net per patient revenue that is more like pelon.

That enzyme replacement therapy like.

Jeffrey Robert Ajer: Turning to commercial supply, we anticipate the release-labelled finished goods will be ready to ship to customers in key markets such as Germany, France, Italy, and the United States within four to eight weeks of approval.

Turning to commercial supply we anticipate the release labeled finished goods will be ready to ship to customers in key markets, such as Germany, France, Italy, and the United States.

Within 4 to 8 weeks of an approval teams.

Jeffrey Robert Ajer: Teams are currently in place and well prepared for what could be Biomarin's largest brand yet. We look forward to sharing more detail on launch plans and potential approvals over the coming weeks in Europe and in November in the United States. In conclusion, results in the first half of 2021 exceeded our expectations and reinforced the essential nature of our commercial brands to the people who rely on them. Despite typical uneven ordering patterns, demand for our products in the more than 75 countries where we do business is robust.

Teams are currently in place and well prepared for what could be Biomarin largest brand yet we look forward to sharing more detail on launch plans pending potential approvals over the coming weeks in Europe and in November in the United States and.

In conclusion.

Net results from the first half of 2021 exceeded our expectations and reinforced the essential nature of our commercial brands to the people who rely on them.

Despite typical uneven ordering patterns demand for our products and the more than 75 countries, where we do business is robust.

Jeffrey Robert Ajer: Biomarin's commercial team continues to execute seamlessly and looks forward to new product launches around the world over the coming quarters, should the timing of approvals align with our expectations. Thank you for your attention, and I will now turn the call over to Hank to provide an R&D update.

Biomarin commercial team continues to execute seamlessly and looks forward to new product launches around the world over the coming quarters should timing of approvals align with our expectations.

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

Henry J. Fuchs: Thanks, Jeff. Beginning with VOXOGO for the treatment of children with achondroplasia, we were thrilled to announce the positive CHMP opinion this quarter, paving the way for potential European approval this quarter. We were also pleased that the positive opinion recommended treatment with VOXOGO for children ages 2 and above, a broader group than we had anticipated, given the importance of starting treatment as early as possible. We appreciate the European Medicines Agency recognizing how important early treatment is, given the window of time when VOXOGO can provide clinical benefits.

Thanks, Jeff.

In dealing with Fox hunger for the treatment of children with Achondroplasia, we were thrilled to announce the positive <unk> opinion in the quarter paving the way for potential European approval and this quarter. We are also pleased with the positive opinion recommended treatment with OXXO go for children ages, 2 and above a broader group than we had anticipated given.

The importance of starting treatment as early as possible. We appreciate the European Medicines agency recognized how important early treatment is given the window of time, when docs, who can provide a clinical benefit.

Henry J. Fuchs: In the United States, two results from the Phase 3 extension study to supplement the new drug application are under review, and we look forward to the PDUFA target action date of November 20, 2021. Boxogo is the first medicine that addresses the root cause of achondroplasia, and it could be the first medicine to be approved for children with achondroplasia.

In the United States <unk> results from the Phase III extension study to supplement the new drug application or under review and we look forward to the producers.

<unk> target action date of November 22021.

<unk> was the first chunk of it was the first medicine that addresses the root cause of achondroplasia and is potentially the first medicine to be approved for children with achondroplasia I would like to convey our gratitude to the families. The advocacy groups investigators and colleagues that supported the development of a box so ago. We're in.

Henry J. Fuchs: I would like to convey our gratitude to the families, the advocacy groups, investigators, and colleagues that supported the development of Boxogo. We're in the cusp of the potential approval of another innovative product that addresses the root cause and tremendous unmet need of a significant pediatric condition. We want to thank everyone who contributed to this important update. Briefly, on Rokkavian, regulatory milestones are tracked into plan.

The potential approval of another innovative product that addresses the root cause and tremendous unmet need of a significant pediatric condition. We want to thank everyone who contributed to this important book.

Briefly on rock Caveon regulatory milestones are tracking to plan, we recently announced that the European Medicines agency has validated our mark.

Henry J. Fuchs: We recently announced that the European Medicines Agency had validated our marketing authorization application, which could lead to a CHMP opinion in the first half of next year under the Accelerated Assessment Timeline. We're very pleased to be tracking towards potential approval next year in Europe, given the breadth of clinical evidence demonstrating dramatic reductions in bleeding rates, factory utilization, and factory infusion rates following Roktavia. In the United States, we expect to resubmit the biologics license application for Octavian in the second quarter of 2022, assuming support of two-year data, followed by an expected six-month review procedure. Further supporting the role we believe Roctavian may play in the treatment of severe hemophilia A, last week we were very pleased to have shared 12 presentations at the International Society on Thrombosis and Hemostas 2021 Virtual Congress

Marketing authorization application, which could lead to a C. H M. P opinion in the first half of next year under the accelerated assessment time line.

We're very pleased to be tracking towards potential approval next year in Europe, given the breadth of clinical evidence demonstrating dramatic reductions in bleeding rates factory utilization factory infusion rates following.

Copper Octavian.

United States, we expect to resubmit, the biologics license application per Octavian in the second quarter of 'twenty, 2 assuming supportive 2 year data followed by unexpected 6 months review procedure.

Further supporting the role we believe per Octavian may play in the treatment of severe hemophilia a last week.

We're very pleased to share 12 presentations at the International Society on thrombosis and Haemostasis as 2021 virtual Congress. The 3 oral presentations 9 coaster spanned a variety of relevant gene therapy topics as well as data updates from both our pivotal generate 1 in phase 1.2 studies from proactive yet as.

Henry J. Fuchs: The three oral presentations and nine posters spanned a variety of relevant gene therapy topics, as well as data updates from both our Pivotal Generate I and Phase I-II studies with Roktavian. As you may have seen in the updates, the largest and longest development program for any gene therapy in hemophilia A, Roktavian demonstrated continued durable clinical benefit through at least five years. Data from our Pivotal Generate 1 study demonstrated that over 90% of all 134 participants had an annualized bleed rate of either zero or lower than it was at their baseline, and remember that their baseline was collected while they were on the best standard of care factory prophylactic therapy.

As you may have.

Seen any updates the largest and longest development program for any gene therapy in hemophilia, a rock kv and demonstrated continued durable clinical benefits are at least 5 years.

Data from our pivotal generate 1 study demonstrated that over 90% of all 134 participants at an annualized bleed rate of either zero.

Or lower than it was.

Then their baseline and.

And reminder, that their baseline was collected while they were on best standard of care factory prophylaxis therapy at 5.1 years after receiving a single dose of <unk> vector genomes per kilo dose cohort of the phase 1.2 study demonstrated.

Henry J. Fuchs: At 5.1 years after receiving a single dose, the 6013 vector genome per kilo dose score of the phase one study demonstrated that after week four, the mean annualized bleed rate was reduced by 95%. Also of importance to patients, when considering the overall benefit from Roktavien and the Pivotal Generate 1 study, all but two of the 134 participants remain off prophylactic factory treatment, and in the Phase 1-2 study for both the 6E and 4E-13 dose cohorts, all participants remain off prophylactic factory treatment through years 5 and 4, respectively. What our investigators are telling us is that this is no prophylactic, and there are no bleeds.

Zero net after week for the mean annualized bleed rate was reduced by 95%.

Also of importance to patients when considering the overall benefit from Octavian and the pivotal generate 1 study all but 2 of the 134 participants remain on prophylactic factor treatment and in the phase 1.2 study for both the <unk> and 40% <unk> dose.

It works all participants remain off prophylactic factory therapy, 3 years $5.4 respectively.

1 of our investigators are telling us that this is no profit no bleed status is hugely meaningful outcome for these.

Patients in the studies, we are very encouraged by these results and look forward to the full 2 year readout.

With all 134 participants in early 'twenty, 2 the basis of our potential U S. BLA submission in the second quarter of next year.

Henry J. Fuchs: Status is a hugely meaningful outcome for these patients in these studies. We are very encouraged by these results and look forward to the full two-year readout with all 134 participants in early 22, the basis of our potential U.S. VLA submission in the second quarter of next year. Lastly, we want to extend our thanks to the community, our investigators, and the people who participated in the clinical program. You're making history, and we thank you for your contributions to the value of knowledge in this important new therapy for hemophilia A.

Lastly, we want to extend our thanks to the community of our investigators and the people who participated in our clinical program Youre, making history. When we thank you for your contributions to the body of knowledge.

And that's important.

Therapy for hemophilia a.

Turning now to earlier stage pipeline and beginning with 307 gene therapy from penalty.

The dose escalation portion of the study continues with incoming subjects now receiving $6.13 vector genome per kilogram dose based on encouraging signals from the 2013 vector genome per kilo dose, we look forward to gathering are meaningful.

Meaningful amount of data with the 60 dose before determining next steps.

Henry J. Fuchs: Turning now to the earlier stage pipeline and beginning with 307 gene therapy for phenylketonuria, the dose escalation portion of the study continues with incoming subjects now receiving the 6E13 vector genome per kilogram dose. Based on encouraging signals from the 2E13 vector genome per kilo dose, we look forward to gathering a meaningful amount of data with the 6E dose before determining next steps.

To remind you we're targeting normal fee a normal diet and we look forward to the readouts from additional subjects given the interest in gene therapy solutions for phenylketonuria.

Behind <unk> 307, we'd been concurrently moving a number of our next generation product support and are pleased to have.

<unk> 2 <unk>.

<unk> II <unk> highlights net.

Last week, our IND for <unk> 331 gene therapy for the treatment of Henry hereditary angioedema or he was activated in the United States.

He is characterized by a predictable painful recurring and self limiting.

Henry J. Fuchs: Remind you, we're targeting normal fees and normal diets, and we look forward to the readouts from additional subjects, given the interest in gene therapy solutions for phenylketonuria. Behind BMN 307 and BMN 303, we've been concurrently moving a number of our Next Generation products forward, and are pleased to have two active INDs to highlight today. Last week, our IND for BMN-331 gene therapy for the treatment of hereditary angioma, or HAE, was activated in the United States.

Acute edematous attacks, which.

Which may occur in multiple locations such as the pace extremities Upper Airways in the Gi tract.

Our NGL attacks from the most serious manifestation of <unk> and that can cause panel asphyxiating due to obstruction of the upper Airways and while standard of care has improved in recent years HIV patients still require chronic therapy still experienced stability.

Unpredictable breakthrough attacks that require a rescue medication.

331 is an AAV 5 based gene therapy intended to restore the deficiency in circulating levels of the missing or dysfunctional <unk> inhibitor protein, causing haa with 1 time, IV infusion, thereby providing a durable preventive effect.

Henry J. Fuchs: HAE is characterized by unpredictable, painful, recurring, and self-limiting acute edematous attacks, which may occur at multiple locations, such as the face, extremities, upper airways, and the GI tract. Laryngeal attacks are the most serious manifestation of HAE, and they can cause fatal asphyxiation due to obstruction of the upper airways.

<unk> tax without the need for regular prophylactic treatments. This will be the first gene therapy clinical trial for the treatment of H E. B U S environments third investigational gene therapy products to the clinic, we're finalizing the study protocols and hope to begin dosing participants by the years yet.

We are pleased to share that in addition to <unk> <unk> 5 our small.

Henry J. Fuchs: And while the standard of care has improved over recent years, HAE patients still require chronic therapy, still experience debilitating, unpredictable breakthrough attacks that require rescue medication. BMN-331 is an AAV5-based gene therapy intended to restore the deficiency in circulating levels of the missing or dysfunctional C1S3 inhibitor protein, thereby providing a durable preventive effect against HE tax without the need for regular prophylactic treatment.

Against that though for the treatment of a subset of chronic renal disease is in the clinic and we are dosing participants we've been very productive and somewhat under the radar with these advances as well as a number of other candidates over the last quarters and we look forward to sharing a deeper dive on the burgeoning next generation pipeline at our upcoming R&D day in day D day in.

Thanks.

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

Thank you Heng. Please refer to today's press release summarizing our financial results for full details on the second quarter of 2021 as usual our comprehensive report on the quarter it will be available in our upcoming form 10-Q, which.

Henry J. Fuchs: This will be the first gene therapy clinical trial for the treatment of HAE in the U.S. and Biomarin's third investigational gene therapy product to go to clinic. We're finalizing study protocols and hope to begin dosing participants by the year end. We are pleased to share that, in addition, BMN-255, our small molecule for the treatment of a subset of chronic renal disease, is in the clinic, and we are dosing particularly well. We've been very productive and somewhat under the radar with these advances, as well as a number of other candidates over the last couple of quarters, and we look forward to sharing a deeper dive on the burgeoning next-generation pipeline at Brian?

Which we are on track to file over the next few days as.

As JJ mentioned, the anticipated timing of revenue and expenses over the course of 2021 resulted in a strong start to the year and the upward revision of full year 2021, total revenue guidance, including Vimizim net impairment as well as improved GAAP.

GAAP and non-GAAP guidance.

With respect to revenues, Jeff mentioned some of the specific markets that place large orders during the first half of the year in both the first and second quarters.

They were concentrated in markets, where countries typically place bullets orders, causing unevenness in revenues on a quarterly basis and in 2020.

On our first half as compared to a second half basis.

Based on these quarterly timing dynamic we continue to emphasize our full year guidance.

Best metrics to measure our performance.

While we continue to steadily identify and add new patients to each of our commercial products over time, we anticipate that demand.

<unk> products will continue to increase in the future notwithstanding global ordering pattern.

Moving to operating expenses R&D expense for the second quarter was $161 million, which was lower compared to R&D expense of $182 million per the second quarter of 2020, which included an upfront payment to our <unk>.

Brian R. Mueller: Thank you, Hank. Please refer to today's press release summarizing our financial results for full details on the second quarter of 2021. As usual, our comprehensive report on the quarter will be available in our upcoming Form 10-Q, which we are on track to file over the next few days. As J.J. mentioned, the anticipated timing of revenue and expenses over the course of 2021 resulted in a strong start to the year and the upward revision of full-year 2021 total revenue guidance. With respect to revenues, Jeff mentioned some of the specific markets that placed large orders during the first half of the year in both the first and second quarters.

<unk> from related to our diet or last year.

Our R&D expense trends through the first half of the year and expectations for the second half of 2021, we have lowered the top end of our full year R&D expense guidance by $10 million.

Next with respect to SG&A expense Q2, 2021SG&A.

<unk> totaled $184 million, which was slightly higher than SG&A expense of $175 million per second quarter of 2020.

We hope to be launching box sogou globally in the second half of this year, which is driving our SG&A expenses to be weighted to the back half of the year of note for 2021 is that our SG&A line. This.

Brian R. Mueller: They were concentrated in markets where countries typically place bullish orders, causing unevenness in revenues on a quarterly basis and, in 2021, in the first half as compared to the second half. Based on these quarterly timing dynamics, we continue to emphasize our full-year guidance as the best metrics to measure our performance. While we continue to steadily identify and add new patients to each of our commercial products over time, we anticipate that demand for Biomarin products will continue to increase in the future, notwithstanding global ordering patterns.

Year includes some charges for idled plant time of approximately $25 million, mostly related to maintaining our rocked hazy in manufacturing capability during its continued development cycle.

Based on these SG&A drivers in 2021, we are narrowing our full year SG&A guidance by $10 million and further note that we're trending.

Towards the higher rent end of the range for SG&A expense.

Turning to bottom line results, we reported GAAP net income of $13 million in the second quarter of 2021 compared to a GAAP net loss of $29 million in the second quarter of 2020, non-GAAP income of $98 million in the second quarter of 2000.

Brian R. Mueller: Moving to operating expenses, R&D expense for the second quarter was $161 million, which was lower compared to R&D expense of $182 million for the second quarter of 2020, which included an upfront payment related to our Dynacor collaboration last year. Based on our R&D expense trends through the first half of the year and expectations for the second half of 2021, we have lowered the top end of our full year R&D expense guidance by $10 million.

<unk> also grew as compared to non-GAAP income of $57 million in Q2.2020.

These bottom line results while at the same circumstances noted earlier higher first half 2021 revenues and higher second half 2021 expenses resulted in a strong profit result through the second quarter.

20 get the second half of the year trends they were expecting hold true.

We predict recognizing a GAAP net loss and lower non-GAAP income from the second half of the year. However back to the full year 2021, we're very pleased to announce the improvements of full year GAAP and non-GAAP guidance.

We've reduced full year non or full year GAAP net loss.

$20 million to between $110 million and $60 million for 2021, non-GAAP income full year guidance is now increased to between $190 million and $240 million, representing an increase of $20 million on each side of the range.

Brian R. Mueller: Next, with respect to SG&A expense, Q2 2021, SG&A totaled $184 million, which was slightly higher than SG&A expense of $175 million for the second quarter of 2020. We hope to be launching Boxogo globally in the second half of this year, which is driving our SG&A expenses to be weighted to the back half of the year. Of note for 2021 is that our SG&A line for this year includes some charges for idle plant time of approximately $25 million, mostly related to maintaining our Roktavian manufacturing capability during this continued development cycle.

That's substantial level.

Non-GAAP income helped generate a continued increase in our total cash and investments as we ended the second quarter of 2021 with 1.47 billion compared to $1.35 billion at the end of 2020.

We set a goal of earning positive operating cash flow in 2021, and while the aforementioned.

<unk> timing dynamics also impact cash flow the business delivered $83 million of positive cash flow from operations in the second quarter and $196 million on a year to date basis in 2021.

This solid cash position, coupled with our strong operating performance through the first half of the year is a strong 5.

<unk> position from which to look forward to the potential launch of box they'll go over the next few months and rock cave in next year and.

Brian R. Mueller: Based on these SG&A drivers in 2021, we are narrowing our full-year SG&A guidance by $10 million, and further note that we're trending towards the higher end of the range for SG&A. On the bottom line, we reported a gap net income of $13 million in the second quarter of 2021, compared to a gap net loss of $29 million in the second quarter of 2020. Non-gap income of $98 million in the second quarter of 2021 also grew as compared to non-gap income of $57 million in Q2 2020. These bottom-line results follow the same circumstances noted earlier.

And the progress of our early stage pipeline that is leveraging the same R&D organization that developed our portfolio of 6 approved products and 2 large market late stage program is an exciting next chapter and Biomarin.

<unk> future growth story.

Thank you for your support and we'll now turn the call over to your questions. Thank.

Thank you.

Operator.

As a reminder to ask a question you will need to press star 1 on your telephone question from.

Please standby.

We compile the Q&A roster.

Your first question is from Corey Kathy Mall from Jpmorgan. Your line is open.

Great. Good afternoon, guys. Thanks for taking my question wanted to ask you about rock JV and I'm curious if you've been able to get much physician and also payer feedback coming out of I S. T. H I just given the.

Brian R. Mueller: Higher first-half 2021 revenues and higher second-half 2021 expenses resulted in a strong profit result through the second quarter. If the second-half-of-the-year trends that we're expecting hold true, we predict recognizing a gap, a net loss, and lower non-gap income in the second half of the year. However, back to the full year 2021, we're very pleased to announce the improvements in full-year GAAP and non-GAAP guidance. We've reduced full-year gap net loss by $20 million to between $110 million and $60 million for 2021.

The virtual nature of it the 5 year update, particularly in the context of factor 8 level demonstrating a continued decline despite a still very favorable ABR. So basically wondering if its up day impacts how they're thinking about the product in the treatment paradigm in any meaningful way. Thank you.

Maybe I'll start and guest will tag team a little bit on the decisions to the payers.

You know it wasn't virtual Congress, that's not quite the same thing you're right Corey, but you know 1 of the things I was struck by.

You know just sort of at a very high level talking to clinicians.

And their experience with rock Teva and the patients.

They're not very focused on the surrogate markers theyre more focused on the patient right in front of them and 1 of the things that struck me was now 5 years later.

Brian R. Mueller: Non-GAAP income full-year guidance is now increased to between $190 million and $240 million, representing an increase of $20 million on each side of the range. That substantial level of non-GAAP income helped generate a continued increase in our total cash and investment as we ended the second quarter of 2021 with $1.47 billion compared to $1.35 billion at the end of 2020. The progress of our early-stage pipeline, which is leveraging the same R&D organization that developed our portfolio of six 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, and we'll now turn the call over to your questions.

What's top of mind for this position was the liberty that rock team and afford us their patients. So we think of this is.

Could you just like just take a few less doses of this other thing its life transformation freedom that these people are experiencing now it's 5 years since they have some big recollection of having this condition called hemophilia.

And so I think that's pretty per fan and I think that's what's more on people's mind necessarily than tomorrow.

Tomorrow is another day so.

I don't know if you want to add anything from your perspective, Thanks, Inc.

In fact, we haven't had a chance to specifically get out and.

Check in with payers and physicians.

Any kind of a formal way since I S. T. H. It just hasn't been enough time, but a couple of observations I would make.

From some REIT.

<unk>.

Prescriber research that we've done in the United States and Germany that follows.

Operator: Operator. As a reminder to ask a question, you'll need to do it.

The availability of a full 301 dataset through through 1 year generate 1.

Operator: Press Star 1 on your telephone. To address questions, press a pound key.

Operator: Stand by while we compile the Q&A roster. Your first question is from Corey Casimov from J.P. Morgan.

Data set through 1 year is.

A lot of stability in the interest.

<unk> relative to the last time, we went out to do this market research 2 years prior.

Operator: Your line is open.

Corey Casimov: Great. Good afternoon, guys. Thanks for taking my question. I wanted to ask you about Roctavian. I'm curious if you've been able to get much physician and also payer feedback coming out of ISPH, just given the virtual nature of it and the five-year update, particularly in the context of factor VIII levels demonstrating a continued decline despite a still very favorable ABR. So basically wondering if this update impacts how they're thinking about the product and the treatment paradigm.

But a significant interest increase in the confidence in the product and that's probably due to a combination.

The longer dataset from the phase 1.2 study and the full dataset from the generate 1 study being available so I find that.

Really encouraging and as you know Corey our U S team has been out talking to payers.

Corey Casimov: Thank you.

Henry J. Fuchs: Maybe I'll start and Jeff and we'll tag team a little bit on the positions for the payers. You know, it was a virtual Congress. That's not quite the same thing. You're right, Corey.

For a year and a half now.

Payers appreciate what what Hank just mentioned they got a lot pivots on a on the final durability.

Henry J. Fuchs: But, you know, one of the things I was struck by. You know, just sort of at a very high level, talking to clinicians about their experience with Roctavian and the patients, they're not very focused on the surrogate markers. They're more focused on the patient right in front of them. And one of the things that struck me was, now five years later, what's top of mind for this position is the liberty that Roctavian afforded its patients.

Of this drug with patients the 5 year data that we've recently released a certainly supportive of continued.

Durability.

And.

Payers, we continue to work with on mechanisms in the U S and in Europe of being able to address a risk of durability in.

Manage access agreements or pay per performance agreements of 1 type or another depending on the market. So.

Confidence as we head into this next round.

We're going to be very helpful. Thanks for the nice words.

Henry J. Fuchs: We think of this as, okay, you just take a few less doses of this other thing. It's life transformation freedom that these people are experiencing. Now it's five years since they have some vague recollection of having this condition called hemophilia. And so I think that's pretty profound, and I think that's what's more on people's minds than, you know, tomorrow's another day. So Jeff, I don't know if you want to add anything from your perspective. Thanks, Hank. We haven't had a chance to specifically get out and check in with payers and physicians in any kind of formal way since ISTH. There just hasn't been enough time.

Yes.

I mean, it appears I mean, you don't measure factory levels. They don't they cannot track them. They don't organize for that when they look at is how much those pieces are asking them maybe at any cost in the north zone.

$200000.

Im really.

So.

So right now we've got 5 years of efficacy so it's supposed to.

$4 million of savings potential from this space.

That's when they look at.

Great. Thank you very much.

Your next question is from Robin Carnahan from Covid.

Securities Your line is open.

Hi team. Thank you for taking the question just a question on MX logo now that you have the European opinion, and you're about to get the U S. Opinion can you talk a little bit about your latest thoughts on the dynamics among the patients and the doctors.

Are you seeing on.

Yes.

Jeffrey Robert Ajer: But a couple of observations I would make from some recent prescriber research that we did in the United States and Germany that followed the availability of a full 301 data set through one year, generate one data set through one year, there was a lot of stability in the interest for Roctavian relative to the last time we went out to do this market research two years prior, but a significant increase in confidence in the product. And that's probably due to a combination of the longer data set from the phase one two study and the full data set from the generate one study being available.

Patients are children.

Reaching out for interest in getting the drug and trying to see whether appointments are being available and how are you going to manage that.

And then what are you seeing on the on the awareness side, especially in Europe, and the United States now.

Now that you're so close to approval where are you out there.

Quick question on about a month ago that you answered for Octavian Inc.

Maybe I'll Ah Hi, Robin This is Jeff maybe I'll take a shot at answering this person at Cancun J J to round out anything I'm missing. So the first thing I would say is.

Jeffrey Robert Ajer: So I find that really encouraging. And as you know, Corey, our US team has been out talking to payers for a year and a half now. And payers appreciate what Hank just mentioned. I think a lot pivots on the final durability of this drug with patients. The five-year data that we've recently released is certainly supportive of continued durability. And the payers, we continue to work with on mechanisms in the US and in Europe to address the risk of durability in managed access agreements or pay for performance agreements.

It's really not possible for us in advance.

So with an approval to be engaging with patients and prescribers. So we're very much looking forward to.

Getting to the point, where we can do that as J J noted in his remarks, we now have an approved early access program in France.

Jeffrey Robert Ajer: Thank you very much.

We just got that and that will allow.

JJ Bien-Aime: Jeff and Hank say, I mean, it appears, they don't measure factory levels, they don't, they cannot track them, they're not organized for that. What they look at is how much these patients are costing them every year. And they're costing them north of $800,000 a year. So right now, we have five years of efficacy, so it's good to $4,000,000 of savings potential for this fair. That's what they look at.

From a similar treating patients in Germany will be poised to will.

We'll be poised to launch.

Right after.

An approval should we be so fortunate to get 1.

Our market research.

But we have done to map out kind of a prescriber.

<unk> networks I would start in Europe is saying there are expert centers in most markets in Europe, and we're going to be relying on those expert centers as as a first wave of.

Corey Casimov: Great, thank you very much.

Operator: Your next question is from Robyn Karnauskas.

Operator: and Robyn Karnauskas from Truist Securities. Your line is open.

Robyn Kay Shelton Karnauskas: Hi team. Thank you for taking the question.

Prescribing for achondroplasia patients, we would anticipate that patients.

Robyn Kay Shelton Karnauskas: Unknown Speaker On VoxOgo, now that you have the European opinion, you're about to get the U.S. opinion. Can you talk a little bit about...

<unk> would migrate from getting started and expert centers being treated and in more local areas and eventually having those more local physicians and <unk>.

Robyn Kay Shelton Karnauskas: about your latest thoughts on the dynamics amongst them.

<unk> treatment in the United States.

Unknown Attendee: Unknown Attendee, Dr. David Lugo, Unknown Attendee, Unknown Attendee,

We have a team in place today, that's been establishing an.

Jeffrey Robert Ajer: Hi Robyn, this is Jeff. Maybe I'll take a shot at answering this first and ask Hank and JJ to round out anything I'm missing.

Initial Ah.

Profiling relationship with.

Pediatric endocrinologists, which we expect to be largely but the base of prescribers in the U S. So these would be <unk>.

Jeffrey Robert Ajer: So the first thing I would say is it's really not possible for us to engage with patients and prescribers in advance of approval, so we're very much looking forward to getting to the point where we can do that. As JJ noted in his remarks, we now have an approved early access program in France. We just got it, and that will allow us to start treating patients. In Germany, we'll be poised to launch right after an approval, should we be so fortunate to get one.

<unk> that are quite accustomed to dealing with and prescribing.

For growth disorders.

We also know that some patients are in genetics clinics, and we have well established relationships and those genetics clinics in the United States that we can.

Canon will leverage our market research indicates a high degree.

JJ Bien-Aime: Our market research that we have done to map out kind of the prescriber networks, I would start in Europe by saying there are expert centers in most markets in Europe, and we're going to be relying on those expert centers as a first wave of prescribing for achondroplasia patients. We would anticipate that patients would migrate from getting started in expert centers to being treated in more local areas and eventually having those more local physicians initiate treatment. In the United States, we have a team in place today that's been establishing an initial profiling relationship with pediatric endocrinologists, which we expect to be largely the base of prescribers in the U.S.

Drug interest in box I'll go on the part of caregivers.

So we're looking forward to getting to that next phase, where we could begin actually selling and promoting.

Maybe the only thing I would add is you know 80% of the patients are born to parents normal in stature and it does not a subtle condition.

Agree this is a big health impacting condition and Theyre looking forward very much to improve health and I would say the evidence that interest and awareness is rising cresting as Jeff was just describing just from the Ema's action in terms of their recommendation.

They were willing to extrapolate a safety.

<unk> efficacy data from the pivotal trial in patients older than 5 to making the product available in children under 5 we saw this week from euro with the EMA as well that sort of their thinking is no child should be left behind so I think they recognized the urgency of the condition and the importance of giving Jeff Jeff's team the tools they need to get this medicine.

JJ Bien-Aime: So these would be physicians that are quite accustomed to dealing with and prescribing drugs for growth disorders. We also know that some patients are in genetics clinics, and we have well-established relationships with those genetics clinics in the United States that we can and will leverage. Our market research indicates a high degree of interest in Boxugo on the part of caregivers, so we're looking forward to getting to that next phase where we can begin actually selling and promotion.

Safety naturally.

Just to clarify you said 48 weeks of a delay between like non approval time and time, you could get drug to the center.

That's true both for the U S and Europe.

JJ Bien-Aime: The only thing I would add is 80% of the patients are born to parents normal in stature, and this is not a subtle condition; this is a big health-affecting condition, and they're looking forward very much to improved health. And I would say the evidence that interest and awareness is rising, cresting, as Jeff was just describing, just from the EMA's actions in terms of their recommendation, they were willing to extrapolate safety and effic We saw this with Granura and the EMA as well; their thinking is that no child should be left behind, so I think they recognize the urgency of the condition and the importance of giving Jeff's team the tools they need to get this medicine to patients early.

How to think about modeling it.

That's right so that's getting.

Greg.

These are patients operations team getting final label product.

Elyse.

Quality release them into a distributions center, where we can ship to customers.

So between problems between leap forward for lease and <unk>.

About 48.

Thanks.

That's not a year, that's what you're kind of tracking.

Thank you Xavier although again, we are going to treat that Chris. This is Brian in the next few days.

Your next question is from Celgene Richter from Goldman Sachs. Your line.

Yeah.

Good afternoon. Thanks for taking my question for Fox.

Do you feel that the FTP is the overall clinical package for approval similarly to the Ami just given the 2 year data comment.

So with regard to the EMA its recommendation from broader age group, Inc. A tiers of <unk> channel.

Robyn Kay Shelton Karnauskas: I think, just to clarify, you said 48 weeks of a delay between, like, approval time and the time you could get drugs to a center. Just want to be clear that that's true both for the U.S. and Europe.

Well as we've talked about it every health authority has their own sort of unique glass on it.

In the case of the U S. FDA, we've been transparent all along talking about the fact that their original recommendation was to your trial and of course, we provided them 2 years' worth of control data on improvement in height velocity, we think we have a.

Robyn Kay Shelton Karnauskas: How do you think about modeling it?

Robyn Kay Shelton Karnauskas: That's right, so that's getting Greg's operations team getting the final label product released, quality released, and into a distribution center where we can ship to customers. So between, Robyn, between week four.

A really strong package, we're getting really close to the finish line and as typical for Biomarin, We're gonna do not get into the sausage, making of the later stage discussions with the health authorities, but we remain very confident in the package that we submitted and I think the European action speaks you know good volumes to the results of diligent peer review.

Operator: Transcribed by https://otter.ai

JJ Bien-Aime: Although again, we are going to treat our first patients in France in the next few days.

Operator: Your next ques-

Operator: Salveen Richter from Goldman Sachs, your line is open. Good afternoon, thanks for taking my question. For Bucks-Zogo, do you feel that the FDA views the overall clinical package for approval similarly to the EMA, just given the two-year data comment and also with regard to the EMA's recommendation for a broader age group of two years of age and older?

Q my perspective might be ever so slightly different but I think you know what I mean.

1 question remains on balance of the benefits exceed the risks here, we're pretty confident.

The coming actions.

Thank you.

Your next question is from Geoffrey Mckinney from Bank of America. Your line is open.

Hey, guys. Thanks, so much good question had 1 rock TVN and it sort of parallels another question. So as you can.

Henry J. Fuchs: In the case of the US FDA, we have been transparent all along talking about the fact that their original recommendation was a two-year trial, and, of course, we provided them with two years' worth of control data on improvement and height loss. We think we have a really strong package. You know, we are getting really close to the finish line, and it's typical for the bottom ring. We are not going to get into the sausage-making of the later stage discussions with the health authorities.

Guys continuing to accumulate long term data.

No.

Bigger and and and and longer follow up are there any themes that you can identify for maybe would characteristics.

You could predict stable factory and longer and longer durability or in contrast, what could.

Maybe a breakthrough bleed or shorter durability I'm, just trying to get a sense for maybe how you could.

Henry J. Fuchs: We remain very confident in the package that we submitted, and I think that European action speaks well volumes to the results of diligent peer review. The perspective might be ever so slightly different, but I think the main question remains whether the benefits exceed the risks here. We are pretty confident, you know, of the coming action.

Maybe optimize that looking to the commercial launch thank you.

Yes.

To have predictability and variability as it comes up a fair amount actually.

The fact that 2 out of the only 2 out of 134 patients that were dosed in that generate 1 trial required.

Operator: Your next question is from Joss Micken from Bank of America. Your line.

Relatively quick return to prophylactic therapy were 132 out of 134 did not require Richard to prophylactic therapy and maintained.

Operator: America.

Operator: Hey guys, thanks so much for the questions. I had one on Roctavian, and it sort of parallels another question.

So I'm doing hemostatic efficacy I think bodes really well for the predictability of response now not everybody is going to respond in the exact same way and of course, that's a regular routine issue in medicine, it's relatively easy to manage and monitor in this space in the sense that we don't remove any options for patients. They can always go back to gain.

Operator: So as you guys continue to accumulate long-term data, you know, just, you know, the bigger end and longer follow-up, are there any themes that you can identify for maybe what characteristics could predict stable factor eight and longer durability? Or, in contrast, what could predict maybe a breakthrough bleed or shorter durability?

Labor factory prophylaxis.

Is that any of the side effect profile as we understand it today seems fairly favorable for that to be a choice that patients could make of course all of this is going to be subject of the review of the health authorities for their final decision making.

Henry J. Fuchs: I'm just trying to get a sense for maybe how you could maybe optimize that looking to the commercial launch. Thank you.

Henry J. Fuchs: The subject of predictability and variability comes up a fair amount. Actually, the fact that only two out of 134 patients that were dosed in the GENERATE-1 trial required a relatively quick return to prophylactic therapy, where 132 out of 134 did not require a return to prophylactic therapy and maintained adequate hemostatic efficacy, I think goes really well for the predictability of response. Now, not everybody's going to respond in the exact same way, and, of course, that's a regular routine issue in medicine.

At the end of the review cycles that we've talked about for the ebay Inc.

So the U S respectively.

All that said you know the durability data that we have gives us confidence that although we don't know exactly where things are going to settle out and when theyre going to settle out it does appear to be a large number of years. After initial transduction, which I think gives you the platform of belief around.

Hey, Jay was talking about which is the commercial value of the product the platform of what Jeff. What's believed it was talking about which is confidence in a product that can transform the lives of people with my Doctor a lot colleagues, who are telling us are sort of.

Henry J. Fuchs: It's relatively easy to manage and monitor in this case in the sense that we don't remove any options for patients. They can always go back to heme-libra or factory prophylaxis. There's not any – the side effect profile, as we understand it today, seems fairly favorable for that to be a choice that patients could make. Of course, all of this is going to be subject to the review of the health authorities for their final decision-making at the end of the review cycles that we've talked about for the EMA and for the U.S., respectively.

Mind blowing level of difference from the outcome for patients at a clinical level.

Yeah and again.

Good day.

We have very few patients that don't respond at all that from 2% based on our current data.

So obviously, although obviously, it's not great news the patients I don't know of any therapy that works in a 100% of the patients.

But given the fantastic COVID-19 vaccines on the market.

About 90.

Operator: All that said, the durability data that we have gives us confidence that, although we don't know exactly where, you know, things are going to settle out and when they're going to settle out, it does appear to be a large number of years after initial transduction, which I think gives you the platform of belief around what JJ was talking about, which is the commercial value of the product, and the platform of what Jeff was talking about, which is confidence in And what my doctor colleagues are telling us is sort of a mind-blowing level of difference in the outcome for patients at a clinical level.

80% response rate.

Hundreds of millions of patients have been taking them.

And as a result.

Yeah.

Okay. Thank you guys.

Your next question is from the Jeep Cabinet per day from Guggenheim Securities. Your line is open.

Hey, good afternoon.

Thanks, you for taking the question so on rotating post approval how long do you think physicians are going to decide on steroids. So would it be profit or on demand, but close monitoring for the first 12 to 16 weeks and secondly, assuming a 7 to 8 year durability. How are you thinking about re treatment, especially on the back of the benign immunogenetics.

Operator: And again, as Hank said, you know... We have very few patients that don't respond at all, less than 2% based on our current data. So obviously, although it's obviously not great news for the patients, I don't know of any therapy that works in 100% of the patients. We've given the fantastic COVID vaccines on the market, we have about 90% response rates, and hundreds and millions of patients. I've been taking

Thank God I Love 85 vectors. Thank you.

Yeah.

Yes, it's a little early to talk about the steroid use in the context of post approval, because we don't have a label yet.

And so we're just in the early stages of prosecuting that with Europe.

And we'll begin that process.

He broke here with the FDA as we talked about what I can say about steroids in the post approval setting is that we have data on both on demand use of steroids.

Operator: Your next question is from Debjit Chattopadhyay from Guggenheim Securities. Your line is open.

And prophylactic use of steroids in our program, we have data on fairly light touch on demand steroids and fairly heavy touch on the non steroids.

Operator: Thank you for taking the question. So under Octavian, post-approval, how do you think physicians are going to decide on steroids? So would it be pro-fee or on-demand with closed monitoring for the first 12 to 16 weeks? And secondly, assuming a 7 to 8 year durability, how are you thinking about re-treatment, especially on the back of the benign immunity and STD profile of AAV5 vectors? Thank you

Extra learned out of all of that is that you probably don't need to treat people as hard with critical steroids from the context of gene transfer and it might be the case that there are simpler regimens. For example, just a prophylactic regimen from the get go and in fact, we have an ongoing study that's enrolling like night quite nicely congratulations to the clinical team.

Henry J. Fuchs: Yeah, it's a little early to talk about steroid use in the context of post-approval because we don't have a label yet. And so we're just in the early stages of implementing that with Europe, and we'll begin that process next year with the FDA, as we talked about. What I can say about steroids in the post-approval setting is that we have data on both on-demand use of steroids and prophylactic use of steroids in our program.

For that and we're gonna be learning more between now and the eventual product availability that I think will inform in addition, as I started the product labels on steroid use.

The other part of your question is now I'll skip to my.

Yes.

Oh in the.

Well, we might binoculars from thinking about what's going to happen in the many years from now future win potentially hundreds of patients. We don't know when we were doing a lot of work on the molecular basis of sector loss.

Henry J. Fuchs: And we have data on fairly light-touch on-demand steroids and fairly heavy-touch on-demand steroids. What we've learned from all of that is that you probably don't need to treat people as hard with corticosteroids in the context of gene transfer. And it might be the case that there are simpler regimens, for example, just a prophylactic regimen from the get-go. And, in fact, we have an ongoing study that's enrolling quite nicely. Congratulations to the clinical team for that!

You've heard us talk about in the past some of this could be liver cell turnover, but some of those could be interest.

Hepatocytes mechanisms that are pretty complicated and tricky. So the good news is that we're trying to learn and we are learning quite a bit about that so that would inform the design of our next generation vector.

I think it's pretty premature to be thinking about that as a development candidate.

Henry J. Fuchs: And we're going to be learning more between now and the eventual product availability that I think will inform, in addition, as I started, the product labels on steroid use. The other part of your question then has now escaped my... Get out my binoculars and think about what's going to happen in the many years from now future when potentially hundreds of patients, We don't know when, you know, we're doing a lot of work on the molecular basis of vector loss, and, you know, you've heard us talk about in the past, some of this could be liver cell turnover, but some of this could be intrahepatocyte mechanisms that are pretty complicated and tricky, so the good news is that we're trying to learn, and we are learning quite a bit about that, so that would inform the design of a next generation vector, and I think it's pretty premature to be thinking about that as a development candidate, I think about this in a more science context, learning and being prepared in the event that there's meaningful loss of vector expression out in the outer years, that's still a long ways away for the vast majority of patients.

I think about this in a more science context learning.

And being prepared in the event that there's meaningful loss of vector expression out in the outer years, that's still a long ways away for the vast majority of patients.

Got it thank you.

Yeah.

Your next question is from Phil Nadeau from Cowen <unk> Company. Your line is open.

Good afternoon, and thanks for taking my question 50 days some of your tissue and gene therapies Advisory Committee recently announced a meeting for early September to discuss the safety of AAV vectors.

Curious to get your thoughts on that meeting and then maybe specifically has biomarin been asked to present at the meeting or do you have any plans to them to.

Indentation, even during the public comment period.

Yeah, I think it's terrific that the FDA is reaching out to their experts early in the course of the development of this of these therapies.

These therapies have obvious transformative potential, but as the community likes to refer to there are still unknown unknowns and some of the known.

Unknowns that were that are the subject to those channel.

Our important therapeutically now.

<unk> named some of those integration considerations thrombotic Microangiopathy for example, ALC or infusion or pretty severe hepatic reactions.

Operator: Your next question is from Phil Nadeau.

We've not been asked to present anything we're going to be watching the discussion.

Operator: Nadeau from Call & Company. Your line is open.

To make it for everybody else as far as we know is a free now.

Henry J. Fuchs: Afternoon, thanks for taking my question. The FDA's Cellular Tissue and Gene Therapies Advisory Committee recently announced a meeting for early September to discuss the safety of AAV vectors. Hank, I'm curious to get your thoughts on that meeting and then maybe specifically, has Biomarin been asked to present at the meeting, or do you have any plans to make a presentation even during the public comments period?

The thing the way I think about that is you don't really have a lot to say on that subject because we haven't experienced the kinds of things.

That the rest of the field was experienced with different cash sets I think.

A common thing for us to be thinking.

Looking about could be is there any read through on product class specific labeling I think that's really premature at this point to talk about the thing that I think we have done that makes our program unique important in this day.

Henry J. Fuchs: Yeah, I think it's terrific that the FDA is reaching out to its experts early in the time course of the development of these therapies. You know, these therapies have obvious transformative potential, but as the community likes to refer to, there are still unknown unknowns, and some of the known unknowns that are the subject of this panel are important therapeutically. Now, you know, and they've named some of those, you know, integration considerations, thrombotic microangiopathy, for example, ALT or infusion, or pretty severe hepatic reaction. But we've not been asked to present anything.

And important is that we have a fairly large dataset. So I think a lot of these things are rising the context.

Context of 1 and 2 and 3 patients worth of events.

And I think the accumulation of a large amount of data is really the only formula for advancing knowledge.

Regards to the safety of the AAV gene therapy platform. So we're very pleased to have already done 134 patients in our phase II trial and following now past.

And your follow up as it represents a pretty exuberant body of accumulating knowledge. So we will watch.

Henry J. Fuchs: We're going to be watching the discussion just like everybody else, as far as we know as of right now. I mean, the thing I think about that is we don't really have a lot to say on that subject because we haven't experienced the kinds of things that the rest of the field have experienced with different capsids. I think a common thing for us to be thinking about could be whether there is any read through on product or class specific labeling. I think that's really premature at this point to talk about.

As interested spectators.

Perfect. Thanks for taking the question.

Your next question from Paul Matthews from Stifel. Your line is open.

Hey.

1 much I had a couple of questions on the short side I was wondering if you've had any engagement with the FDA on the 2 year data and how important you think that is for the FDA and determining durability of effect.

And then second I don't know if its premature but I guess, there's a couple of ways. You can think about pricing for this drug in the U.

Henry J. Fuchs: The thing that I think we have done that makes our program unique, important, and distinct is that we have a fairly large data set. So I think a lot of these things are arising in the context of one and two and three patients' worth of events. And I think the accumulation of a large amount of data is really the only formula for advancing knowledge as regards the safety of the AV gene therapy platform. So we're very pleased to have already dosed 134 patients that are finished through the trial, and following now past one year of follow-up represents a pretty exuberant body of accumulating knowledge. So we'll watch as interested spectators.

So 1 is based on prevalence and the other is kind of looking at growth hormone, which really isn't.

Kind of in the normal orphan ballpark in net BOE span a wide range. So it would be kind of curious at least in your philosophy.

Those 2 are the kind of right right brackets be thinking about thanks.

I'll start on the 2 year data.

I mean, there's not a lot more to say about that other than that they flagged. This as a consideration for discussion at their advisory Committee and we believe that we address the issue of durability not in the exact way that the FDA wanted but in a way that is robust scientifically.

At least for them to come to their conclusions, but as you know they reiterated their request we have provided the data we are interacting with the sound about data as I mentioned, we're getting close enough to the finish line now that we won't go into the sausage, making of the back and forth, but suffice to say with a <unk> date of November 20, I think we'll all know the answer to the F. D. A.

Operator: Perfect. Thanks for taking the question.

Operator: Your next question is on Paul Matteis from Stifel. Your line is open.

Operator: Hairline, Adelton

Operator: Hey, thanks so much.

Operator: I had a couple of questions on Vasoratide. I was wondering if you've had any engagement with the FDA on the two-year data and how important you think that is for the FDA in determining durability of effect. And then second, I don't know if it's premature, but there are a couple of ways you can think about pricing for this drug in the U.S. One is

Fairly short shortly and we remain confident that the data package addresses the issues of their consideration that is to say that that box. So those effect will accumulate over time that day.

Net debt.

<unk> of the natural boat regulator bone growth will facilitate.

JJ Bien-Aime: I'd be kind of curious, at least in your philosophy, and if those two are the kind of right brackets to be thinking about. Thanks.

Well being and all the other control bonuses.

The body, resulting from both stature gained ultimately over time improvement in their health.

Henry J. Fuchs: Let me go to your data, Paul. There's not a lot more to say about that other than that they flagged this as a consideration for discussion at their advisory committee, and we believe that we addressed the issue of durability not in the exact way that the FDA wanted, but in a way that is robust scientifically for them to come to their conclusions, but as you know, they've reiterated their request. We have provided the data, and we are interacting with them about the data, as I mentioned.

I'll start with the pricing and an adjusted even though you've got some payer research to be done.

Again, I think we've stated before and we are reiterating that we anticipate day pricing here.

It would be similar to <unk>.

2 value index.

It's just.

Around $200000 a year for patients in the U S.

And that is based on English research and the value proposition that we have here.

I would say growth hormone is not is not a good comparator.

Well someone insufficiency or deficiencies.

JJ Bien-Aime: That is to say that Boxogo's effect will accumulate over time, that the benefit of the natural regulator bone growth will facilitate well-being in all the endochondral bones of the body, resulting in both stature gain and, ultimately, over time, improvement in their health. I'll start with the pricing, and then Jeff can tell you about some bigger research we've done. Again, I think we've stated before, and we'll be reiterating it, that we anticipate the pricing here.

Much much less severe disorder, you're talking.

Talking about.

2.

From 2 standard deviations from normal in terms of final adult height is no associated with Comorbidities.

Talking about 5 to 6 standard deviation from normal interest of adult high here. So.

Much more severe disorder.

Which puts it in New York.

And you often accounting.

Category and this is supported by payer research that Jeff can talk about yes. Thanks, J J I think you largely cover it but.

But thinking about.

JJ Bien-Aime: That would be similar to Palindex, which is around $200,000 a year for patients in the U.S. And that is based on various research and the value proposition that we have here. I would say growth hormone is not a good comparator. Growth hormone deficiencies are a much, much less severe disorder. You're talking about around two standard deviations from normal in terms of final adult height, but no associated comorbidities. We're talking about five to six standard deviations from normal in terms of adult height here, so much more severe disorder, which puts it in the... in the orphan category, and this is supported by peer research that Jeff can talk about. Yeah, thanks, J.K.

Box several in the context of.

The probably 1 treatment population, which is is relatively small compared to the population of.

Ah patients that would be eligible for growth hormone, but more importantly, thinking about the the.

The unmet medical need in achondroplasia, and the potential long term on lifetime benefits.

Sogo.

For those patients who have done a lot of work with payers in.

Europe and in the United States.

To characterize the unmet needs in achondroplasia and to model out.

Could be benefits from box I'll go beyond what we will be the significant improvement.

Jeffrey Robert Ajer: I think you largely cover it, but thinking about Voxelgo in the context of the prevalent treatment population, which is relatively small compared to the population of patients that would be eligible for growth hormone, but more importantly, thinking about the unmet medical need in achondroplasia and the potential long-term and lifetime benefits of Voxelgo for those patients, we've done a lot of work with payers in both Europe and in the United States to characterize the unmet needs in achondroplasia and to model out what could be benefits from Voxelgo beyond what we will be the significant improvements in and durable improvements in growth velocity that are the primary things that we're studying in the phase two and the phase three study. I think we've made a lot of progress with payers in that regard, and so, as J.J. notes, we're much more bullish about the prospects for pricing than in the context of growth hormone pricing.

In and durable improvements in growth velocity that are the primary.

Things that we're studying in the phase 2 and the phase III study and I think we've made a lot of progress with payers and in that regard and so as J J.

Some.

Much more.

More bullish about the prospects for pricing then.

Then in the context of growth hormone pricing and also a summary here, we're going to have new competition for many years to come.

And there's 5 or 6 years, it's been more growth.

Well, it's always a very competitive market, including Biosimilars.

Quite the same situation here.

Another dynamic.

Thanks very much.

Your next question is from Gena Wang from Barclays. Your line is open.

I have 1 question regarding vulcanian any thoughts on possibility that if he could.

We gotta go longer.

Then to your follow up post completion.

So when would you expect to hear back from them.

Jeffrey Robert Ajer: And also, he was going to have no competition for many years to come. And these five or six years, it's done more. Boracay is a very competitive market, including biostimulants. We're not quite in the same situation here.

[laughter] well Gina you know the FDA can ask for anything they want anytime they want and as you've seen before they can ask for much longer data.

Even after they've communicated the complete response letter as the first subject dosed. The first communication that expectation I know, that's really frustrating for everybody. They're there. They have a lot of excuses about that I think our side, we can't control what he does and we can't control.

Operator: Your next question is from Gina Nguyen from Barclays. Your line is open.

Operator: I have one question regarding Woktavian. Any thoughts on the possibility that FDA could ask for a longer than two-year follow-up after submission? And if so, when would you expect to hear back from the FDA?

All COVID-19 and things like that where we can do is we can generate a lot of data and trying to develop the best possible drugs, we can with the strongest evidence packages and I think that.

JJ Bien-Aime: Well, Gina, you know, the FDA can ask for anything they want, anytime they want, and, as you've seen before, they can ask for much longer data, even after they've communicated the complete response letter as the first object, as the first communication execution. I know that's really frustrating for everybody, you know, they have a lot of excuses about that.

You know judging by the fact that the European agency is willing to get their application of you started with the 1 year data knowing full well that the 2 year data is around the corner again.

And then also I think bodes well for how our health authority can look at the accumulating package of information, even with uncertainties remaining about longer term durability and I think the agency as you know has been fairly clear about.

JJ Bien-Aime: I think our side, you know, we can't control, you know, what the FDA does, and we can't control COVID and things like that. What we can do is we can generate a lot of data and try to develop the best possible drugs we can with the strongest evidence packages, and I think that, you know, judging by the fact that the European agency is willing to get their application review started with the one-year data, knowing full well that the two-year data is around the corner again also, I think bodes well for how a health authority can look at the accumulating package of information, even with uncertainties remaining about longer-term durability, and I think the agency is, you know, has been fairly clear about the time, the U.S. FDA has been fairly clear about wanting the two-year data.

The times the U S. FDA has been fairly clear about wanting to to your data.

It's not etcetera, and so much by any worries they have about the data or what they've seen so far because they've seen the same thing as you've seen.

Well actually the day, they haven't gone and probably as much depth. When your data as you have they just made up their mind and they want to to your data. So I'm optimistic that that will get them. There in terms of a positive benefit risk I think if you step back and say 2 years ago I got a single.

Single infusion of something in 2 years later I'm still not suffering the underlying condition that I was originally diagnosed with I think as you know.

It's reasonably profound but let's.

JJ Bien-Aime: It's not, it's not driven so much by any worries they have about the data or what they've seen so far because they've seen the same things you've seen. Actually, they probably haven't gone in probably as much depth on the one-year data as you have; they just made up their minds they want the two-year data, so I'm optimistic that that will get them there, you know, in terms of a positive benefit risk.

Let's just keep our fingers crossed if that's the way it holds all the way through the next review cycles.

So we haven't had any communication so far with your EBITDA that would lead us leaves that they are required.

Yes.

Thanks, Dan.

Okay, I think I believe and I'm asking because we saw the reason we had a unique cure can be upbeat shortly before some machines. So just want to make sure.

So when that happens.

Hi, Judy.

1 of them being 1 year and I understand the Air Force 18 month zone.

JJ Bien-Aime: I think if you step back and say, two years ago, I got a single infusion of something, and two years later, I'm still not suffering from the underlying condition that I was, you know, originally diagnosed with, I think, you know, it's reasonably profound, but let's, you know, let's just keep our fingers crossed that that holds all the way through the next review cycle. And also, we have not had any communication so far with the FDA that would lead us to believe that they are a required monitor. But I thank you for the mic.

There were still below 24, most of the ear.

Okay, great. Thank you.

Your next question from Joseph Schwartz from SBB Leerink. Your line is open.

Hi, I'm Jerry dialing in for Joe Thanks for taking our question.

So questions on box so ago, how confident are you that you understand all the influencers and influences.

The achondroplasia market. So for example, the adoption of Kuban was influenced by dietitian, but needed to be convinced of the merits of the drug. So ahead of OXXO book launch our question.

Operator: Okay, I think the reason I'm asking is because we saw the

Question confident are you that you have a handle on.

Operator: Unicure can be updated, you know, shortly before submission, so just want to make sure similar things will not happen.

Buy in from all the stakeholders that matter that will be important for widespread adoption of the product.

Ooh.

Well, thank you for that question.

Operator: I was just planning on submitting one year's worth, but I understand they asked for 18 months, so we're still...

Good 1.

In fact, we have a we have a commercial model.

Operator: There were still a beautiful 24 miles for you to hear.

Hum.

Unclear.

Paying attention to the the different stakeholders.

Operator: Okay, great. Thank you. Your next question is on Joseph Schwartz from SBB Lyrinc. Your line is open.

That are likely to influence the entire range of commercial.

Operator: Hi, I'm Joori Valiant for Joe. Thanks for taking our question. Our question is on VoxZogo. How confident are you that you understand all the influencers and influences in the achondroplasia market? So, for example, the adoption of Kuvan was influenced by dieticians that needed to be convinced of the merits of the drug. So ahead of VoxZogo's launch, our question is, how confident are you that you have the support and buy-in from all the stakeholders that matter that will be important for widespread adoption of the product?

Decisions, we call it our <unk> model.

Those include.

<unk> an advocate.

But all the patients physicians and payers and so we pay attention to all of those influencers in terms of a degree of confidence.

Each of those groups is not a monolithic thing there are different individuals'.

Some are more bullish.

Cash from our more skeptical some are early adaptors. Some are later adapters. So there is a variability inside of there as it relates for example to patient advocacy organizations and depending on where you're standing in the world. Some are.

Henry J. Fuchs: Well, thank you for that question. That's a good one.

Henry J. Fuchs: In fact, we have a commercial model that includes paying attention to the different stakeholders that are likely to influence the entire range of commercial decisions. And depending on where you stand in the world, some are really excited about having a treatment option; others less so. Same thing with payers.

Really excited about it.

Its treatment option and others less so same thing with same thing with payers. So I think that we're reasonably confident in our ability to pull off a strong commercial launch starting in Europe and hopefully later this year in the United States.

Henry J. Fuchs: So I think that we're reasonably confident in our ability to pull off a strong commercial launch starting in Europe and, hopefully, later this year in the United States. But 100% assurance is probably not something that I could promise. Yeah, I mean, although, again, I think there is a lot of excitement about the drug in many parts of the world here, based on the feedback we're getting from our commercial organizations. And you know, in some countries like Italy and Spain, I think around 80% of patients undergo limb extension surgery, which is dangerous, painful, and expensive.

100 percentage.

Having endurance is probably not something that I can promise you.

Yeah, I mean, although although again I think.

You know there is a lot of excitement about the drug in many parts of the world here based on the feedback we're getting from our commercial organization.

And as you know in some countries like Italy, and Spain on EBITDA.

Finishing operations under it.

To the extent from surgery.

Oh, she's central it's painful and expensive.

But it gives you a day and ideas too.

Whether they really want to go.

Henry J. Fuchs: So that gives you an idea as to whether they really want to, you know... Grow faster than they're growing right now, if they're willing to do these things, uh, and here we are trying something that We are not too concerned about here. I think the patient demand is going to be there and also, as Hank said earlier, I think 80% of the patients, [inaudible] Unknown Speaker, University of Michigan, San Diego, California, www.universityofmichigan.com; all of them are adults.

Royal faster than they bring right now if youre willing to do these things.

And here we.

I think something that.

We more than against an extensive surgery recently impacts but.

To both of their bodies.

No.

We're not too concerned here I think the patient day man instead of be there also.

As Hank said earlier, I think 80% of.

They go to a page that patients are born.

The operations that are from parents that are unaffected by the disorder.

Vast majority of them are interested in the in force.

Of course, it also D N a.

Final adult height for their kids.

And indeed, there were a few patients, but it's a minority distributions of you replacing.

Operator: Are we not counting them in our forecast anymore?

People.

From day.

Operator: My next question is from Michelle Gilson from CannaCore Genuity. Your line is open.

It might be less interest in either is it.

Product, but they're not they're not eligible for the product.

If you've got all of them are adults.

But we're not counting them on a per guest anyway.

Operator: Hi, thank you so much for taking my question. I have one quick one and one more robust question.

Next question is Michelle Gilson from Canaccord Genuity Your line is open.

Hi, Thank you so much.

Sure.

I have 1 quick 1 and.

1 more robust question I guess, the first being as you have seen the power of your data on factory activity.

Operator: I guess the first being, have you ever seen the five-year data on factor VIII activity for Valrock to Roktavian and reiterated their guidance to you for two years of data from the GENERATE study to file? And then, also on Roktavian, you know, it seems like the first market you'll be launching into is Europe. And you know, based on some European KOL feedback we've gotten, it really seems like KOLs overseas are expecting maybe one or two gene therapies at most for hemophilia A to be reimbursed and for the government to really be the Deciding Factor in Determining Which Gene Therapy is Going to be Available.

Iraq to watch TV and reiterated their guidance to you for 2 years of data from regenerate study.

Kyle.

King.

Second.

Ian.

It seems like the first person that you'll be launching into Europe, and you know based on some European Kols feedback from thought it really seems like Kols overseas are expecting maybe 1 or 2 gene therapies that most for hemophilia a.

Ought to be reimbursed.

And for the government to really be the deciding.

The deciding factor in determining which gene therapy is going to be available.

Operator: I guess with respect to this dynamic, in your experience marketing in Europe, how important is it to be the first mover there? And maybe you could comment a bit on your expectations around both the near and long term expectations for Roktavian uptake in the region.

I guess with respect to this dynamic in your experience marketing in Europe, how important is it to be the first mover there and maybe if you could comment.

And then on your expectations around both the near and long term.

Patients for for rock cave in them all.

<unk> taken the region.

Henry J. Fuchs: I'll start while Jeff's warming up in his local courts. The five-year data press release; the FDA is aware of it. I have no idea whether they went to the presentations, actually, but they had reiterated their demand for the two-year data before the one-year data was seen, and there was no point in them reiterating their demand after the five-year period. We knew what their request was going to be, even if we'd asked them.

Sure well just warming up in the social court.

5 year data press release, the FDA is aware of it.

EBITDA, whether they went through the presentations actually.

But they have reiterated their demand for the 2 year data before the 1 year data is seen and there was no point in them reiterating their demand. After the fact I mean, we know what their request was gonna be even if we had asked them. So there's a 5 year availability of the 5 year data did that change the dialogue to be net.

Henry J. Fuchs: So the five-year data availability did not change the dialogue that we had. And maybe circling back to your question about Europe and payers and preferences for one or more gene therapies, Roktavian is substantially ahead of potential competitive programs, so you're exactly right. Having a first mover advantage in Europe and in the United States comes with many, many, many advantages. First, assuming approval on the kind of timelines that we've been planning, there is no second approved program. There is no viable alternative in the wings second program, and if there was, that program would have less durability data.

And maybe circling back then to your question about Europe, and payers and preferences for 1 or more of gene therapies.

Brought patheon is substantially ahead of our competitive potential competitive programs. So.

You're exactly right, having first mover advantage in in Europe, and in the United States comes with many many many advantages.

Our first win.

I mean, assuming an approval on the timelines that we've been planning there there is no second.

Oh approved program there is no viable in.

In the wings second program and if there was that program would have.

Less durability data, we know theyre going to have less.

Henry J. Fuchs: We know they're going to have less robust data sets in terms of numbers of patients, but by the time that happens, Biomarin will be well into life cycle management initiatives, exploring other aspects of the treatment of Roktavian for Hemophilia A. So I think you're exactly on the money thinking that a first-mover advantage is so valuable in so many different ways for Roctavian. And we're really bullish about the kind of uptake prospects in terms of treating patients that come along with that and noting that once those patients are treated with Roctavian, they're off the table for potential later entrance into the market.

Robust datasets in terms of numbers of patients.

By the time that happens biomarin will be well into lifecycle management initiatives exploring at other aspects of the prefab of rock KVM for for.

For hemophilia, a so I think you're exactly on the money thinking that our first mover advantage is so.

And so many different ways for where Octavian and we're really bullish about the kind of uptake prospects are in terms of treating patients that come along with that and noting that once those patients are treated with <unk>. They are off the table for potential later entrants.

So the market. So thanks for shining a light on that 1 yeah. So again I want to be treated with brocade and they cannot be treated with another gene therapy.

Henry J. Fuchs: So thanks for shining a light on that, AAV Vector, which is basically all the ones that are in development right now. So that's obviously a major first mover advantage that we will have as compared to our competitors. So we are again pretty excited about it. And also, one other aspect which is important is that our vector, AD5, has basically the lowest prevalence of any other AD vectors in terms of preexisting antibodies. We should also advise them what they have to get.

Is with an AAV vector, which is basically all of them.

1 that are in development right now.

Hmm So that's obviously a major first mover advantage.

Net debt.

Valuable have as compared to.

Our competitors. So we are again pretty excited about it.

And also 1 other aspect, which is important is that our vector 85.

As the Louis Berger.

The large prevalence of any other AAV vectors in terms of our preexisting antibodies.

Which is also an advantage.

We have a good start with it.

Henry J. Fuchs: Hi, thanks for squeezing us in. Just a quick pipeline question. For BMM-307, wondering if you could sort of give us an update on additional patients that have been dosed here, if you've dosed beyond sort of that lowest dose, and within that program and that fearless study, just what you're looking for during dose escalation, essentially with a vector like this, and a disease like this, how do you decide on a go-forward dose when, you know, more reduction is Thank you.

Your next question is from Kennan Mackay from RBC capital markets. Your line is open.

Alright, thanks for.

Squeezing that Ben.

Quick pipeline question for you remain free of 7 I'm wondering if you could sort of give us an update on additional patients that have been dosed.

Advantage with beyond sort of that lowest dose.

Within that program and in that study.

Study.

Just what youre looking for during dose escalation essentially.

Back from like this.

And the disease.

How do you.

On a go forward dose when more reduction.

Henry J. Fuchs: You know, we are, in fact, at a second dose level. So we've dosed patients at the first entry dose level, which was 2E13, vector genome for kelo. And we saw some signs of C-lowering efficacy.

<unk> go ahead or being over thank you.

Yeah.

We are in fact that a second dose level. So we've dosed Ah.

Patients at the first entry dose level of the study, which was $2.13 vector genomes per kilo.

We saw some signs of C lowering efficacy so it says to us that we're probably on the dose.

Henry J. Fuchs: So it says to us that we're probably on the dose response curve. On the basis of that, we increased the dose in the next group of patients. We haven't communicated the data from that next group of patients, but what we have communicated is that, based on what we've seen in the 2E group and based on what we've seen with Roctavian, we're encouraged to think that it's possible that the 6E group would be the group that we choose to dose expand.

Those response curve on the basis of that we elevated the dosing. The next group of patients we haven't communicated the data, but what we from that next group of patients, but what we have communicated is that based on what we've seen in the TUI group and based on what we've seen with rock KPN. We're encouraged to think that it's possible that the <unk> group would.

The group that we choose the dose expand.

Henry J. Fuchs: You know, as regards how you pick a dose, I mean, the target of therapeutic effectiveness is effectively normal feed, normal diet. So the dose that gives that result in, you know, the largest fraction of the population tested is going to be the dose. And as soon as we meet the criteria for dose cohort expansion and move into the registration phase, we'll take you through the data in particular and illustrate why we chose that dose to believe that that was the dose that was going to give us the right target product profile. So that's very much right in front of us, and we look forward to sharing this data when it's available.

As regards how do you pick a dose that's targeted therapeutic effectiveness effectively as normalcy normal diet. So the dose that give the dose that gives that result in as you know.

The largest fraction of the population tested is going to be the dose and as.

B we are.

Meet the criteria for dose cohort expansion and moving into the registration phase will take you through the data in particular and illustrate why we chose that dose to believe that that was the dose that was going to give us the right target.

Product profile.

That's very much right in front of us.

As soon as afford share those data when they're available.

Operator: Your next question is from Matthew Harrison from Morgan Stanley.

Alright, thank you.

Yep.

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

Operator: and Morgan Stanley, your line is open.

Operator: Um, great. Good afternoon. Thanks for taking the question. I was just hoping, Jeff, that maybe you could comment a little bit on, in more detail, some of the PKU Center dynamics you were talking about and how much visibility you have into the flow of patients coming back or the flow of patients coming into those centers and sort of how confident you are in a second half recovery there. Thanks, Matt.

Yeah.

Great. Good afternoon. Thanks for taking the question I was just hoping Jeff that maybe you could comment a little bit on in more detail some of the.

PKU Center dynamics, you were talking about how much visibility you have into.

The flow of patients coming back or the flow of patients coming into those centers and sort of how confident you are in a in a second half recovery there.

Yeah.

Thanks, Matt and fast.

Jeffrey Robert Ajer: Thanks, Matt. In fact, particularly in the United States, where our biggest business is the biggest, we have a lot of visibility into how the different centers are operating, to the extent that they're open or not, if they are open, to what percent of their previous capacity, whether or not they're doing work through telemedicine or not, whether or not they're busiest. And what kind of wait times for patients that are looking to get started on palliative therapy. So we've got a lot of intelligence.

Similarly in the United States, where our biggest businesses Vegas, we have a lot of visibility into how the the different centers are operating.

To the extent that they're open or not if they are open to what percentage of their previous capacity.

Particularly are not there.

They're doing work through telemedicine, not bus tomorrow, and what kind of wait times for patients that are looking to get started on oncology therapy. So we've got a lot of intelligence what I would say is the.

Jeffrey Robert Ajer: What I would say is the, by and large, the PKU clinics are operating to some level, and they are starting new patients. They're just not starting them at the pace that would look like. Dr. David Meecham, Debjit Chattopadhyay, Christopher Raymond, Philip Nadeau, David Lebowitz, Timothy Lugo, Joseph Schwartz, Henry Fuchs, Jeffrey Ajer, Salveen Richter, Alexander Hardy, Leland Gershell, Unknown Attendee, Huidong Wang, Mohit Bansal, Luca Issi, Konstantinos Biliouris, Kevin Eggan, Biomarin Pharmaceutical Inc Timothy Lugo, Joseph Schwartz, Henry Fuchs, Jeffrey Ajer, Salveen Richter, Alexander Hardy, Logan Weiss, David Nadeau, Joseph Schwartz, Henry Fuchs, Leland Gershell, Unknown Attendee, Huidong Wang, Mohit Bansal, Luca Issi, Christopher Raymond, Biomarin Pharmaceutical Inc, Well, given developments with the Delta variant and, you know, the CDC announcement yesterday, I would say, you know, I'm still optimistic, but not Not really highly confident.

<unk> are by and large the PKU clinics.

Our operating to some level and they are starting new patients.

They're just not starting them at the pace that would look like.

The pace that they were starting new patients prior.

Prior to the pandemic.

So so that's our that's our issue is as we noted we have really nice year over year growth of <unk> patients on therapy.

By the end of the second quarter.

Had it not been from the pandemic, yes that rate of growth.

I I can confidently say would have been substantially higher and we know that there is a patient population out there that's interested in getting onto balance sheet and and so we've been we've been optimistic as as the pandemic has kind of flowed in the United States in particular that these centers would be able to get.

Back up and running degree.

A degree of confidence from the second half.

Well given the developments with the Delta variance and you know the the.

The C D C announcement yesterday I would say.

I'm still optimistic but not <unk>.

Not really highly confident.

Jeffrey Robert Ajer: In Europe, it's more of a mixed bag, depending on the market that we're talking about. Europe has been on a different path. I'm optimistic, but not 100% confident that we'll be able to get more patients started in our key markets in Europe in the second half. So that being said, in that sense, we are raising the guidance of CUVA and challenging by $10 million each.

And then in Europe, it's more of a mixed bag, depending on the market that we're talking about.

Europe has had been on a different path.

I'm optimistic, but not 100% confident that we'll be able to get more patients started in our key markets and in Europe.

Second half.

So that being said net net we are raising the guidance.

LNG by $10 million each day.

Operator: We have reached the end of the Q&A session, and we will now turn it back over to you.

We have reached the end of the Q&A session and we will now turn the call back to Biomarin, CEO and chairman J J D on me.

Operator: We will now turn the call back to Biomarin's CEO and Chairman, J.J. Bionime.

JJ Bien-Aime: Thank you all for joining us today. As we described, Biomarin is on the cusp of our next significant stage of revenue growth, our starting cash position, foundational business, two significant market opportunities, and with four potential approvals on the horizon, starting with the potential approval of VoxTogo, or likely approval of VoxTogo in Europe next month, and a robust early-stage pipeline that we've been investing steadily over the last four quarters It sets up for transformational growth beginning in 2022. So, thank you for your attention today, and we look forward to speaking with you again soon.

So thank you all for joining us today, so as we.

You described the Biomarin is on the.

The cost of our next.

You're gonna stage of revenue growth, our solid cash position.

Our foundational base business, 2 significant market opportunities and we have 4 potential approvals on the horizon.

Starting with the potential approval of OXXO go are likely approval of OXXO in Europe.

Next small study and a robust early stage pipeline that we have been investing steadily over the past quarters.

This is up for Retrans fishing transformational growth beginning in 2022. So thank you for your attention today and.

We look forward to speaking with you again soon.

Operator: Thank you for joining today's conference. You may now disconnect. Have a great day.

Yeah.

Thank you for joining us.

You may now disconnect have a great day.

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