Q2 2022 Biomarin Pharmaceutical Inc Earnings Call

Welcome to the Biomarin second quarter 2022 financial results Conference call.

Welcome to the Biomarine Second Quarter 2022

Financial Results Conference Call.

Hosting the conference call today from Biomarine, is Traci McCarty, Group Vice President of Investor Relations.

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

Please go ahead, Traci.

Thank you, Rob.

Thank you Ross. Thank you everyone for joining us today to remind you. This non confidential presentation contains forward looking statements.

Thank you, everyone, for joining us today.

To remind you, this non-confidential presentation, contains forward-looking statements about the business prospects of Biomarine Pharmaceutical Inc, including expectations regarding Biomarine'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 Biomarine's product program, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical market, and developments by competitors, and those factors detailed in Biomarine's filings with the Securities and Exchange Commission, such as 10Q, 10K, and 8K reports.

Prospect Biomarin pharmaceutical, Inc, including expectations regarding <unk> 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 <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 Securities and Exchange Commission, such as 10-Q, 10-K, and I can report on.

On the call from Biomarine's management team today

On the call from Biomarin management team today are J J C M&A, Chairman and Chief Executive Officer, Jeff HR Executive Vice President Chief Commercial Officer. Thank you President worldwide Research and development, Greg Guyer Executive Vice President Chief Technical Officer, and Brian Mueller Executive Vice President and Chief Financial Officer, I will now turn the call over.

are JJ Bien-Aimé, Chairman and Chief Executive Officer,

Jeff Ager, Executive Vice President,

Chief Commercial Officer,

Hank Fuchs, President, Worldwide Research and Development,

Greg Geyer, Executive Vice President,

Chief Technical Officer,

and Brian Mueller, Executive Vice President

and Chief Financial Officer.

I will now turn the call over

to Biomarine's Chairman and CEO, JJ Bien-Aimé.

Biomarin, chairman and CEO JB enemy.

Thank you, Traci, and good afternoon, everyone.

Thank you Christy and good afternoon, everyone.

Thank you for joining us today on the call. So the first half of 22, is our strongest six-month results to date, with over $1 billion in combined total revenues from our record-breaking first and second quarters. BoxStock revenues of $34 million in the first half, I'm sorry, $54 million in the first half of the year contributed to these results, and they were driven by continued rapid expansion of global commercial access for children with achondroplasia.

Thank you for joining us today on the call.

The first half of 'twenty two is.

Our strongest six months results to date.

Over over a billion dollars in combined revenues from our record breaking.

First and second quarters.

October revenues of <unk>.

A $34 million in the first half and $54 million in the first half of the year contributed to these results and they were driven by continued rapid expansion of global commercial access for children with achondroplasia.

Box over growth.

BoxStock growth led to today's increase, in top and bottom line guidance for the full year, despite ongoing economic challenges, including considerable foreign currency exchange, rate fluctuations, and the strength of the dollar.

To today's increase in top and bottom line guidance.

For the full year.

But ongoing economic challenges, including considerable funding foreign currency exchange rate fluctuations and the strength of the dollar.

Turning now to some of the key highlights of the second quarter all of which were first in our industry. In late June we were thrilled to have received a positive <unk> opinion.

Turning now to some of the key highlights, in the second quarter, all of which were first in our industry.

In late June, we were thrilled, to have received a positive CHMP opinion for Rocavian. We continue to expect European Commission approval, in the third quarter, which will be opening access to thousands of people with severe hemophilia who are interested in a one-time infusion of Rocavian gene therapy.

For Europe for GBS.

We continue to expect European Commission approval in the third quarter, which will be opening access to thousands of people with severe.

<unk> is just that a onetime infusion of leukemia in gene therapy.

This will be the first gene therapy, to treat any hemophilia recommended for approval in Europe.

This will be the first gene therapy to treat 80, he must be recommended for approval in Europe .

Jeff and his team already.

Jeff and his team are ready to launch Rocavian, upon potential ET approval later this quarter.

We're ready to launch we'll give you an a plus the castle EC approval. They go to school.

Sure Andy.

And in the U.S., we remain on track, to recently the BLA by the end of September, the end of next month.

In the U S. We remain on track to resubmit the BLA by the end of the September the end of next month.

Another first was the approval of our store in Japan for children of all ages and income Yoplait yogurt no age restriction.

Another first was the approval of BoxStock in Japan, for children of all ages with achondroplasia and no age restriction. This approval represents our largest, commercial opportunity to date in Japan.

This approval represents our largest commercial opportunity to date in Japan.

And we look forward to working closely, with the achondroplasia community there.

And we look forward to working closely with the acreage will be adjusted many of you there.

We also received approval in Australia for children ages, two years and older.

We also received approval in Australia, for children ages two years and older.

These important additions to the global access footprint are expected to be meaningful contributors with revenues from Japan beginning later this year.

These important additions to the global access footprint I expect it to be meaningful contributors with revenues from Japan.

Beginning later this year.

With Biomarin's financial outlook and robust global launch of VOXOGO tracking to plan and obtaining approval on the horizon in Europe, we are on our way to achieving the goals set forth at the start of the year.

With Biomarin financial outlook and robust global launch of OXXO go dragging to plan and with David approval on the horizon.

We are on our way to achieving the goals set forth at the start of the year.

Turning the corner to sustainable gap profitability, ramping up our largest opportunity to date with VOXOGO, and then progressing with Octavian to approval in Europe and pursuing approval in the U.S. and also advancing the broadest early stage pipeline in our history.

Turning the corner to sustainable Gaslog digitally ramping up our largest opportunity that we've got so low and then progressive Octavian to approval in Europe and pursuing approval in the U S.

We also advanced <unk> brought us early stage pipeline in our history.

I would add that as compared to where we were a year ago. We have made major progress to substantially reduce regulars.

I would add that as compared to where we were a year ago, we have made major progress to substantially reduce regulatory risk for Biomarin with the global approval of VOXOGO and upcoming approval of Octavian in Europe.

The regulatory risk or boundaries with a global approval of box, Togo and upcoming approval productivity in Europe .

And with our successful launch of VOXOGO the commercial risk is also significantly reduced.

And we are and with our successful launch of OXXO as well as the commercial risk is also <unk>.

And as you can see reduced.

We will continue to build on this financial, commercial, and regulatory momentum in the second half of 2022 and beyond as we make the transition to an earnings goal start.

We'll continue to build all these financial commercial and regulatory momentum in the second half of 2022 and beyond as we make the transition to on earnings call start.

Thank you for your continued support and I will now turn the call over to Jeff to discuss the commercial business updates.

Thank you for your continued support and I will now turn the call over to Jeff to discuss the commercial business updates Jeff. Thank you J J I'm very pleased with our record performance in the second quarter of 2022, resulting in $534 million in total revenues, which represents 6%.

Jeff?

<unk> growth year over year, including command and 13% growth, excluding <unk>, which continues to experience increasing market share loss of exclusivity.

Thank you, JJ.

Great.

Year to date, all brands marketed by Biomarin with the exception of Kabam experienced revenue growth year over year Star.

I'm very pleased with our record performance in the second quarter of 2022, resulting in $534 million in total revenues, which represents 6% growth year-over-year, including Kuvan, and 13% growth excluding Kuvan, which continues to experience decreasing market shares and loss of exclusivity in the United States.

Starting with box logo, we are pleased to share that as of June 32020 to an estimated 446 children were being treated with commercial box Sogo. This includes 282 children in countries outside of the United States and 164 children within the United States.

At the end of the second quarter of box cellular sales were spread across 20 active market, including sales of new market soft previously reported in Brazil.

China.

Hong Kong.

In Russia.

Outside of the EU, we're thrilled to have received approvals in Japan, and Australia during the second quarter, giving us a strong foothold in the Asia Pacific region with revenue contribution expected to begin later this year from Japan.

Turning to launch dynamics in the United States, we continue to see prescription demand ramp up.

We have been able to rapidly convert patient referrals to patient starts in the quarter. We saw prescription mainly from Genesis and pediatric endocrinologists as expected we are making continued progress in creating the referral pathway to pediatric endocrinologists.

We also see more payer coverage policies published which are largely consistent with our label or our clinical trials criteria and are aligned to our expectations.

We also continue to experience patient growth in European markets, consistent with what we've seen in the previous quarter, including new patients from new markets as reported.

As a result of the continued strong box they'll go ramp we are increasing full year guidance once again to between $130 million and $160 million for the full year 2022.

In summary for box so ago, we're very pleased with the pace of uptake during the first half of this year and note that we are well into the global watch Cascade Abbotts ago. These results underscore the ability of our experienced commercial team to tap into the large market opportunities regardless of location.

Launching in the EMEA region ahead of the United States provides the team an important framework for a potential JV and launched in the coming months should the European decision be supportive.

Turning now to our enzyme replacement therapy brands collectively achieved record results in the first half of the year with Q2 sales lower than Q1 due to the volume of large irregular orders placed in Q1 relative to Q2.

This is consistent with our experience of uneven quarterly revenue patterns, particularly for magazines xylem in Vimizim and.

In 2022 for both brands, we expect a higher concentration of revenues in the first half of the year compared to the second half hour.

Our expectations for the full year are reflected in today's updated guidance, where we have narrowed the range for both vimizim and <unk> and increased the top of the range of diagnosis, but $10 million for the full year for.

Or burner at 24% growth year over year and revenue of $38 million in the second quarter was driven by 18% growth in commercial basis versus a year ago for a narrow guidance remains unchanged.

Moving now to <unk> net product revenues grew 4% to $62 million in the second quarter as compared to the second quarter of 2021.

While we expect meaningful year over year growth and saw continued net patient growth in the quarter balancing performance trailed our expectations, resulting in an adjustment to our full year guidance downward to between $250 million $275 million, we expect the patient trends.

Continued to grow, albeit at a slower pace than initially expected.

It is clear that the capacity of PKU clinics, particularly in the U S to treat adult PKU patients with politic has not recovered the capacity loss due to the pandemic.

As a result, we have an active initiative to identify alternate prescribers in parts of the United States, where clinic capacity is at a deficit compared to adult patients that could benefit from balance sheet.

We are targeting adult endocrinologists for this initiative and our research indicates both net interest and trading PKU and the ability to manage treatment with talent.

We are early on in this effort, we have rems certified a number of new prescribers and we will keep you informed of the impact of this initiative has on our business going forward.

Continuing with the PKU franchise prevented contributed $58 million of revenue in the second quarter of 2022 down slightly from the first quarter of this year as.

As we have stated previously as Kuban nears the end of its lifecycle, losing market exclusivity in the U S. In October 2020, we're gratified to be able to retain meaningful market share and resulting revenues.

However, based on current trends, we are lowering our full year 2022, Kuban revenues guidance to between 210 $235 million.

Lastly, with the potential positive EMA decision for <unk>.

<unk> expected in the near future. We are ready for launch our team is prepared and encouraged that our longer term data results offer a comparable compelling value proposition and treatment option for adults with severe hemophilia, a and we look forward to providing you with more detail.

Upon approval.

Year-to-date, all brands marketed by Biomarin, with the exception of Kuvan, experienced revenue growth year-over-year.

In conclusion in 2022, we anticipate increased demand for all of our commercial brands with the exception of Kuban Thats just described.

Our <unk> products are expected to contribute significantly to revenue growth. This year. We also expect box so gotta be a meaningful factor in this ramp year.

Noted in today's increase in full year revenue guidance, we believe that robust prescription demand represents a foundation for continued growth, including in new markets throughout 2022.

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

Thanks, Jeff and thank you all for joining us today with the European decision for Octavian now on the horizon following the positive cgmp recommendation.

Our working to studiously on the BLA for Resubmission by the end of September our belief in the potential for Octavian to be transformational for people with severe hemophilia, a only strengthens with each passing year.

As we announced in May and also included in an oral presentation at <unk> ph in July durable hemostatic efficacy was maintained over six years and our ongoing phase one two study of <unk> in the fixed 13 cohort with a mean cumulative annualized bleeding rate of less than one substantially below baseline levels on standard up.

Care.

The safety profile from this study remains consistent with previously reported data with no delayed onset treatment related adverse events.

Needless to say, we've been very pleased with <unk> results across the phase III and phase one two programs and look forward to a potential marketing authorization in Europe in the third quarter.

Turning to box Sogo in June we were pleased to share a favorable 52 week results from our global Phase II study in infants and young children with achondroplasia at the Endocrine Society annual meeting the improvement observed in height Z score and annualized growth velocity observed was consistent with what was observed in children over five years of age we plan to meet with.

Starting with VOXOGO, we are pleased to share that as of June 30, 2022, an estimated 446 children were being treated with commercial VOXOGO. This includes 282 children in countries outside of the United States and 164 children within the United States. At the end of the second quarter, VOXOGO sales were spread across 20 active markets, including sales in new markets not previously reported in Brazil, China, Hong Kong, Qatar, and Russia.

U S health authorities in the second half of the year to discuss expanding access to younger children.

Finally, turning to the early stage pipeline all of the candidates under development continued to advance.

But with Biomarin, $2, 55, which addresses a subset of chronic renal disease gotten the go ahead from the food and drug administration to move forward with the multiple ascending dose portion of our phase one two study.

With B M and $3 31 for hereditary angioedema, we have dose patients in the phase one two harmony study to evaluate this investigational AAV five mediated gene therapy for patients with hereditary angioedema.

Concerning P. M N 351 for Duchenne muscular dystrophy, we expect to file an IND D. This winter.

Our preclinical studies of violent and $3 49 to continue to build our enthusiasm for its potential to.

To dramatically improve liver health and people living with <unk> deficiency.

For being in 293, formerly referred to as Diana One we are on track to be the next gene therapy clinical candidate in this case for the treatment of hypertrophic cardiomyopathy caused by mutations in the bias in dining protein C. Three gene Lastly, we continue to advance <unk> 349, 293 towards <unk> in the second half of tuna.

A 2023.

Outside of the EU, we were thrilled to have received approvals in Japan and Australia during the second quarter, giving us a strong foothold in the Asia-Pacific region, with revenue contributions expected to begin later this year from Japan.

In the coming weeks, we look forward to the Ec's decision for Octavian to be followed by Resubmission of the BLA in the United States. Thanks for your support and I'll now turn the call over to Brian to update financial results in the quarter Brian .

Thank you Hey, please refer to today's press release summarizing our financial results for full details on the second quarter of 2022.

Jeff touched on many of the top line results from the commercial business.

Primarily focused on operating expenses Bottomline results and other key financial updates this quarter.

As usual all results will be available in our upcoming Form 10-Q, which were on track to file over the next couple of days.

As we have been highlighting over the course of this year. We believe that 2022 is an exciting and transformational year for Biomarin is resuming a cycle of substantial revenue growth and expectation to transition to sustainable GAAP profitability, our aspirational milestones that we have been working toward for years, where.

Please in the tracking the plan based on the company's second quarter and first half results provided today.

Total revenue growth of 13% in the second quarter of 2022 as compared to the second quarter of 2021, excluding two that has put us on a path to achieve our 2022 GAAP and non-GAAP income goals one comment on our planned 2022 revenues are split between the first half second half of the year.

Is that while <unk> and Vimizim order timing were weighted to the first half of the year as Jeff noted second half revenues are expected to benefit from growing box sogo and pound deep revenues compared to the first half of the year plus the potential for a modest amount of rock TVN revenue as.

As a result total revenues in the second half of the year are expected to be roughly even with the first half of the year. The strong box yoga launch in consideration of the trends observed across our other brands drove the increase to our full year 2022 total revenue guidance to between to between 2.06 billion to $2, one 6 billion.

Also to comment on the impact of foreign currency exchange rate volatility on revenues. The strong U S. Dollar has impacted many companies foreign currency denominated revenue in 2022, well biomarin is not immune from the resulting decreases in most of the euro based revenue. We are pleased to observe that our foreign currency hedging.

Graham is providing the intended protection.

Based on current exchange rates, we project that the net impact on our full year 2022 revenues after hedges will be a relatively modest negative effect of approximately $15 million versus our original 2022 guidance expectations, which did incorporate some of the exchange rate volatility observed early in the year.

Moving to operating expenses for the second quarter of 2022, both R&D and SG&A expense fell in line with our expectations R&D expenses for the second quarter were $158 million, a slight decrease as compared to the second quarter of 2021, reflecting decreased box they'll go development efforts after the <unk>.

Marketing approvals in the second half of last year, which was mostly offset by increased R&D on our early stage programs.

SG&A expenses for the second quarter of 2022 were approximately $197 million as compared to $184 million in the same period last year with the largest components of the increase being the vocs Silvio global commercial launch efforts and rock cave in commercial launch preparation costs.

Moving to bottom line results for the second quarter and first half 2022, just a reminder that during the first quarter of 2022. The company sold the priority review voucher received with the approval of <unk> in the United States, while the gain on the sale of the PRD remains the largest single contributor in the first half GAAP net income we are pleased to.

Reported GAAP net income during the second quarter of 2022 totaling $28 million and $149 million for the first half of the year.

Based on this strong first half 2022 performance, we've slightly improved our full year 2020 to GAAP net income guidance range by $10 million to $105 million to $145 million.

While we have improved our full year guidance, we recognized that the full year math in light of $149 million of first half GAAP net income suggests that we may recognize the net loss for parts of the second half of the year. This is due to some of the aforementioned revenue timing and it's impossible larger expense items in the second half of the year we.

Confident in our core business generating GAAP net income this year and beyond.

With respect to non-GAAP income Q2, 2022, non-GAAP income of $109 million.

With slightly higher than 2021 second quarter non-GAAP income of $98 million and full year 2022, non-GAAP income guidance remains unchanged at between $350 million to $390 million.

Turning to launch dynamics in the United States, we continue to see prescription demand ramp up.

Turning to total cash and investments we ended the second quarter of 2022 with $1 5 billion flat compared to year end 2021.

We have been able to rapidly convert patient referrals to patient starts.

The company continues to incur quarterly timing differences and several cash flow categories, mainly working capital timing. However, the business did earn approximately $56 million of operating cash flow during the second quarter of 2022.

In the quarter, we saw prescriptions mainly from geneticists and pediatric endocrinologists.

As expected, we are making continued progress in creating the referral pathway to pediatric endocrinologists.

In closing Biomarin team is pleased to use the midway point of 2022 to both acknowledge the strong business performance through the first half of the year and the promising expectations for the rest of 2022, we continue to believe that our strategy of substantially growing revenues that drive increasing profitability and positive operate.

We also see more payer coverage policies published, which are largely consistent with our label or our clinical trials criteria and are aligned to our expectations.

We also continue to experience patient growth in European markets, consistent with what, we have seen in the previous quarter, including new patients from new markets, as reported.

As a result of the continued strong Boxogo ramp, we are increasing full-year guidance, once again to between $130 million and $160 million for the full year 2022. In summary for Boxogo, we are very pleased with the pace of uptake during the first half, of this year, and note that we are well into the global launch cascade of Boxogo.

These results underscore the ability of our experienced commercial teams to tap into large, market opportunities, regardless of location.

And cash flow, while also investing in developing an innovative pipeline are the best financial levers to fuel growth further into this decade.

For your attention and we will now open up the call to your questions operator.

If you would like to ask a question. Please press star one on your telephone keypad now and he will be placed in the queue in the order received.

Please be prepared to ask your question when prompted once again, if you'd like to ask a question. Please press star one on your phone now.

Our first question comes from South being director from Goldman Sachs. Please go ahead.

Good afternoon, and thank you for taking my questions.

Two questions here one is.

Launching in the EMEA region ahead of the United States provides the team an important, framework for a potential Octavian launch in the coming months, should the European decision be supportive.

With regard to your outlook from Octavian are you ready to launch here and you know once you have revenue from this product and how our margin and profitability is expected to be impacted longer term and then the second question is just about drug pricing performance.

Actually I'm looking at the proposed ballot here and how do you how biomarin be impacted and just orphan drugs in general just wondering anything get carved out to get to a good degree here.

Yeah.

Jeff.

Turning now to our enzyme replacement therapy brands, collectively achieved record results, in the first half of the year, with Q2 sales lower than Q1 due to the volume of large irregular orders placed in Q1 relative to Q2.

Thank you solving for the question.

In particular, the outlook for Ross avian launch in EMEA.

This is consistent with our experience of uneven quarterly revenue patterns, particularly, for Naglozyme and Vimizem.

Super excited about that also have a team in place.

In 2022, for both brands, we expect a higher concentration of revenues in the first half, of the year compared to the second half.

Our expectations for the full year are reflected in today's updated guidance, where we have, narrowed the range for both Vimizem and Naglozyme, and increased the top of the range of Naglozyme by $10 million for the full year.

For Vernura, 24% growth year-over-year and revenue of $38 million in the second quarter, was driven by 18% growth in commercial patients versus a year ago.

Vernura guidance remains unchanged.

Moving now to Palantik, net product revenues grew 4% to $62 million in the second quarter, as compared to the second quarter of 2021.

While we expect meaningful year-over-year growth and saw continued net patient growth, in the quarter, Palantik performances trailed our expectations, resulting in an adjustment to full-year guidance downward to between $250 million to $275 million.

That's most recently been busy successfully with avast Sogo launch it is largely that team that will be passed with the block cave and launch so.

We expect Palantik patient trends to continue to grow, albeit at a slower pace than initially, expected.

It is clear that the capacity of PKU clinics, particularly in the U.S., to treat adult PKU, patients with Palantik has not recovered the capacity lost due to the pandemic.

As a result, we have an active initiative to identify alternate prescribers in parts, of the United States where clinic capacity is at a deficit compared to adult patients that could benefit from Palantik. We are targeting adult endocrinologists for this initiative, and our research indicates, both an interest in treating PKU and the ability to manage treatment with Palantik.

We are early on in this effort.

We have REM certified a number of new prescribers, and we will keep you informed of the impact, of this initiative has on our business going forward.

KUVAN contributed $58 million in revenue in the second quarter of 2022, down slightly from the first quarter of this year.

As we have stated previously, as KUVAN nears the end of its life cycle since losing market exclusivity in the U.S. in October 2020, we are gratified to be able to retain meaningful market share and resulting revenues.

However, based on current trends, we are lowering full year 2022 KUVAN revenues guidance to between $210 and $235 million.

Lastly, with the potential positive EMA decision for Roktavion expected in the near future, we are ready for launch.

Our team is prepared and encouraged that our longer-term data results offer a compelling value proposition and treatment option for adults with severe hemophilia A, and we look forward to providing you with more detailed updates upon approval.

Good track record there.

In conclusion, in 2022, we anticipate increased demand for all of our commercial brands, with the exception of KUVAN, as just described.

Our NPS products are expected to contribute significantly to revenue growth this year.

I would say, what's the reason to believe.

Prospectively and rock Tavy and success in Europe , if we get the positive.

Approval from the EC and I'd go back quickly to what we believe are the five core.

Criteria.

That should be met too.

To set up a successful commercial gene therapy program.

Which rocked Damian satisfies all five criteria and those include one disease.

Disease with a significant remaining unmet need as we've described in hemophilia too.

Material treatment effect size, which will include all of our clinical affect quality of life.

Act and a convenience benefit.

Three would be a pharmacodynamic benefits, which brought fabian.

As clearly set up to deliver and as we've described over and over previously four would be a material population.

Two three so we believe there's a lot of gene therapies that are being developed to treat esoteric with small patient populations have limited commercial potential, but certainly severe hemophilia a adults is a significant large population.

<unk> five would be.

Our prepared.

Team on the ground that is experienced and ready to watch so as I said <unk> and meets all of those criteria. That's the reason to believe in our view.

Yeah. Thanks, Tobey this is Brian I'll comment on margins. Thanks for the question.

In short we believe the block cave in EU launch is going to be a significant contributor to what was already planned.

Margin improvement into our future.

We also expect Boxogo to be a meaningful factor in this ramp year, as noted in today's increase in full year revenue guidance.

We believe that robust prescription demand represents a foundation for continued growth, including in new markets throughout 2022.

Already today, we are observing that go back Sogou launched as a contributor.

When we look at our SG&A as an example, as a percentage of revenue today at about 40%. That's the global infrastructure, we built to support our seven approved products today, which we sell in in over 70 countries and.

The box Sogo contribution alone is getting leverage out of the commercial organization and while Iraq JV in severe hemophilia a market launch is going to take incremental investment, it's mostly a leverage story from that commercial infrastructure that Jeff mentioned, so well while it will take some time for Octavian revenues to ramp we expect.

The investments in operating expenses, along the way to be significantly less which over time is going to contribute to the bottom line and margin improvement.

So we look forward to observing that.

The direct pricing reform impact is going to go.

Yeah, so the drug pricing reform should that get through in.

The legislation and it will be impactful to us.

Companies that have large <unk>.

Medicare drugs in particular in companies that have a history and a practice of greater price increases that exceed.

Inflation rates in the United States CPI you in particular.

Biomarin are our portfolio is.

Has very limited exposure in <unk>.

Medicare and it is not our practice to.

<unk> raised prices ahead of CPI U. So while we see this is unfortunate move forward in the general sense, we don't see a material impact to our business.

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

Okay.

Yes.

And our next question comes from Joseph Schwartz from <unk> Securities. Please go ahead.

Hi, Thanks, very much congrats on the great quarter I have a question on Buck. So go and then we're Octavian.

So I was curious if you could talk about weather.

Whether you're working on any lifecycle management strategies to fortify. Your condra plays your franchise are ahead of a potential competition or are you still working on long acting formulations and can you give us an update on that status and are you doing anything to improve the administration device or procedure or generate more data too.

To.

Show the real world value of Bucks are those still your brand could have more staying power of competition arise.

Hank?

Thank you.

Are you worried about that as opposed to let Hank answer the rest of the question.

So we do a we have announced or we do.

Have a T.

Device in late stage development.

Which we hope could hit the markets.

It's around 2024.

It would make the administration of the drug even easier and she maybe Greg Guyer. This charter. This device maybe you can say a few words and then we will have.

I'll have Hank answer your question on the long acting formulation and other other lifecycle activities, the Brexit, particularly work, yes. Thanks, J J. So yeah. So the thing that is well underway.

We do believe it will be a step change in terms of convenience.

For many patients and a lot simpler to administer so that's well underway. We've got some studies, we need to do with the pen and obviously go through approval process and we hopefully that will hit the market in the U S and in Europe in 2024.

Maybe you didn't guide.

Go ahead sorry.

Oh, sorry, I was going to say the thing that I would add about the your question about the lifecycle and this we have very robust plans.

You know the needy.

Immediately next up is interactions with the food and drug administration around.

Broadening the label in the United States as it is more appropriately represented on a global basis as you recall, Japan just approve the product are unrestricted in regard to the younger living wage. So that's a key piece of fortifying the franchise. The pen you've heard a lot about the conversion to full approval on the basis of final adult height very much in motion very.

Important from a regulatory perspective to fortify the brand.

Lots of emerging information about.

Potential for good activity.

Activity in additional indication work.

Beyond achondroplasia.

And then maybe the final thing to say is taking a really long view.

But you know sort of the pen is step one and delighting the population with an easier and simpler approached administration.

We do have a long acting program and we're thinking about as we get more experience in this population.

What might be even better than that and so we have a lot of activity going on that will play itself out over a number of years to make box I go into an even bigger brand and you can see just based on this launch.

Thanks, Jeff, and thank you all for joining us today.

Yeah.

Okay.

And our next question comes from Geoff Meacham from Bank of America. Please go ahead.

With the European decision for Roktavion now on the horizon following the positive CHMP recommendation, we are working fastidiously on the BLA for resubmission by the end of September. Our belief in the potential for Roktavion to be transformational for people with severe hemophilia A only strengthens with each passing year. As we announced in May and also included in an oral presentation at ISDH in July, durable hemostatic efficacy was maintained over six years in our ongoing Phase I-II study of Roktavion in the 6013 cohort, with a mean cumulative annualized bleeding rate of less than 1, substantially below baseline levels on standard of care. The safety profile from this study remains consistent with previously reported data with no delayed onset treatment-related adverse events.

Hey, guys congrats on the quarter and thanks for the question.

I had a couple on an honor Octavian. So the first one is you know as you approach the European approval, maybe what what have you done or can you do to you.

Needless to say, we've been very pleased with the Roktavion results across the Phase III and Phase I-II programs and look forward to a potential marketing authorization in Europe in the third quarter.

To inform the are the cost benefit analysis I wasn't sure.

If there was any extra work that you guys have done as you approach. The the approval just to talk to some of the payers about the obviously the price tag.

And I know JJ you did talk about you know the the model shifting away from kind of an annualized kind of model into a single dose.

Single payment and then the second question also on Octavian, It's just.

When you look at the potential for re treatment.

Using a different expression vector a viral effect or maybe just give us a status update on anything youre doing there. Thank you.

Turning to Voxogo in June, we were pleased to share favorable 52-week results from our global Phase II study in infants and young children with achondroplasia at the Endocrine Society's annual meeting. The improvement observed in Hype C score and annualized growth velocity observed was consistent with what was observed in children over five years of age.

Thanks, Jeff just talked to not have.

Yes, and then Brian just on the revenue recognition plans for European revenues and then.

We plan to meet with U.S. health authorities in the second half of the year to discuss expanding access to younger children.

Uh huh.

Your last question.

So.

Indeed, we are.

Finally, turning to the early-stage pipeline, all of the candidates under development continue to advance. With bimarin-255, which adjusts a subset of chronic renal disease, we've gotten the go-ahead from the Food and Drug Administration to move forward with the multiple ascending dose portion of our Phase I-II study.

As compared to we were like two or three years ago.

We're right, where we thought the payers, whether it's in Europe or U S will be interested in.

With BMN-331 for hereditary angioedema, we have dose patients in the Phase 1-2 Harmony Study to evaluate this investigational AAV-5 mediated gene therapy for patients with hereditary angioedema.

For BMN-293, formerly referred to as Dyna-001, we are on track to be the next gene therapy clinical candidate, in this case for the treatment of hypertrophic cardiomyopathy caused by mutations in the myosin-binding protein C3 gene.

Pay overtime.

Lastly, we continue to advance BMN-349 and 293-TORC INDs in the second half of 2023.

We actually are not interested they're not organized for that because most of them work on a annual just so they are difficult as committing to paying over 345 years, we thought before that it would be interesting for them.

However, they are extremely interesting in outcome based agreements.

And Jeff and Brian can you explain the mechanics of that.

I'd also just.

The only thing I would add here is I would say.

In the coming weeks, we look forward to the EC's decision for Roctavian to be followed by resubmission of the BLA in the United States.

Based on the very strong.

The phase II data that we have that now.

Jos.

Jubilee.

Oh, leading protection for basically six years, we believe even we were in a strong position to causes agreements in place.

With very little risk to Dubai on rate I need a sense eliminate eliminate the.

Uh huh.

Cost reasonable for the payers.

And even if this whole question of durability.

Basically evacuated without outcome based agreements because there is no waste for the payer is the case of durability as long as the anticipated so.

Is that preamble just maybe you could explain exactly what are we thinking about and Brian took on the revenue recognition on that and then I can answer the last question.

Yeah. Thanks, J J. So we've got the outcomes based agreements that we are working towards and that we've discussed in many instances.

With European payers.

Notably, Germany, which will be our first launch and as JJ said.

We're taking with those agreements the risk of of.

Non response and the risk of durability over time.

Off the table for the payers so that addresses that.

Are they around uncertainty and based on the clinical trial data that we've got both.

The phase III full data set at two years early cohort at three years and the phase one two.

60, 13 dose data six years.

We judge the risk of non response is very very low and the risk of going back to prophylaxis, which is essentially what we would be through a period of time in these agreements is also similarly low.

A relevant public analysis I would refer you back to is the ice or analysis from two years ago, which concluded that at the time that <unk> was a superior choice.

So you can libre or standard of care at a presumed price of $2 $5 million the data behind.

Ross avian is is materially filled in in the ensuing two years. So we expect that that type of incremental cost effectiveness analysis will still hold and as you know every payer system in Europe has a slightly different unique requirements.

And so we prepare such incremental cost effectiveness.

Analyses and cost benefit analyses be spoke for all of those are systems, we're getting ready to file in the major EU markets. Shortly after an anticipated approval. So I think we're ready to go here.

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

And then Jeff. Thanks. This is Bryan briefly on the financials and we'll elaborate more on the details of this at our anticipated March but as J J noted, we would expect upfront not just payment, but revenue recognition for Octavian.

Brian.

Thank you, Hank.

Please refer to today's press release summarizing our financial results for full details on the second quarter of 2022.

As we deliver to customers.

And in all of these outcomes based agreements will need to recognize the financial exposure from these commitments to customers, although as Jeff noted because of the real strong response rates and durability in <unk> TV and I believe it was only.

Six out of 134 patients in the phase III study that had resumed prophylaxis.

That's going to mean that when we estimate what will be.

Since Jeff touched on many of the top-line results from the commercial business, I will primarily focus on operating expenses, bottom-line results, and other key financial updates this quarter.

As usual, all results will be available in our upcoming Form 10-Q, which we are on track to file over the next couple of days.

Balance sheet, a liability to capture these commitments.

As we have been highlighting over the course of this year, we believe that 2022 is an exciting and transformational year for BioMarin. Resuming a cycle of substantial revenue growth and expectations to transition to sustainable gap profitability are aspirational milestones that we have been working toward for years.

We are pleased to be tracking the plan based on the company's second quarter and first half results provided today. Total revenue growth of 13% in the second quarter of 2022, as compared to the second quarter of 2021, excluding KUVAN, has put us on a path to achieve our 2022 gap and non-gap income goals.

Also, to comment on the impact of foreign currency exchange rate volatility on revenues, the strong U.S. dollar has impacted many companies' foreign currency-denominated revenue in 2022.

While Biomarin is not immune from the resulting decreases in mostly Euro-based revenue, we are pleased to observe that our foreign currency hedging program is providing the intended protection. Based on current exchange rates, we project that the net impact on our full year 2022 revenues, after hedges will be a relatively modest negative effect of approximately $15 million versus our original 2022 guidance expectations, which did incorporate some of the exchange rate volatility observed early in the year.

Moving to operating expenses for the second quarter of 2022, both R&D and SG&A expense fell in line with our expectations. R&D expenses for the second quarter were $158 million, a slight decrease as compared to the second quarter of 2021, reflecting decreased Voxelgo development efforts after the marketing approvals in the second half of last year, which was mostly offset by increased R&D on our early stage programs. SG&A expenses for the second quarter of 2022 were approximately $197 million, as compared to $184 million in the same period last year, with the largest components of the increase being the Voxelgo global commercial launch efforts and Roktavian commercial launch preparation costs.

Moving to bottom line results for the second quarter and first half 2022, just a reminder that during the first quarter of 2022, the company sold the priority review voucher received with the approval of Voxelgo in the United States. While the gain on the sale, the PRV, remains the largest single contributor to, first half gap net income, we are pleased to report gap net income during the second quarter of 2022, totaling $28 million and $149 million for the first half of the year.

We believe there'll be modest and well recognize them in our gross to net revenue adjustment.

Based on this strong first half 2022 performance, we have slightly improved our full year 2022 gap net income guidance range by $10 million to $105 to $145 million.

While we have improved the full year guidance, we recognize that the full year math, in light of $149 million of first half gap net income, suggests that we may recognize a net loss for parts of the second half of the year. This is due to some of the aforementioned revenue timing and some possible larger expense items in, the second half of the year.

We remain confident in our core business generating gap net income this year and beyond. With respect to non-gap income, Q2 2022 non-gap income of $109 million was slightly higher than 2021 second quarter non-gap income of $98 million, and full year 2022 non-gap income guidance remains unchanged at between $350 million to $390 million.

Turning to total cash investment, we ended the second quarter of 2022 with $1.5 billion, flat compared to year-end 2021. The company continues to incur quarterly timing differences in several cash flow categories, mainly working capital timing. However, the business did earn approximately $56 million of operating cash flow during the second quarter of 2022.

In closing, the BioMarin team is pleased to use this midway point of 2022 to both acknowledge, the strong business performance through the first half of the year and the promising expectations for the rest of 2022.

We continue to believe that our strategy of substantially growing revenues that drive increasing profitability and positive operating cash flow, while also investing in developing an innovative pipeline, are the best financial levers to fuel growth further into this decade.

And the way we model it thus far it should fit within what you've observed as sort of normal biomarin gross to net revenue.

So stay tuned for more but that's how we're thinking about it.

And how did you want to answer the question on Retrenchments.

Strategy sure.

Sure you know acknowledging the outcome on the 634 patients.

Suboptimal, we do have research programs.

Under way that.

Or intending to address this you know we have the largest collection of liver biopsy data and it's actually growing and we're learning a lot about mechanisms of of attrition of expression, which could include both sector loss as well as the DNA being there, but RNA expression is diminished.

And so that could encompass.

We have research programs that are looking at things like non viral vector delivery or alternate C serotypes or or other strategies to if you will wake up expression.

But having said that it's six out of 134 or we should also.

Take a look at Johnny Milan Goose presentation that I S T H.

And it goes back to something you just said about how.

The tier two for weird tied the resumption of prophylaxis to being at a sort of 1% that great level, but with Johnny showed was that the what was a you.

You know where there were inflections at five 1% in natural history studies of mutated factory proteins. These appear to be left shifted to lower factor levels with the transgene protein, which is more native and its configuration. So.

For all those reasons I can't say that we view this as a major opportunity right now and so that's why we're in sort of the research phase of <unk>.

Flooring the opportunities to either re dose of reawaken expression.

Thank you for your attention, and we will now open up the call to your questions.

Okay, great. Thanks, guys.

Mhm.

Operator?

Okay.

Next question comes from Phil Nadeau from Cowen and company. Please go ahead.

If you would like to ask a question, please press star 1 on your telephone keypad now, and you will be placed in the queue in the order received.

Good afternoon, thanks for taking our questions are two.

Please be prepared to ask your question when prompted.

Once again, if you would like to ask a question, please press star 1 on your phone now.

Two from US also went on <unk> and one on box will go on Rocky in the press release mentions a likely nine months review for the Refiling.

Whereas this standard Purdue for six months. So we are we're curious as to why you believe in nine months is likely is that something that's been communicated to you by the FDA or is that your own assessment and then.

How would that work would you can actually get a six month to do first and then.

It would be extended when you submit the data that you know in the press release or some other mechanism.

Thanks.

Yeah.

I think we're likely review came along I think we're really simply just reiterating something that we said back in May which is we have an awareness.

Of.

The fact that with the delay as a result of the F. D. A asking pressed for additional information at the time of submission that the review could overlap with the availability of both the three year data as well as the corticosteroid data.

We actually do not want to guide you one way or the other to whether it is likely or it is unlikely.

At the time that we were informed.

By the agency of these additional requests none of those requests were about those additional studies.

As I say, we don't usually guide you one way or the other to the likely or unlikely. However, the purpose of the communication today is to just remind you that that the agency can request additional time for reviews based on either a major amendment major submissions or any other reasons that they feel like they need more time.

And so the way it would work Bill is since that we would get a new paducah date on the acceptance of our.

So the complete response letter.

And at some time during the review if they wanted more time, they would inform us that they want more time and they would extend the paducah clock as well.

Sit here today like I said, we're anticipating the initial submission in September and a six months produce a designation.

But we are aware that these studies are emerging and we wanted you to be aware both to reassure you that first of all that there will be no surprises if it it has to happen.

And to make that very clear and second to reassure you that we're prepared in either direction. So it will be ready for launch if launch happens at the six month time clock.

And we'll be ready to respond quickly to the FDA if they ask for additional data.

That's very helpful and then on Voc Sogo.

The press release notes that Theres 164 patients on commercial therapy in the U S, which implies about 164 patients were added over the first six months of the year is that a pace that we should expect to continue in the second half of the year were there any reasons for bolus in that number or do you think it's possible that it could accelerate in the second half as expert centers get their referral networks up and running.

Thanks.

Great question, Phil. Thank you for paying attention I would guide towards relative continuity of patient growth.

It probably is true that there were patients located in.

And her expert clinics centers.

The participated in the clinical trial other genetic and skeletal dysplasia clinics that are of particular interest in achondroplasia and are treating kids with achondroplasia and probably we got a fast run on it gets from those sources more recently and as we guide.

Two and expect it to all along we've been getting more kids referral referred in from let's call it their community.

Physician and you know as we've guided we're trying to build that referral network to mainly pediatric endocrinologists that can treat these kids was box I'll go on an ongoing basis. So those things are kind of happening at the same time early on.

More patients referred from those extra clinics now our referrals coming in from the community picking up net net.

Yeah, My expectation is relative continuity.

Patient growth in the United States.

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

And our first question comes from Salveen Richter from Golden Text.

Okay.

Our next question come from Palma teeth from Stifel. Please go ahead.

Hi, great. Thanks, so much for taking my questions I wanted to ask a couple of things about <unk> TV uptake in Europe , maybe Jeff could you frame for us just how attitudes towards prophylaxis therapy, and he may vary across European countries, how that might impact the target population for octavian across different countries and.

Yes, when we talk to clinicians just the feedback is really variable on the target population in their mind in terms of early adopters. How are you thinking about the first wave of patients that are most likely to get this drug and what proportion of the overall population does that does that demographic makeup. Thanks so much.

Okay a lot in there.

Yes, there is variability in Europe . It is it is a particular facts that we are focusing on the major markets in Europe .

Early on so what we would now call the EU for <unk>.

Germany, France that I've talked about a lot.

Italy, and Spain, So I would say the main impact on variable adoption in Europe in the first couple of years is going to be our ability to unlock when reimbursement in different markets across Europe . So I would say that piece.

Will trump kind of local treatment practices and preferences.

And remember in Germany.

Particularly with our ability to get outcomes based agreements in early in the one year free pricing period them, Germany is the largest market. We think we will go first there.

Been preparing.

Or for that eventuality, France, being let's call. It the second largest market in Europe , and where we have guided that we are applying for an early access program that will give us a limited but material access if approved.

During the approximately one year that it'll take to gain reimbursement approval fully in France.

Spain, and Italy with a different dynamic so I think it's the geographic piece that introduces most relevant variability in the first couple of years.

In terms of target population and we cant specify for competitive reasons exactly R.

Our our target early adopters, but as noted on the see HMP opinion call. There is there's a couple of factors at work here.

First as you know we've seen a lot of adoption of Libra Libra looks like it's working well for patients.

That's also given the lie to the previous Ah Ah conventional wisdom that.

Hemophilia patients won't won't switch their treatment. So we'll be looking at he labor patients that.

That are looking for superior outcomes, and we'll be looking at a factor of patients that are not adequately controlled on their factor a regimen.

As you know early early adapters.

And in terms of what percent.

We've got lots and lots of market research, but most recently, we went out and have said European and U S physicians and patients and advocacy organizations after.

The phase III two year data results were released.

And what we heard was prescribers think that.

At peak about 35% of their eligible patients would be on RASK ABN and that 80% of prescribers indicated that they were interested in prescribing for at least one basin in the first year. Following approval those are pretty positive signals that too.

Go on.

James Let me just.

Comment on lots of numbers floating around you know.

Docks are being asked off the cost percentage of patients that are going to go to treat with <unk>.

That'd be.

You you got to be careful as to how the questions are traded on the context of the question because.

If the Doctor says well.

Well I mean, it was 10% of my thesis on gene therapy.

Is that a doctor talking about all his or her <unk> ambitions are just as if you want but it says he over 80. So I mean, so this question is answers a rebate, that's where those numbers are all over the place so.

Because 10% of all ages AP, so there's quite a large number.

So I just wanted to point that out.

In terms of being able to understand sometimes the discrepancies between the deep and market research.

Please go ahead.

Great. Thanks very much.

Good afternoon.

Yes.

Our next question comes from Gena Wang from Barclays. Please go ahead.

Thank you for taking my questions.

Thank you for taking my questions also two questions. The first one is if oxoco.

What is the practice practice like in Japan, and Australia are patients also concentrate in the big centers and also other prices for Japan, and Australia in the range of 250000.

And the second question is regarding Octavian.

After your BLA Resubmission when will you know if you will have an outcome do you think of FTE to fishing, whether you're gonna cure will have an outcome for the year.

The program will have a direct read through for you.

Two questions here.

So there's lots of the Japan so.

So thank you Jean at let's start with Japan, So Japan has a.

Large market.

In Japan <unk> for Achondroplasia, and then it is the only market in the world where growth hormone is approved the street achondroplasia now I have oh.

I have personally been to Japan, and talk to investigators and achondroplasia training pediatric endocrinologists and what they've told me is they.

They know the growth hormone doesn't work, but anyway parents are dedicated to getting their patients kids on treatment and that's an available option.

That's actually a really favorable environment than to be bringing box I'll go into because there is a there is an established a treatment network.

Kids are actively under treatment in a way that they arent really in the United States or most other markets and so it's kind of an active market for us to jump into.

Instead of having to build a like we're doing and as I've described for the United States. It is true that we have a switch component and our competition compound that to deal with but we think that now that that's pretty favorable and the way that the Japanese pricing system works with.

With our approval timing there.

<unk> really got a couple of publish references one of the United States and the other is Germany, so that bodes very well for pricing.

One is with regard to your outlook for Octavian, are you ready to launch here?

At a competitive level with Germany, and United States, when we get that far which will which will be just another month or so.

And, you know, once you have revenue from this product, how are margins and profitability expected to be impacted longer term?

And then the second question is just about drug pricing reforms.

Turning to Australia, Australia is also another unique place because we have a really active.

Investigation.

Our investigator in Australia, So there's a really active treatment.

Treatment community for Achondroplasia, and a big appetite for wanting to treat these kids are and help them, including.

Throughout the whole box I'll go Ah clinical development.

Programs. So we're starting out there with a really enthusiastic.

And an experienced investigator.

Australia is a market of 27 million soles compared to about $125 million and span and with with the epidemiology of of Achondroplasia, you would expect that the available market would be in Australia would be about 20% the size of Japan and also.

It takes longer to get reimbursement approval in Australia think a year or even longer. So why is Australia is important.

Australia is important because by the time were two to three years into the global launch Cascade when it comes.

Comes on it is gonna be illustrative of the additional markets in our 78 markets footprint that we bring on board over a period of several years or more to keep the growth of the brand.

Being driven so think of Australia as being one of those mid to late growth drivers and just illustrative of one one market of many that we'll be doing that thanks for the question.

As we're looking at the proposed bill here, how will Biomarin be impacted in just orphan drugs in general?

So.

To answer the question regarding that.

Yes sure.

Yeah, So you know that.

The it's a little hard to answer with deliberate specificity and that's to some extent because a resubmission process is not as structured by the FDA as a original submission you know with the Resubmission. They tell you whether it was the original submission. They tell you what the day 14 filing letter than you have in <unk>.

You know the mid cycle meeting in our late cycle meeting all of which are formal contact points all of which is there going to be an AD com is formally on the agenda. So you kind of know to expect to hear from those and the Resubmission is don't have those same milestone dates. So I think the short answer to your question about where the wheel when when would we know it would be when they tell.

And that's not going to be tied necessarily.

As far as reading off of unit cure and what that means in general for all application or for weather would have an AD com I'd point out that to the best of our understanding the unit cure Paducah date is gonna be sometime in November which means if there was going to be an AD com it would likely be before we submitted that's assuming they.

Stay on track for that in November <unk> action date now.

It's hard to handicap that as well for a variety of different reasons, not least of which is just the public comments that are being made by either unicare CSL are both around.

Working on companion diagnostic and that's the kind of thing that could conceivably. So somebody down. So if that were to happen. Then then intersections of the applications might be more apparent and then the question will get re asked about AD comps, but back to your original question. When will we know we will know only when they tell us.

Not it prescribed milestone dates.

Just wondering if they get carved out to a good degree here.

Okay.

Our next question comes from Robyn Karnataka from true at the Securities. Please go ahead.

Thank you, Salveen, for the question.

Hey, guys. This is coupon for Robyn. Thank you so much for taking our questions or.

Got opinion Heng can you comment on your confidence in your filings or Octavian.

We're filing for September is on track have you submitted.

Any more data since you last updated and have there been any more communications with FDA.

Give you confidence that this is this is going to be the timeline.

And then a question on what's still go Gorilla, you know really impressive bump in patients quite of a quarter, which is in line with your expectations and also maybe it's too early especially in the U S. But any early compliance data points. Thank you.

Thank you.

And in particular, the outlook for Octavian launch in EMEA.

Yeah Yeah.

The confidence comes from.

We are confident that we will be submitting in the September timeframe and the confidence comes from a combination of both in formal communications, we've had with the FDA to just clarify around some specific points about what they're looking for and how they want it presented.

Which all seem straightforward for us and as well just making progress on doing the work.

Having good line of sight. So we're reiterating today, our confidence that we can get the application on.

The F D a but by September .

So again I am sorry.

Jeff can elaborate if I'm getting your question on the long walk sogo.

Yeah, I mean, that's Judy Fox or as long as she is doing better than we anticipated. This is what it was.

On your question here.

And regarding compliance.

Compliance is very very good.

And as far as we can tell we are only.

<unk> heard of about two or three patients to commercial patients.

It continues today that's worldwide.

And actually this is kind of different from <unk>.

I know that he is one of your competitors at least some of Kiwi to I'll call with our U S also be surgeon who claim to have.

<unk>, two or three patients that discontinued blocks. So we have no evidence that.

It did happen.

With a doctor, but Jeff do you want to add.

Yeah, and just to clarify that the compliance.

Drop off where we only have that in the United States. So those figures are relative to our U S experience, but anecdotally, we havent havent.

Heard anything outside of the United States that would be would indicate some other.

Our experience.

Relative to expectations.

We've not been shy however.

The market opportunity for box sogo in achondroplasia, and so relative to expectations I would say that's the adoption curve is just happening faster.

Then than we had built into our original guidance.

But but we thought per year. This is likely to be our biggest pediatric opportunity in the portfolio and the early returns are supportive of that kind of thinking.

Great. Thank you so much.

Super excited about that.

Our next question comes from Matthew Harrison from Morgan Stanley . Please go ahead.

Also have a team in place that's most recently been busy successfully with the Voxogo launch. It is largely that team that will be tasked with the Octavian launch. So good track record there.

Great I. Appreciate you guys fitting me in I guess, two two small ones from me. So first first on on Palin Zeke outside the the treatment center issue and anything else you can do to try and Reaccelerate. The trajectory there and then second just just on diner core.

You know, I would say, what's the reason to believe prospectively in Octavian success in Europe?

And that asset what we know what's happened because I believe I don't know maybe it was two years ago. I think you were close to filing in I N. D. So can you tell us what changes you've had to make in that program in and why you feel confident you'll be able to get towards and I N. D next year. Thanks.

If we get the positive approval from the EC?

I'll start on policy can have yet to continue with his perspective and then.

And I'd go back quickly to what we believe are the five criteria that should be met to set up a successful commercial gene therapy program.

Of which Octavian satisfies all five criteria.

And those include one disease with a significant remaining unmet need, as we've described in hemophilia. To a material treatment effect size, which would include all of clinical effect, quality of life effect and a convenience benefit.

Three would be a pharmacoeconomic benefit, which Octavian is clearly set up to deliver.

And as we've described over and over previously, four would be a material population to treat.

So we believe that a lot of gene therapies that are being developed to treat esoterically small patient populations have limited commercial potential.

Accurate answer the dinosaur question somebody.

But certainly severe hemophilia A adults is a significant large population.

And five would be a prepared team on the ground that is experienced and ready to launch.

So as I said, Octavian meets all of those criteria.

I'll, probably do you guys think about it.

That's the reason to believe in our view.

<unk> is an enzyme and like all enzymes.

And growing slowly but surely.

Mike can take the examples of magnesium and citizens.

A very substantial drags I assure you even starting as fast as box.

Our filing date.

So how does he says he's going to continue to grow and I think we anticipate double digit growth. This.

This year it would be.

The challenge with it.

With the Vicki with sensors, which are <unk>.

Basically in office.

Launch any centers.

And because of Covid is easier.

Tennessee, I D. We open to prioritize.

As with severe disorders, instead of patients with PKU, but we do have a plan that is being implemented to actually now I'll start the patient not only outside of the hospital and if he use sensors also use other prescribers.

Beyond sharing that.

And then Jeff can talk about Jeff Yeah.

Yeah, thanks, Delvin.

Thank you J J exactly correct.

This is Brian.

I'll comment on margin.

The situation for adult PKU patients.

Thanks for the question.

I mean, in short, we believe the Octavian EU launch is going to be a significant contributor to what was already planned.

You know, margin improvement into our future.

Patience is a little unique because historically.

You know, already today, we're observing that the Vox Ogo launch is a contributor.

When we look at our SG&A as an example, as a percentage of revenue today at about 40%, that's, you know, the global infrastructure we've built to support our seven approved products today, which we sell in over 70 countries.

So while it will take some time for Roctavian revenues to ramp, we expect that the investments in operating expenses along the way to be significantly less, which over time is going to contribute to the bottom line in margin improvement.

So we'll look forward to observing that.

Brickley all of their care has come from these PKU clinics that are either part of a larger genetics clinic.

The drug pricing reform impact, do you want to go over that?

Yeah, so the drug pricing reform, should that get through and be legislation, I think it will be impactful to companies that have large Medicare drugs in particular, and companies that have a history and a practice of greater price increases that exceed inflation rates in the United States, CPIU in particular.

Biomarin, our portfolio has very limited exposure in Medicare, and it is not our practice to raise prices ahead of CPIU.

So while we see that it's unfortunate if it moves forward in the general sense, we don't see a material impact to our business.

<unk> or mixed in with the larger genetics clinic at mainly large academic institutions and and that back because really had a huge impact on their their ability to access a life care, which is necessary for talent Z in contrast for <unk>.

Ample to what we've been experiencing with community base pediatric Endocrinologists for example for box yoga wear.

Access is not nearly as impacted so we mentioned the.

The alternative prescriber.

Initiative and the idea there is.

Is to tap into adult endocrinologist that are accustomed to dealing with concept complex therapy.

It's the fact that they haven't historically seen PKU patients doesn't mean that there's not an interest and a natural length, there and an ability to deal with a policy where just in the early stages of a try.

To make that one go in addition, one thing that we did implement them, but over the last year as a begin at home program. So recall under the Rems policy patients have to take their first injection and the presence of a health care professional.

All of them.

Historically that would've been attracted to the PKU clinic for that first injection. So we were able to remove that barrier for new patients that are starting that that's just an example of some of the things that we're doing to try to get around the impact that the pandemic has had on PKU quacks.

We will keep you posted.

Uh huh.

Yeah.

And then second.

Yes.

Yeah, Yeah, So I I don't know where you got the original impression about the filing timeline.

We're actually pretty optimistic about our current filing timeline of them feel like it's at or ahead of schedule slightly Greg Guyer.

Keep checking them answers team has done a lot of work on manufacturing the vector.

Our.

Our preclinical groups have done a lot of work.

Within our core on a human cardiomyocyte as well as doing a lot of work in vivo in animal models of Muslim binding protein G III deficiency.

So we're feeling pretty good but 23 R&D as a possibility.

Along with frequent and nine of course, but no we are.

We're pretty pleased with the progress we've made with planting so far.

And our next question comes from Joseph Schwartz from SBB Securities.

Great. Thank you. Thank you Hank.

Okay.

Our next question comes from Tim Lugo from William Blair. Please go ahead Sir.

Please go ahead.

Oh, Thanks for squeezing me in as well and congratulations on the strong lunch.

Hi, thanks very much.

Can you give us a update on about Gogo for instance, I know you have the investigators study, which should have 52 week data next year. You also have the phase III patients at risk of surgery study ongoing.

Kind of what's just the regulatory strategy for these patients.

Thanks.

Well, so you mentioned a bunch of different things and so so quickly just.

Talk about the children.

Children with no other recognize morbidities.

We completed the so called to a six phase two study trends in the right direction I think reasons to believe that that could lead to a label Amendment are.

To some extent patients globally on other health authorities acceptance of the data that we provided so far.

But also that the biology and the unmet need here are very strongly favorable.

The results trending in the right direction could be viewed as meeting the bar the reasons not to believe our S E.

Can get hung up on things like the values and and that sort of thing.

And then we do have a study in children.

Who have potential risk for premium Magnum compression I believe that is.

Is completely enrolled nearly completely enrolled at this point with a data readout to come and then finally, we have some.

Work going on with the N I S T with Doctor Dawber at children's in D. C. That's exploring the activity of OXXO go in children with mutations other than the one that causes achondroplasia, which is also very encouraging and that we'd do some signs preliminary signs of enhanced growth after a run in period.

So again this goes back to our very early much earlier question about the things that we're doing to build out the Buck Sogo brand.

In its lifecycle to demonstrate the value of across the spectrum of agents a spectrum of delivery kinds of considerations of spectrum of potentially a spectrum of indications.

Alright, thank you.

Our next question comes from a cash Tiwari from Jefferies. Please go ahead.

Hi, This is heavy for Akash. Thanks for taking all the questions. We have one quick question Alex logo.

Have you already touched on these topics during the call regarding the phase two data in the three indications you presented at <unk> earlier. This year can you comment on the development timeline now so how do you forget at one P M.

Is that the case she would you pursue like.

Accelerated approval for this indication and when can we expect to hear updates on those thank you.

Yes.

Pension, yes, I just mentioned that that study by Dr. Dobber is still very much in flight.

And and there doesn't need to be a lot of regulatory interaction around the design of clinical trials.

What about sugar outside of achondroplasia indication.

I don't want to set a specific timeline of expectations at this point as we're still in the process of strategizing and engaging health authorities. We will provide updates when we have specific updates to provide but we are very encouraged by the activity that talks about brewers demonstrating improving height.

Hi, this is very much what was predicted.

Biologically well before we completed the phase III trial with not so good at comparable Asia.

So we do have a great deal of passion to try to find pathways to make this novel.

Natural regulator of bone growth available to patients with other statutory deficiencies besides achondroplasia.

Okay.

Thank you.

Okay.

Our next question come from that chit chat too, but how are you.

Guggenheim Partners. Please go ahead.

Hey, Thanks for taking my questions. So I've got a couple on books. So go on what's the net price and ex U S territories right now and then on rock Tavy and how should we think about the number of hub centers in Germany. Initially and then the three major markets over the remainder of say 23.

Thanks, so much.

Sure that's right ex U S.

Yeah. So.

So far in box ago. The listed prices are in Germany, and the United States. We've previously disclosed that we are close to.

Getting a finalized a price on reimbursement.

Post the one year free pricing period in Germany, and that will involve a.

Confidential discount so.

So we won't be disclosing those confidential discounted prices, so far what we've been able to achieve and other named patient sales markets.

Around the world is a prices.

Reasonably close to what we see in the United States and in Germany. So far over time those prices are going to go down as we complete reimbursement deals and as we have guided since.

Prior to the launch of boss yoga, but nothing more particular to report there and sorry to your question about rock TVN in Europe in 2022 is sorry, I missed that one.

So I was wondering how should we think about the number of hub centers, because I believe it's a hub and spoke model that's being talked about in terms of screening patients and identifying patients from that neutralizing antibody perspective.

From a number of hub centers that you would likely need in Germany, and in France, Italy, and Spain between now and end of the end of 2023.

Yeah.

Great question, So just to put out on the table that Havent spoke model was was published by the European Hemophilia community. So you can find more in the May 2020, and leave September 2021.

Publication of hemophilia.

That describes that initiative more completely that's not a biomarin initiative that is a European hemophilia community initiative, so back to Germany, and France, I think low double digits of hub centers in each country, which is which is really nice because it'll allow us to both.

Guess on relatively small number of centers get them trained and in service and ready to treat patients and then we will have a relatively small number of centers that are gaining critical experience actually treating those.

Those patients in the hub and spoke model would involve essentially.

You know the work up a patient at the smoke.

Hemophilia treatment center referral in for treatment referral back out to the slopes for a post treatment follow up thank.

Thank you.

Appreciate it thank you so much.

Our next call.

Next question comes from.

And looking at that person went out.

Okay. It looks like the call we run out of time, So we're going to turn the call back to our CEO Biomarin fee O J D of your enemy for closing remarks.

Congrats on the great quarter.

Thank you operator, and thank you all for joining us today. So our results in the first half of the year underscore the strength of our brands and our execution across the organization Asics as reported. The addition of OXXO go to our commercial path forward.

I have a question on Voxogo and then Roctavian.

So I was curious if you could talk about whether you're working on any lifecycle management strategies to fortify your Econdroplasia franchise ahead of potential competition.

Are you still working on long-acting formulations?

And can you give us an update on that status?

And are you doing anything to improve the administration device or procedure or generate more data to show the real-world value of Voxogo so your brand could have more staying power if competition arrives?

Thank you.

Just a few words about the device.

Important component of our growth story.

Seeing the way for <unk>.

GAAP profitability this year and beyond.

I'll let Hank answer the rest of the question.

So we look forward to the potential launch of our next significant opportunity wisdom teeth in Europe . Later this year, so I would say combined with.

Yes, so we have an answer.

We do have a planned device in late-stage development, which we hope could hit the market around 2024. It will make the administration of the drug even easier.

Actually, maybe Greg Geyer is in charge of this device.

I had a couple on Roctavian So, the first one is, as you approach the European approval, maybe what have you done, or can you do to inform the cost-benefit analysis?

Maybe he can say a few words.

I wasn't sure if there's any extra work that you guys had done as you approached the approval, just to talk to some of the payers about, you know, obviously the price tag.

And then we'll have Hank answer your question on the long-acting formulation and other lifecycle activities.

And I know, JJ, you did talk about, you know, the model shifting away from, you know, kind of an annualized kind of model into a single, you know, single payment.

Greg, you want to say a few words?

And then the second question, also on Roctavian, is just, Hank, when you look at the potential for retreatment and using a different, you know, expression vector or viral vector, maybe just give us a status update on anything you're doing there.

I'll just start, and then I'll have Jeff, and then Brian will be doing the, revenue recognition plans for Roctavian revenues, and then Hank on your last question.

Yeah, thanks, JJ.

Thank you.

So, indeed, we are, as compared to where we were like two, three years ago, where we thought that payers, whether it's in Europe or the U.S., would be interested in pay-over-time, they actually are not interested.

So, yeah, so the PIN device is well underway. We do believe it will be a step change in terms of convenience for patients and a lot simpler to administer.

Thanks, Jeff.

They're not organized for that because most of them work on an annual budget, so their difficulty is committing to paying over three, four, five years.

So that's well underway.

We no longer would leave that.

We thought, you know, before that it would be interesting for them, but it's not something that can work.

We've got some studies we need to do with the PIN, and then obviously the approval process.

Our next question comes from Phil Nadeau from Cowan & Company.

However, they're extremely interested in outcome-based agreements, and Jeff and Brian can explain the mechanics of that.

So hopefully that will hit the market in the U.S. and in Europe in 2024.

Please go ahead.

And also, just the only thing I would add here is that I would say, based on the very strong phase 2 data that we have that now shows durability of bidding protection for basically six years, we believe we are in a strong position to put these agreements in place.

Go ahead, Hank.

Both of these drugs will drive substantial value for our patients our employees and our shareholders over the next few years. So thank you all for your continued support and.

Good afternoon.

Biomarin Pharmaceutical Inc. is a company that has a very low risk to biomarine and in a sense eliminates the cost-risk for the payers and eliminates this whole question of durability is basically evacuated without outcome-based agreements because there is no risk for the payers in case the durability is not as low as they anticipated so that preamble just that you can explain exactly what we're thinking about and Brian talked about record viewers, recognition and then I can answer the last question.

Sorry.

Thanks for taking our questions.

Also, two questions.

Yeah thanks JJ so we've got the outcome-based agreements that we are working towards and that we've discussed in many instances with European payers notably Germany which will be our first launch and as JJ said we're taking with those agreements the risk of non-response and the risk of durability over time off the table for the payers so that addresses their uncertainty and based on the clinical trial data that we've got both the phase 3 full data set at two years early cohort at three years and the phase 1 to 60 13 dose data six years we judged that the risk of non-response is very very low and the risk of going back to prophylaxis which is essentially what we would be guaranteeing through a period of time in these agreements is also similarly low.

Oh, sorry, Joe.

Two from us, also one on Roctavian and one on Voxelgo.

The first one is a Voxogo.

A relevant public analysis I would refer you back to is the ICER analysis from two years ago which concluded that at the time that Roctavian was a superior choice to standard of care at a presumed price of two and a half million dollars the data behind Roctavian has materially filled in in the ensuing two years so we expect that that type of incremental cost-effectiveness analysis will still hold and as you know every payer system in Europe has slightly different unique requirements and so we prepare such incremental cost-effectiveness for analyses and cost-benefit analyses bespoke for all of those systems we're getting ready to file in the major EU markets shortly after an anticipated approval so I think we're ready to go here.

I was going to say the thing I would add about, the question about the lifecycle, and there's very robust plans.

On Roctavian, the press release mentions a likely nine-month review for the refiling, whereas the standard PDUFA is six months.

What is the practice like in Japan and Australia?

And then Jeff thanks this is Brian briefly on the other financials and we'll elaborate more on the details of this yeah at our anticipated launch but as JJ noted we would expect upfront not just payment but revenue recognition for Roctavian as we deliver to customers and and on these outcomes-based agreements we'll need to recognize the the financial exposure from these commitments to customers although as Jeff noted because of the real strong response rates and durability in, Roctavian I believe it was only six out of 134 patients in the phase 3 study that have resumed prophylaxis that's going to mean that when we estimate what will be

Immediately next up is interactions with the Food and Drug Administration around broadening the label in the United States as it is more appropriately represented on a global basis.

So we're curious as to why you believe nine months is likely.

Are patients also concentrate in the big centers?

The balance sheet reserves are liabilities to capture these commitments.

As you recall, Japan just, approved the product unrestricted in regard to the younger limit of age.

Is that something that's been communicated to you by the FDA, or is that your own assessment?

And also, are the prices for Japan and Australia in the range of 250,000?

We believe they'll be modest and we'll recognize them in our growth to net revenue adjustment. And the way we model it thus far, it should fit within what you've observed as sort of normal Biomarin growth to net revenue.

So that's a key piece of fortifying the franchise.

And then how would that work?

And the second question is regarding Roctavian.

So stay tuned for more, but that's how we're thinking about it.

The pen you've heard a lot about.

Would you initially get a six-month PDUFA, and then it would be extended when you submit the data that you know in the press release, or is there some other mechanism?

After your BLA resubmission, when will you know if you will have an outcome?

Hank, do you want to answer the question on retreatment strategies?

The conversion to full approval on the basis of final adult height very much in motion.

Yeah, I'm just going to say where likely review came along.

Do you think FDA decision on whether Unicure will have an outcome for their hemophilia B program will have a direct read-through for you?

Thank you so much for taking our question.

Sure.

Very important from a regulatory perspective to fortify the brand.

I think we're really simply just reiterating something that we said back in May, which is we have an awareness of the fact that with the delay as a result of the FDA asking for us for additional information at the time of submission, that the review could overlap with the availability of both the three-year data as well as the corticosteroid data.

So, Voxogo, Japan.

On Roktavian, Hank, can you comment on your confidence in U.S. filing for Roktavian, that the U.S. filing for September is on track?

Acknowledging the outcome on the 634 patients is suboptimal. We do have research programs underway that are intending to address this.

Lots of emerging information about potential for activity and additional indication work beyond achondroplasia.

We actually do not want to guide you one way or the other to whether it is likely or it is unlikely.

Thank you, Gina.

Have you submitted any more data since you last updated and have there been any more communications with FDA that give you confidence that this is going to be the timeline?

So thank you all for your continued support, and we look forward to seeing you soon.

We have the largest collection of liver biopsy data and it's actually growing and we're learning a lot about mechanisms of attrition of expression, which could include both vector loss as well as the DNA being there, but RNA expression is diminished.

And maybe the final thing to say is, in taking a really long view, that, you know, sort of the pen is step one in delighting the population with an easier and simpler approach to administration.

At the time that we were informed by the agency of these additional requests, none of those requests were about those additional studies.

Let's start with Japan.

And then a question on Waxilgo growth, you know, really impressive bump in patients quarter over quarter.

And so that could encompass, and we have research programs that are looking at things like non-viral vector delivery or alternative serotypes or other strategies to, if you will, wake up expression.

We look forward to see you.

We do have a long-acting program, and we're thinking about, as we get more experience, in this population, what might be even better than that?

So, as I say, we don't wish to guide you one way or the other to the likely or unlikely.

So, Japan is a large market, and Japan is unique for achondroplasia in that it is the only market in the world where growth hormone is approved to treat achondroplasia.

Was this in line with your expectations and also maybe still early, especially in the U.S., but any early compliance data points?

But, you know, having said that it's six out of 134, we should also take a look at Johnny Malango's presentation at ISTH.

And so we have a lot of activity going on that will play itself out over a number of years to make Voxego into an even bigger brand than you can see just based on this launch.

However, the purpose of the communication today is to just remind you that the agency can request additional time for reviews based on either major submissions, or any other reasons that they feel like they need more time.

Now, I have personally been to Japan and talked to investigators in achondroplasia treating pediatric endocrinologists, and what they've told me is they know that growth hormone doesn't work, but anyway, parents are dedicated to getting their kids on treatment, and that's an available option.

Thank you.

Use it.

And it goes back to something that Jeff said about how, you know, the here to four, we had tied the resumption of prophylaxis to being at a sort of 1% factory level.

And our next question comes from Jeff Beecham from Bank of America.

And so the way it would work, Bill, is that we would get a new PDUFA date on acceptance of our response to the complete response letter.

That's actually a really favorable environment, then, to be bringing Voxogo into because there is an established treatment network.

Yeah, the confidence comes from, you know, we are confident that we will be submitting in the September timeframe.

But what Johnny showed was that what was, you know, where there were inflections at five and 1% in natural history studies of mutated factory proteins, these appear to be left shifted to lower factor levels with the transgene protein, which is more native in its configuration.

Please go ahead.

And at some time during the review, if they wanted more time, they would inform us that they want more time and they would extend the PDUFA clock.

Acon kids are actively under treatment in a way that they aren't really in the United States or most other markets, and so it's kind of an active market for us to jump into instead of having to build like we're doing, and as I've described, for the United States.

And the confidence comes from a combination of both informal communications we've had with the FDA to just clarify around some specific points about what they're looking for and how they want it presented, which all seem straightforward for us.

This concludes today's conference call. Thank you for attending.

This concludes today's conference call.

So for all those reasons, I can't say that we view this as a major opportunity right now.

Hey, guys.

As we sit here today, like I said, we're anticipating the initial submission in September and a six-month PDUFA designation.

It is true, then, that we have a switch component and a competition component to deal with, but we think that net-net, that's pretty favorable, and the way that the Japanese pricing system works with our approval timing there, we've really got a couple of published references.

And as well, just making progress on doing the work and having good line of sight.

So that's why we're in sort of the research phase of exploring the opportunities to either redose or reawaken expression.

Congrats on the quarter, and thanks for the question.

But we are aware that these studies are emerging, and we wanted you to be aware, both to reassure you that, first of all, that there will be no surprises if it is to happen and to make that very clear, and second, to reassure you that we're prepared in either direction.

One is the United States, and the other is Germany, so that bodes very well for pricing at a competitive level with Germany and the United States when we get that far, which will be just another month or so.

So we're reiterating today our confidence that we can get the application on into the FDA by September.

Okay, great.

Thank you for attending.

So we'll be ready for launch if launch happens at the six-month time clock, and we'll be ready to respond quickly to the FDA if they ask for additional data.

Turning to Australia, Australia is also another unique place because we have a really active investigation or investigator in Australia, so there's a really active treatment community for achondroplasia and a big appetite for wanting to treat these kids and help them, including throughout the whole Boxogo clinical development.

So maybe Jeff can elaborate better regarding your question on Waxilgo.

Thanks, guys.

That's very helpful.

Program, so we're starting out there with a really enthusiastic and experienced investigator.

Yeah, I mean, actually Waxilgo's launch is doing better than we anticipated.

And then on VoxOgo, the press release notes that there's 164 patients on commercial therapy in the U.S., which implies about 164 patients were added over the first six months of the year.

Australia is a market of 27 million sold compared to about 125 million in Japan, and with the epidemiology of achondroplasia, you would expect that the available market would be in Australia would be about 20% the size of Europe.

This is what was behind your question here.

Is that a pace that we should expect to continue in the second half of the year?

It also takes longer to get reimbursement approval in Australia, I think a year or even longer.

And regarding compliance, compliance is very, very good.

Were there any reasons for bolus in that number, or do you think it's possible that it could accelerate in the second half as expert centers get their referral networks up and running?

So why is Australia important?

As far as we can tell, we have only heard of about two or three patients, commercial patients that have discontinued to date worldwide.

Thanks.

Australia is important because by the time we're two to three years into the global launch cascade, when it comes on, it is going to be illustrative of the additional markets in our 78 market footprint that we bring on board over a period of several years or more.

And actually, this is kind of different from, I know there is one of your competitors that did some QL call with our U.S. orthopedic surgeon who claims to have by himself two or three patients that discontinued Waxilgo.

Great question, Phil.

To keep the growth of the brand being driven, so think of Australia as being one of those mid to late growth drivers and just illustrative of one market of many that will be doing that.

We have no evidence that it happened with that doctor.

Thank you for paying attention.

Thanks for the question.

But Jeff, you want to add?

The host has ended this call.

The host has ended this call goodbye.

I would guide towards relative continuity of patient growth.

So, Hank, do you want to answer the question regarding outcome?

Yeah, and just to clarify, the compliance and persistence drop off, we only have that in the United States.

It probably is true that there were patients located in expert clinic centers, those that participated in the clinical trial, other genetic and skeletal dysplasia clinics that have a particular interest in achondroplasia, and are treating kids with achondroplasia.

Yeah, sure.

So those figures are relative to our U.S. experience.

Goodbye.

And probably, you know, we got a fast run on kids from those sources.

Yeah, do you know that the it's a little hard to answer with deliberate specificity and that's to some extent because a resubmission process is not as structured by the FDA as a original submission with a resubmission.

But anecdotally, we haven't heard anything outside of the United States that would indicate some other experience.

More recently, and as we've guided to and expected to all along, we've been getting more kids referred in from, let's call it their community physician.

They tell you with an original submission, they tell you what the day 14 filing letter and you have an early, you have a mid cycle meeting and a late cycle meeting, all of which are formal contact points.

But we've thought for years that this is likely to be our biggest pediatric opportunity in the portfolio, and the early returns are supportive of that kind of thinking.

And, you know, as we've guided, we're trying to build that referral network to mainly pediatric endocrinologists that can treat these kids with Boxogo on an ongoing basis.

All of which is there going to be an ad comments formally on the agenda.

Thank you so much.

So those things are kind of happening at the same time.

So you kind of know to expect to hear from those and the resubmissions don't have those same milestone dates.

Our next question comes from Matthew Harrison from Morgan Stanley.

Early on, more patients referred from those expert clinics.

So I think the short answer to your question about whether we'll, when would we know it'd be when they tell us and that's not going to be tied necessarily.

Please go ahead.

Now, referrals coming in from the community picking up.

You know, as far as reading off of Unicure and what that means in general for our application or for whether they have an adcom, I'd point out that for the best of our understanding, the Unicure PDUFA date is going to be sometime in November, which means if there was going to be an adcom, it would likely be before we submitted. That's assuming they stay on track for that November PDUFA action date.

Great.

Net net, you know, my expectation is relative continuity of patient growth in the United States.

Now, it's hard to handicap that as well for a variety of different reasons, not least of which is just the public comments that are being made by either Unicure, CSL or both around, you know, working on companion diagnostic and that's the kind of thing that could conceivably slow somebody down.

I appreciate you guys fitting me in.

That's very helpful.

So if that were to happen, then the intersections of the applications might be more apparent and then the question will get re-asked about adcoms.

I guess two small ones for me.

Thanks again for taking our questions.

But back to your original question, when will we know?

So first on Palanzec, you know, outside the treatment center issue, anything else you can do to try and re-accelerate the trajectory there?

Our next question comes from Paul from faithful.

We will know only when they tell us and not at prescribed milestone dates.

And then second, just on Dynacor and that asset, what's happened?

Please go ahead.

Our next question comes from Robyn Karnauskas from Truett Securities.

Because I believe, I don't know, maybe it was two years ago, I think you were close to filing an IND.

Great.

Please go ahead.

So can you tell us what changes you've had to make in that program and why you feel confident you'll be able to get towards an IND next year?

Thanks so much for taking my questions.

Hey guys, this is Kripan for Robyn.

Thanks.

I wanted to ask a couple of things about rock TV and I'm taking Europe.

I'll start on Palanzec and have Jeff continue with his perspective and then actually answer the Dynacor question.

Maybe Jeff, could you frame for us?

On Palanzec, I think, you know, Palanzec is an enzyme and like all enzymes, it grows slowly but surely.

Just how attitude towards prophylaxis therapy and he may vary across European countries.

You can take the examples of Magnesam and Levizem that are very substantial drugs that can even start as fast as Vox as Palanzec.

How that might impact the target population for Octavian across different countries.

So Palanzec is going to continue to grow and I think we anticipate double digit growth this year.

And I guess when we talk to clinicians, just the feedback is really variable on the target population in their mind in terms of early adopters.

There's been a challenge with the PKU centers, which are basically an office in large genetic centers. And because of COVID, indeed, they had a tendency as they reopened to prioritize patients with severe disorders instead of, you know, patients with PKU.

How are you thinking about the 1st wave of patients that are most likely to get this drug and what proportion of the overall population does that does that demographic makeup?

But we do have a plan that is being implemented to actually now start the patients not only outside of the hospital and the PKU centers, but also use other prescribers beyond geneticists that Jeff can talk about.

Thanks so much.

Yeah, thank you, JJ.

Okay, a lot in there.

Exactly correct.

Yes, there is variability in Europe.

The situation for adult PKU patients is a little unique because historically all of their care has come from these PKU clinics that are either part of a larger genetics clinic, or mixed in with a larger genetics clinic at mainly large academic institutions. And that fact has really had a huge impact on their ability to access live care, which is necessary for Palanzec.

It is it is a particular fact that we are focusing on the major markets in Europe early on.

In contrast, for example, to what we've been experiencing with community-based pediatric endocrinologists, for example, for Voxoga, where access is not nearly as impacted.

So what we would now call that you for Germany, France that I've talked about a lot Italy and Spain.

So we mentioned the alternate prescriber initiative, and the idea there is to tap into adult endocrinologists that are accustomed to dealing with complex therapy.

So I would say the main impact on variable adoption in Europe in the 1st couple of years is going to be our ability to unlock reimbursement in different markets across Europe.

And the fact that they haven't historically seen PKU patients doesn't mean that there's not an interest and a natural link there and an ability to deal with Palanzec.

So I would say that piece will Trump kind of local treatment practices and preferences and remember in Germany, particularly with our ability to get outcomes based agreements in early in the 1 year free pricing period.

We're just in the early stages of trying to make that one go.

Germany is the largest market.

In addition, one thing that we did implement over the last year is a begin-at-home program.

We think we'll go 1st there and have been preparing that for for that eventuality France being let's call it the 2nd largest market in Europe and where we've guided that we are applying for an early access program that will give us limited but material access of approved during the approximately 1 year that it'll take.

So recall under the REMS, Palanzec patients had to take their first injection in the presence of a healthcare professional. Historically, that would have meant a trip to the PKU clinic for that first injection.

To gain reimbursement approval fully in France, Spain, Italy with different dynamics.

So we were able to remove that barrier for new patients that are starting. That's just an example of some of the things that we're doing to try to get around the impact that the pandemic has had on PKU clinics.

So I think it's the geographic piece that introduces most relevant variability in the 1st couple of years in terms of target population.

And we'll keep you posted.

And we can't specify for competitive reasons exactly our target early adopters.

I don't know where you got the original impression about the filing timeline because we're actually, pretty optimistic about our current filing timeline and feel like it's at or ahead of schedule slightly.

But as noted on the opinion call, there's a couple of factors at work here.

Greg Guyer, our Chief Technical Officer's team has done a lot of work on manufacturing the vector and our preclinical groups have done a lot of work with Dynacore on human cardiomyocytes as well as doing a lot of work in vivo in animal models of myosin-binding protein C3 deficiency.

1st is we've seen a lot of adoption in Libra.

So we're feeling pretty good that a 23-IND is a possibility along with C49, of course, but we're pretty pleased with the progress we've made with Dynacore, Great.

It looks like it's working well for patients.

Thank you.

That's also given the lie to the previous conventional wisdom that hemophilia patients won't won't switch their treatment.

Thank you, Hank.

So, we'll be looking at labor patients that are looking for superior outcomes and we'll be looking at factor patients that are are not adequately control on their factory regimen as early early adapters.

Our next question comes from Tim Lugo from

And in terms of what percent, we've got lots and lots of market research, but most recently, we went out and tested European and U. S. physicians and patients and advocacy organizations after the, the phase 3 2 year data results were released, and what we heard was prescribers think that at peak about 35% of their eligible patients would be on roctavian and that 80% of prescribers indicated that they were interested in prescribing for at least one patient in the first year following approval. Those are pretty positive signals to go on.

William Blair.

Can you tell me just a comment on, there are lots of numbers floating around, you know, docs are being asked off the cuff, you know, percentage of patients they're going to treat with gene therapy.

Please go ahead, Tim.

You have to be careful as to how the questions are phrased on the context of the question because if a doctor says, I'm going to put 10% of my patients on gene therapy, is that doctor talking about all his or her hemopoietic patients or just the severe ones or the severe over 80?

Thanks for squeezing in as well and congratulations

So, I mean, so this question's answers are pretty vague.

on the strong launch.

That's why some numbers are all over the place.

Can you give us an update on about DOGO for infants?

So, because 10% of all hemopoietic patients, 80% is a pretty large number.

I know you have the investigators study, which should have 52-week data next year.

So, I just want to point that out in terms of being able to understand sometimes the discrepancies between the different marketing research.

You also have the 206 phase 2 patients at risk of surgery study ongoing.

Great.

What's just the regulatory strategy, for these patients?

Thanks very much.

Well, so you mentioned a bunch of different things.

Our next question comes from Gina Wang from Barclays.

So let's talk about children with no other recognized morbidities.

Please go ahead.

We completed this so-called 206 phase 2 study.

Thank you for taking my questions.

Trends in the right direction.

I think reasons to believe that that could lead to a label, amendment are, to some extent, based globally on other health authorities' acceptance of the data that we've provided so far, but also that the biology and unmet need here are very strongly favorable and the results trending in the right direction could be viewed as meeting the bar.

The reasons not to believe are FDA can get hung up on things like T-values and that sort of thing.

And then we do have a study in children who have potential risk for foramen magnum compression.

I believe that is completely enrolled or nearly completely enrolled at this point with a data readout to come.

And then finally, we have some work going on with an IST with Dr. Dauber at Children's in D.C. that's exploring the activity of Oxogo in children with mutations other than the one that causes achondroplasia, which is also very encouraging in that we do see preliminary signs of enhanced growth after a run-in period.

So, again, this goes back to a much earlier question about the things that we're doing, to build out the Oxogo brand in its life cycle to demonstrate the value across a spectrum of ages, a spectrum of delivery, kinds of considerations, a spectrum of...potentially a spectrum of indications.

All right, thank you.

Our next question comes from Akash Tewari from Jefferies.

Please go ahead.

Hi, this is Ivy for Akash.

Thanks for taking our question.

We have one

quick question on Oxogo.

I knew you already touched on this topic during the call, but regarding the phase two data in the three new indications you presented at NEF earlier this year, can you comment on the development timeline and also how will you further advance these indications?

Is there a potential to pursue, like, accelerated approval for these indications, and when can we expect to hear updates on those?

Thank you.

Yes, as I just mentioned, yes, I just mentioned that that study by Dr. Dauber is still very, much in flight.

And, and there does need to be a lot of regulatory interaction around the design of clinical trials for Voxego outside of the Acondroplasia indication.

Don't want to set a specific timeline of expectation at this point, as we're still in the process of strategizing and engaging health authorities will provide updates when we have specific updates to provide.

But we are very encouraged by the activity that Dr. Dauber is demonstrating improving height.

This is very much what was predicted biologically well before we completed the phase three trial of Voxego and Acondroplasia.

So we do have a great deal of passion to try to find pathways to make this novel, you know, natural regulator bone growth available to patients with other statural deficiencies besides Acondroplasia.

Thank you.

Our next question comes from Debjit Chattopadhyay from Guggenheim Partners.

Please go ahead.

Hey, thanks for taking my questions.

So I've got a couple on Voxego.

What's the net price in ex-US territories right now?

And then on Roktavian, how should we think about the number of hub centers in Germany initially, and then the three major markets over the remainder of, say, 2023?

Thanks so much.

So the net price ex-US, so far in Voxego, you know, the listed prices are in Germany, and the United States.

We've previously disclosed that.

We are close to getting a finalized price on reimbursement post the one-year free pricing period in Germany, and that will involve a confidential discount. So we won't be disclosing those confidential discounted prices.

So far, what we've been able to achieve in other inpatient sales markets around the world is a price that's reasonably close to what we see in the United States and Germany so far.

Over time, those prices are going to go down as we complete reimbursement deals and as, we have guided since, you know, prior to the launch of Voxego, but nothing more particular to report there.

And sorry, your question about Roktavian in Europe in 2022, sorry,

I missed that one.

So I was wondering, how should we think about the number of hub centers?

Because I believe, it's a hub-and-spoke model that's being talked about in terms of screening patients and identifying patients from the neutralizing antibody perspective.

So from a number of hub centers that you would likely need in Germany and in France, Italy, and Spain between now and end of 2023.

Great question.

So just to put out on the table, that hub-and-spoke model was published on by the, European hemophilia community.

So you can find more in the May 2020 and, I believe, September 2021 publication of hemophilia that describes that initiative more completely.

That's not a, BioMarin initiative.

That is a European hemophilia community initiative.

So back to Germany and France, think low double digits of hub centers in each country, which is really nice because, it'll allow us to focus on relatively small number of centers, get them trained and in service and ready to treat patients. And then we'll have a relatively small number of centers that are gaining critical experience actually treating those patients. And the hub-and-spoke model would involve essentially the workup of the patient at the spoke hemophilia treatment center, referral in for treatment, referral back out to the spokes for post-treatment follow-up.

Thank you.

Appreciate it.

Thank you so much.

Our next question comes from, it looks like that person went out of key.

Okay, it looks like the call, we run out of time.

So we're gonna turn the call back to our CEO,

Biomarin CEO, JJ Bien-Aimé, for closing remarks.

Thank you, operator, and thank you all for joining us today.

So our results in the first half of the year, underscore the strength of our brands and our execution across the organization.

As reported, the addition of VoxLogo, to our commercial portfolio is an important component of our growth story, and it does pave the way for gap profitability this year and beyond.

So we look forward to the potential launch, of our next significant opportunity with Octavian in Europe later this year.

I would say combined with VoxLogo, we believe that both of those drugs will drive substantial value for our patients, our employees, and our shareholders over the next few years.