Q1 2022 Biomarin Pharmaceutical Inc Earnings Call

Good day, and thank you for standing by welcome to the Biomarin first quarter 2017.

Operator: Good day and thank you for standing by.

Operator: Welcome to the Biomarin First Quarter 2022 Financial Assaults Conference Call.

<unk> financial results conference call.

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

Operator: Thank you for participating.

Hosting the conference call today from Biomarin is J P mccurdy.

Vice President of Investor Relations. Please go ahead Traci.

Operator: Please go ahead, Traci.

Operator: You may now disconnect.

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

Operator: Thank you, Ashley.

Thanks.

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 with Biomarin products programs actions of regulatory authorities availability of capital future actions in the pharmaceutical market and developments by competitors and those factors detailed in <unk> filings Securities and Exchange Commission such as 10-Q.

Your 10-K report.

Operator: Thank you, everyone, for joining us today.

On the call today from Biomarin management are.

The enemy Chairman and Chief Executive Officer, Jeff <unk> 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 to our chairman and CEO J J P. MMA.

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

Operator: On the call today from Biomarin Management are JJ Bien-Aimé, Chairman and Chief Executive Officer, Jeff Ager, Executive Vice President,

Thank you Tracy.

Thank.

Thank you for joining us today so.

Operator: Chief Commercial Officer, Hank Dukes, President, Worldwide Research and Development, Greg Geyer, Executive Vice President,

So we begin.

Two boys for significant growth.

And the transition to sustainable GAAP profitability.

Interesting box it'll go from assembly seeking a treatment option.

Addresses the underlying cause of that you can grow.

Has been very positive as underscored by today's increase in full year 2022 boxes guidance to between 100 million and $125 million.

We also reaffirm previously released financial guidance for all other metrics.

Yes.

Full year 2022 guidance.

Operator: Chief Technical Officer, and Brian Mueller, Executive Vice President and Chief Financial Officer.

So we generated 519 used record revenues in the first quarter.

Representing 11% growth year over year, excluding <unk>.

The startup offerings returns are significant.

Well different drugs.

The revenues for products marketed by Biomarin were up 15%, including through that so really off to a.

Strong start in June .

Our revenue growth.

Over the next few years.

So these results highlight the strength of our base business.

And the significant opportunity that lies ahead with box suitable.

It is important to note that <unk>.

$13 million of the $20 million.

Total for the first quarter because October sales were from outside the United States.

Emphasizing the breadth of our global footprint and commercial capabilities.

And the importance of the ex U S markets.

This will be done.

As we prepare for the potential European launch of our rotation in the second half of this year.

The potential U S approval.

We just finished.

And robust global launch of OXXO, who are tracking to plan.

Look forward to the race to the next important regulatory steps with them okay.

You were there.

Theyre coming months.

People with hemophilia.

Seeking PAA.

Troll and <unk>.

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Suggest that up to your corporate actually please keep forgiving.

Presenting next training.

Treatment option based on the results that we are observing a piece too.

The phase III study.

We believe these data provide supportive evidence of efficacy.

Part of the marketing authorization application currently under review in Europe and plan for inclusion in our BLA for Resubmission.

In late June .

Operator: I will now turn the call over to our Chairman and CEO, JJ Bien-Aimé.

We were also pleased to share that use today and we have completed the genomic analysis of the salivary gland that only participant.

To date, we spent 300 over five years ago.

JJ Bien-Aime: Thank you, Tracey, and good afternoon, everyone.

The findings from the completed analysis did not identify if you did that.

After integration contributed to the salivary gland.

This is great news for patients and the safety profile of Octavius and actually before they enter our AAV gene therapy.

And if we see a few more words on this.

As we go forward.

The remainder of 2022.

Thank you.

To achieving the goals set forth.

Out of the year.

Turning the corner.

Does it really well.

Wrapping up our largest pediatric opportunity today between Portugal.

And progressive or TV applications with health authorities in Europe , and the United States.

Advent advancing the broadest.

The exchange rate in our history.

We will continue to build on these financial commercial and regulatory momentum is likely to appeal.

The transition to an earnings growth alright.

JJ Bien-Aime: Thank you for joining us today.

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

JJ Bien-Aime: So we begin 2022, of course, for significant growth and the transition to sustainable gap profitability.

Thank you J J I'm very pleased with our performance in the first quarter of 2022 recording $119 million in total revenues with 20 million Pops logo contributions in the first quarter Grub increase but they'll go in 2022 full year guidance to between 100 million and $100.

JJ Bien-Aime: Interest in VoxOvo from families seeking a treatment option that addresses the underlying cause of econdropasia has been very positive, as underscored by today's increase in food year 2022 VoxOvo guidance to between $100 million and $125 million.

$45 million and will be an important component of our 2022 growth story.

Now turning to the specifics of the box they'll go launch we are pleased to share that as of March 31. This year, an estimated 284 children were being previewed with commercial launch. So ago. This includes 201 children in countries outside of the United States and 83.

They'll bring within EMEA.

Hey.

An estimated additional 53 children were in process in the United States as of April 15.

At the end of the first quarter sales were spread across 15 active markets, including sales in new markets, not previously reported Saudi Arabia, Slovenia, Czech Republic, United Arab Emirates, and Italy.

We continue to be very pleased with uptake in the EMEA region, which has been driven by a combination of growth in Germany, and collectively for them individually smaller markets.

Upcoming it outside of the EU, we expect potential approvals in Japan, and Australia later in the year the opportunity in Japan is expected to be significant and we expect revenue contributions to begin there later this year.

Turning to launch dynamics in the United States, we have seen prescription demand pick up quickly we have been able to rapidly convert patient referrals to patient starts in the quarter, we experienced prescriptions for Genesis and pediatric endocrinologists as expected. We also see more payer cover.

Its policies publish which are largely consistent with our label or our clinical trials criteria and are aligned to our expectations. In summary, we're very pleased with the pace of uptake during this ramp year for box logo.

Once again, the EMEA regions ahead of the United States was a first for Biomarin and underscores the ability of our experienced commercial teams to tap into large market opportunities regardless of location. This is of particular importance as we look toward a potential what pay being launched in the coming months should the C. H O b.

And then and Europeans decision be supportive.

Turning now to our enzyme replacement therapy brands Vimizim Fabulous on both achieved record quarterly results in Q1 of 2022.

JJ Bien-Aime: We also reaffirmed previously released financial guidance for all other metrics included in our food year 2022 guidance. So we generated $519 million record revenues in the first quarter, representing 11% growth year-over-year, excluding KUVA.

JJ Bien-Aime: This marks the start of BioMarine's return to significant double-digit growth. Actually, the revenues for products marketed by BioMarine were up 15%, including KUVA. So really after a strong start to double-digit revenue growth, hopefully over the next few years.

Consistent with our experience last year for both brands, we fulfill large orders during the first quarter from such markets as Turkey, Brazil, Egypt, Russia, and Saudi Arabia.

JJ Bien-Aime: So these results highlight the strength of our base business and the significant opportunity that lies ahead with VoxOvo.

JJ Bien-Aime: It is important to note that $13 million of the $20 million total for the first quarter of VoxOvo sales were from outside the United States, emphasizing the breadth of our global footprint and commercial capabilities and the importance of the ex-U.S. markets.

This demand is gratifying and good for our business and we expect will cause the first half of 2022 to have some concentration of our annual revenues similar to our experience last year relative to the second half of 2022.

JJ Bien-Aime: This will be advantageous as we prepare for a potential European launch of Octavian in the second half of this year, ahead of a potential U.S. approval.

JJ Bien-Aime: With a financial outlook and robust global launch of VoxOvo tracking to plan, we look forward to the next important regulatory steps with Octavian over the coming months.

As J J mentioned, we reaffirmed our annual guidance for them that goes on in Vimizim revenues.

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33% growth year over year and revenue of $36 million in the first quarter was driven by 18% growth in new patients starting therapy.

Moving now to <unk> net product revenues grew 2% for the first quarter as compared to the first quarter of 2021 and were impacted by a variety of factors.

In the U S seasonality of health care coverage.

I wanted to walk with experience with <unk>.

Past resulted in a Q1 dip in <unk> revenues as compared to the fourth quarter of 2021.

And while we expect this dynamic in the U S to recover for the remainder of 2022 impact per mom going PKU clinic limitations has full year pounds Zeke revenues trending to the lower end of the guidance range for full year.

Continuing with the PKU franchise.

Contributed $59 million in revenues in the first quarter of 2022 down 16% as compared to Q1 2021.

Since the loss of U S market exclusivity in October of 2020, we experience a further step down in the U S. In the first quarter.

Kuban nears the end of its lifecycle as we would expect from a small molecule drugs, we are gratified to be able to retain the market share and resulting revenues we are experiencing.

Based on market conditions, we expect full year demand resume at some point in 'twenty due to trend closer to the lower end of the previously provided full year guidance range in 2022.

Lastly, with the CH B opinion on rock KVM expected in the near future launch readiness activities continue to progress the team is onboard and well prepared to watch assuming regulatory approvals later this year.

JJ Bien-Aime: For people with severe hemophilia seeking COPAA, seeking B control, that is superior to test-set-up care for pediatrics, we think Rokdevan presents an excellent treatment option based on the results that we observed in our phase 2 and phase 3 studies.

We are encouraged that our longer term data results offer a potentially attractive value proposition and treatment option for those with severe hemophilia, a and we look forward to providing you with more detail updates that locks.

In conclusion in 2022, we anticipate increased demand for all of our commercial brands with the exception of Cuba.

As described.

Our MBS products are expected to contribute significantly to revenue growth. This year, we also expect but still.

So I'm going to be a meaningful factor in this ramp you are noted in today's increase in box. So the revenue guidance. We believe that robust prescription demand represents a foundation for continued growth, including in new markets throughout 2022. Thank.

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, the R&D organization had a very busy quarter as well our regulatory team has been focused on health authority interactions with the European Medicines agency on their Octavian applications currently under review and our preparations for the June Resubmission of our biologics license application in the United States.

JJ Bien-Aime: We believe this data provides supportive evidence of efficacy as part of the marketing authorization application currently under review in Europe and planned for inclusion in our PLA Plan 4 written mission in late June.

We have enjoyed a high degree of collaboration with the EMA as we enter the later stages of the review procedure, thus far we've been able to satisfy their requests for information putting us on track for a potential <unk> mid year as precise scheduling in subjects with EMEA.

JJ Bien-Aime: We were also pleased to share the news today that we have completed the genomic analysis of the salivary gland mass from the participants in our phase 2 Rokdevan study, which was treated over five years ago.

As J J mentioned, we were pleased to have completed the analysis of the private land tumor that was identified in one of our phase III study participants as noted in our presentation. This past February results are consistent with a benign integration profile for Octavian as we did not observe octavian integration associated with growth of the tumor cells, we plan to provide.

JJ Bien-Aime: The findings from the completed analysis did not identify evidence that vector integration contributed to the salivary gland mass.

Mad's data as part of an ongoing review of our market authorization application as well as include the data to the biologic license application in the United States and the Resubmission in June .

JJ Bien-Aime: This is great news for patients and the safety profile of Rokdevan and actually for the entire avian therapy field.

Just to say, we're pleased with the filings with the findings as it further supports the safety profile of Octavius demonstrated.

JJ Bien-Aime: I could say a few more words on this in a moment.

As leaders in the field of gene therapy, we look forward to sharing the results of the analysis of the scientific community at the upcoming World Federation of Hemophilia, a 2022 World Congress.

And the annual American Society of cell and gene therapy and <unk>.

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Turning to Mexico, we are pleased to share that Dr. <unk> and her daughter will present results from his study in genetics short central conditions that the pediatric Endocrine Society meeting this coming Sunday May one S.

We shared in our last R&D day, the study spans six different genetic central conditions. So we look forward to learning about the potential of Bucks I go to positively impact children with other conditions. Besides achondroplasia.

Next milestone without setting alone was a data update from our phase II randomized double blind placebo controlled lots of a study in infants and young children up to five year space with achondroplasia.

<unk> has the opportunity to analyze results since they were on blood in February and we expect and we expect to share them at a medical meeting in the middle of the year.

JJ Bien-Aime: As we look forward to the remainder of 2022, we are on our way to achieving the goals set forth at the start of the year, starting the corner to sustainable gastroactivity, wrapping up our largest pediatric opportunity to date with Varsovo, and progressing Rotavian applications with health authorities in Europe and the United States, and also advancing the broadest early-stage pipeline in our history.

JJ Bien-Aime: We will continue to build on this financial, commercial, and regulatory momentum in 2022 and beyond as we make the transition to an earnings-based start.

Finally, turning to the earlier stage pipeline all of the candidates under development continues to advance.

With me today is that we have begun dosing patients in the phase one two eharmony one study using <unk> hundred 31, our gene therapy for hereditary angioedema. We are encouraged by this new opportunity for AG patients as our preclinical data suggests that <unk> can reduce the frequency and severity of attacks and potentially eliminate product there.

RFP for some patients significantly reducing treatment burden of H eight.

Current centered care, we're excited to begin this development journey and learn about the potential for being down 331 to restore cement Australia's inhibitor proteins in humans based on encouraging preclinical data service.

With me now to slide five which addresses a subset of chronic renal disease. We completed the single ascending dose arm of the phase one study and are in a process of analyzing results concerning began on 351 for duchenne muscular dystrophy.

To file the IND in the first half of the year with a goal of treating the first patient in boys in the fourth quarter of this year.

Clinical studies have been a $3 nine continue to build our enthusiasm for its potential to dramatically improve liver health of people living with the.

Alpha one antitrypsin deficiency, and Vienna 293, formerly referred to as Diana one is on track to be our next gene therapy clinical candidates in this case for the treatment of hypertrophic cardiomyopathy caused by mutations in cardiac myosin.

C III.

We continue to advance 390 293 towards the.

The second half of 2023.

Lastly, on <unk> 307, PKU gene therapy, we await the results of non clinical studies required to remove the current clinical hold and as we said in January and February we believe that this will be a multi quarter process. So we'll update that program status when available.

Foreign to keeping you apprised of our progress of course, the R&D across the R&D organizations as we advance our Octavian applications present data at upcoming medical meeting to move the earlier stage pipeline product sport. Thanks for your support and I'll now turn the call over to Brian <unk> of the financial results for the quarter.

JJ Bien-Aime: Thank you for your continued support, and I will now turn the call over to Jeff to discuss the commercial business update.

Jeff Ajer: Jeff?

Jeff Ajer: Thank you, JJ.

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

As Jeff touched on many of the top line results in the commercial business I will primarily focus on operating expenses bottom line result, 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 few days.

As we highlighted in February we believe that 2022 is an exciting year for Biomarin as.

The company anticipates transitioning to sustainable GAAP profitability driven by the continued strong growth of our base business plus a significant contribution from box Togo and its last year.

We are pleased to be tracking to plan based on the company's first quarter result provided today.

Jeff Ajer: I'm very pleased with our performance in the first quarter of 2022, recording $519 million in total revenues.

Total revenue growth of 11% in the first quarter of 2022 as compared to the first quarter of 2021, excluding Kuban sets us up nicely to achieve our full year GAAP and non-GAAP income goals in 2022.

Jeff Ajer: The $20 million Varsovo contributions in the first quarter drove increased Varsovo 2022 full-year guidance to between $100 million and $125 million, and will be an important component of our 2022 growth story. Now, turning to specifics of the Varsovo launch, we are pleased to share that as of March 31 this year, an estimated 284 children were being treated with commercial Varsovo.

Jeff Ajer: This includes 201 children in countries outside of the United States and 83 children within the United States.

Leveraging upon one important comment Jeff while we expect nachman gone in Vimizim orders to be weighted to the first half of 2022 based on the ordering patterns in select markets. We expect that our total revenues for the full year will be balanced out by growth in our other brands in the second half of the year.

Jeff Ajer: An estimated additional 53 children were in process in the United States as of April 15.

Jeff Ajer: At the end of the first quarter, Varsovo sales were spread across 15 active markets, including sales in new markets not previously reported in Saudi Arabia, Slovenia, Czech Republic, United Arab Emirates, and Italy.

Jeff Ajer: We continue to be very pleased with uptake in the EMEA region, which has been driven by a combination of growth in Germany and collectively from individually smaller markets.

Jeff Ajer: Upcoming and outside of the EU, we expect potential approvals in Japan and Australia later in the year. The opportunity in Japan is expected to be significant, and we expect revenue contributions to begin there later this year.

Jeff Ajer: Turning to launch dynamics in the United States, we have seen prescription demand pick up quickly.

Total biomarin revenues will be roughly even between the first and second half of 'twenty two.

Also comment on box yoga, while we are pleased to observe the early patient uptake trends for vaccine will go globally, which drove our increased expectations for the full year 2022, it's important to note that even though we expect to continue to add new by sogo patients over the remainder of 2020 to the mechanics of daily dosing.

Jeff Ajer: We have been able to rapidly convert patient referrals to patient starts.

Jeff Ajer: In the quarter, we experienced prescriptions from geneticists and pediatric endocrinologists as expected.

Meaning that these new patients on therapy for just a portion of the year will contribute slightly less to full year 2022 revenue.

Jeff Ajer: 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.

Jeff Ajer: In summary, we're very pleased with the pace of uptake during this ramp year for Voxelgo.

Moving to operating expenses for the first quarter of 2022, both R&D and SG&A expense fell in line with our expectation.

<unk> expenses for the first year were $161 million, a slight increase as compared to the first quarter 2021, reflecting increased block caving and development efforts and increased R&D on our early stage programs SG&A expenses for the first quarter 2022 were $195 million as compared to 174.

For the same period last year and reflect the global Blackstone low commercial launch efforts since the European and U S approvals in the second half of last year as well as the <unk> commercial launch preparation costs.

Jeff Ajer: Launching into immediate regions ahead of the United States was a first for Biomarin, and underscored the ability of our experienced commercial teams to tap into large market opportunities regardless of location.

Jeff Ajer: This is of particular importance as we look toward a potential Roctavian launch in the coming months, should the CHMP opinion and European decision be supportive.

Jeff Ajer: Turning now to our enzyme replacement therapy brands, Vimazin and Maglazine both achieved record quarterly results in Q1 of 2022. Consistent with our experience last year for both brands, we fulfilled large orders during the first quarter, from such markets as Turkey, Brazil, Egypt, Russia, and Saudi Arabia.

Jeff Ajer: This demand is gratifying and good for our business, and we expect we'll cause the first half of 2022, to have some concentration of our annual revenues, similar to our experience last year relative to the second half of 2022.

Jeff Ajer: As JJ mentioned, we reaffirm our annual guidance for Maglazine and Vimazin revenues.

Jeff Ajer: For Vernura, 33% growth year over year and revenue of $36 million in the first quarter was driven by 18% growth in new patients starting therapy.

Moving to bottom line results for the first quarter as we shared in February during the first quarter of 2022, we sold the priority review voucher received with the approval of <unk> in the United States.

Jeff Ajer: Moving now to Palantik, net product revenues grew 2% in the first quarter as compared to the first quarter of 2021, and were impacted by a variety of factors. In the U.S., seasonality of healthcare coverage, similar to what was experienced with QVAN in the past, resulted in a Q1 dip in Palantik revenues as compared to the fourth quarter of 2021. And while we expect this dynamic in the U.S. to recover for the remainder of 2022, impact from ongoing PKU clinic limitations has full year Palantik revenues trending to the lower end of the guidance range for the full year.

Jeff Ajer: Continuing with the PKE franchise, QVAN contributed $59 million in revenues in the first quarter of 2022, down 16% as compared to Q1 2021. Since the loss of U.S. market exclusivity in October of 2020, we experienced a further step down in the U.S. in the first quarter.

Jeff Ajer: As QVAN nears the end of its life cycle, as we would expect from a small molecule drug, we are gratified to be able to retain the market share in the resulting revenues we are experiencing.

The transaction was recognized as a gain on sale of a non financial asset.

Thinking of operation and what is the primary driver of Q1, GAAP net income of $128 million.

While GAAP profitability in 2022 will benefit from the CRB Israel, We note that our business plan for the year and the related profitability expectations are not dependent upon the after tax gain from the PRP sale.

With respect to non-GAAP income Q1, 2022, non-GAAP income of $105 million excludes the gain on the sale of the <unk> and was relatively flat to 2021 first quarter non-GAAP income of $104 million and represents a strong start to our expectation of earning between 350 to 300.

Third $90 million of non-GAAP income this year.

Turning to total cash and investments we ended the first quarter 'twenty two with $1 5 billion, mostly flat to year end 2021, while our total cash increased with the proceeds from the sale of the PRD. We also experienced quarterly working capital timing differences. During Q1 2022, as we said when we provided.

Jeff Ajer: Based on market conditions, we expect full year QVAN revenues in 2022 to trend closer to the lower end of the previously provided full year guidance range in 2022.

Jeff Ajer: Lastly, with the CHMC opinion on Roctavian expected in the near future, launch readiness activities continue to progress. The team is on board and well prepared to launch, assuming regulatory approvals later this year.

Jeff Ajer: We are encouraged that our longer term data results offer a potentially attractive value proposition and treatment option for those with severe hemophilia A, and we look forward to providing you with more detailed updates at launch.

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

2022 guidance, we do expect positive operating cash flows for the full year.

Briefly on the Ukraine crisis, given our global footprint and commercial presence in this region as.

As we previously shared the Russia, and Ukraine markets represent approximately 2% to 3% the Biomarin total revenue.

Based on what we know today, we expect that to be consistent in 2022.

Given the essential nature of our products, which treat underlying condition for which no alternative pharmaceutical treatments are available. We continue to serve our patients in the region and are working to minimize the treatment disruptions for Ukrainian pizza.

In fact, we have already fulfilled a significant portion of the expected 2022 supply do you framed in Russia.

In closing 2022 is off to a great start and we are on track to achieve our transition to sustainable profitability with record first quarter revenues driven by a strong global launch of backfill Bill and solid growth in the base.

Jeff Ajer: Our MDS products are expected to contribute significantly to revenue growth this year.

Jeff Ajer: We also expect Voxelgo to be a meaningful factor in this ramp year, as noted in today's increase in Voxelgo revenue guidance.

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

Our plan to support both continued product approval and innovative pipeline growth while at the same time generating sustainably increasing revenue profit and operating cash flow is being realized with an eye toward continued growth further into this decade. Thank you for your attention and we will now open up the call to your questions.

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

Hank Dukes: Hank.

Operator.

Hank Dukes: Thanks, Jeff.

Ladies and gentlemen, if you would like to ask a question. Please press Star then the number one on your telephone keypad.

So the jewelry question Ross.

Your first question comes from the line itself.

Of course.

Your line is now open.

Hank Dukes: I thank you all for joining us today.

Hank Dukes: The R&D organization has a very busy quarter as well.

Good afternoon, Chris Congratulations on turning profitable and two questions for me for a Buck So go.

Howard outreach in absolute progressing pediatrics endocrinologists, and then for our Canadian anything you can provide us on how regulatory discussions are playing out in the U S. Thank you.

Hank Dukes: Our regulatory team has been focused on health authority interactions with the European Medicines Agency on the Roctavian application currently under review, in preparation for the June resubmission of our biologics license application in the United States. We have enjoyed a high degree of collaboration with the EMA as we enter the later stages of the review procedure. Thus far, we have been able to satisfy their requests for information, putting us on track for a potential CHMP in the year, as prescribed scheduling is subject to the EMA.

I saw the and I'll take the first question.

Yes, we're doing really well with outreach to pediatric endocrinologists.

It is a new call point and.

It was we're emerging from the shut down.

Our teams are establishing connections with this new call point in the United States and other markets where we're.

Active for example, in Germany, and we're seeing prescriptions coming in from a mix of.

Physician specialties as I noted, but mainly from Genesis.

Pete N does as screen would expect so I wouldn't I wouldn't say, it's going right on track with nothing nothing notable to describe that's kind of surprising or different than we expected.

I am.

On regulatory discussions.

The bulk of the conversations have been.

With the European Medicines agency, and we felt pretty good about the connection between the remaining questions. They have and the information that we have to provide them, including the recently completed genomic analysis salivary gland tumor which is favorable in regards to the U S. We do plan to have even further discussions with the food and drug administration in advance of our.

Hank Dukes: As JJ mentioned, we were pleased to have completed the analysis of the parotid gland tumor that was identified, and one of our Phase II study participants is noted in our EHEP presentation this past February.

Hank Dukes: The results are consistent with the benign integration profile for Roctavian, as we did not observe Roctavian integration associated with growth of the tumor cells.

Hank Dukes: We plan to provide EMAD's data as part of the ongoing review of our marketing authorization application, as well as include the data in the biologic licensing application in the United States in the resubmission in June.

Hank Dukes: Needless to say, we're pleased with the findings, as it further supports the safety profile Roctavian has demonstrated to date.

Hank Dukes: The next milestone with Batsuga will be the data update from our Phase 2 randomized double-blind placebo-controlled Batsuga study in infants and young children up to five years of age with achondroplasia. The team has had the opportunity to analyze the results since they were unblinded in February, and we expect to share them at a medical meeting in the middle of the year.

Hank Dukes: As leaders in the field of gene therapy, we look forward to sharing the results of the analysis with the scientific community at the upcoming World Federation of Haemophilia 2022 World Congress, and the annual American Society of Cell and Gene Therapy meeting in addition.

Hank Dukes: Finally, turning to the earlier stage pipeline, all of the candidates under development continue to advance. A new update today is that we have begun dosing patients in the Phase 1-2 Harmony 1 study using BMN-331, our gene therapy for hereditary angioedema. We are encouraged by this new opportunity for HAE patients, as our preclinical data suggests that BMN-331 can reduce the frequency and severity of attacks and potentially eliminate chronic therapy for some patients, significantly reducing the treatment burden of HAE and the current standard of care. We're excited to begin this development journey and learn about the potential for BMN-331 to restore C1 esterase inhibitor protein in humans based on the encouraging preclinical data observed.

Hank Dukes: Turning to Batsuga, we are pleased to share that Dr. Andrew Dobber will present results from his study in genetic short spectrum conditions at the Pediatric Endocrine Society meeting this coming Sunday, May 1.

Hank Dukes: As we shared at our last R&D day, the study spanned six different genetic central conditions, so we look forward to learning about the potential of Batsuga to positively impact children with other conditions besides achondroplasia.

Hank Dukes: The BMN-255, which addresses a subset of chronic renal disease, we completed the single-setting, dose arm of the Phase 1-2 study and are in the process of analyzing the results.

Hank Dukes: Concerning BMN-351 for Duchenne muscular dystrophy, we expect to file the IND in the, first half of the year, with the goal of treating the first Duchenne boys in the fourth quarter of this year.

Hank Dukes: Lastly, on BMN-307 PKU gene therapy, we await the results of non-clinical studies required, to remove the current clinical hold, and as we said in January and February, we believe that this will be a multi-quarter process, so we'll update that program status when available.

Hank Dukes: Our preclinical studies of BMN-349 continue to build our enthusiasm for its potential, to dramatically improve liver health in people living with A1HD, Alpha-1 Antitrypsin Deficiency, and BMN-293, formerly referred to as Dyna-001, is on track to be our next gene therapy clinical candidate, in this case, for the treatment of hypertrophic cardiomyopathy-caused agitations in cardiac myosin binding protein C3.

Hank Dukes: We look forward to keeping you apprised of our progress across the R&D organizations, as we advance our Octavian applications, present data at upcoming medical meetings, and move the earlier-stage pipeline products forward.

Hank Dukes: We continue to advance 349 and 293 towards INDs in the second half of 2023.

Brian Mueller: Thanks for your support, and I'll now turn the call over to Brian to update financial

Resubmission pre submission interaction isn't back scheduled with food and drug administration, but we've also already had quite a bit of dialogue since the CRM about information.

Brian Mueller: results in the quarter.

Brian Mueller: Brian?

They'll want us to provide back to them when we do resubmit. We also feel pretty good about the sufficiency of the data that we have in hand or.

Satisfy the concerns that were raised shotspotter.

So feeling pretty good about.

Regulatory situation in both markets.

Brian Mueller: Thank you, Hank.

Got it thank you.

Brian Mueller: Please refer to today's press release summarizing our financial results for full details on, the first quarter of 2022.

Your next question comes from Chris Raymond of Piper Sandler.

Brian Mueller: 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.

Hey.

Thanks for taking the question.

It sounds like <unk>, maybe just a couple of questions on the dynamic there.

I think what the number guidance you guys gave about a third or so of revenue last quarter was in the U S.

And just a little less than a third of patients I know, it's early but is this may be indicative of more sort of parity pricing or is there some sort of patient add dynamic.

And then also just doing the math on that.

On the revenue and then the patients that seems to be a relatively high number for the quarter.

Is there any thing you can add there in terms of the pricing.

<unk> if I can ask a pipeline question no mention of Ah I.

I think I heard no mention of the M. 307 can you just give us a sense of where that program sort of sits thank you.

Brian Mueller: As usual, all results will be available in our upcoming Form 10-Q, which we are on track, to file over the next few days. As we highlighted in February, we believe that 2022 is an exciting year for BioLarynx, as the company anticipates transitioning to sustainable gap profitability driven by the continued strong growth of our base business, plus a significant contribution from VoxOvo in its launch year.

Brian Mueller: We are pleased to be tracking the plan based on the company's first-quarter results provided, today. Total revenue growth of 11% in the first quarter of 2022, as compared to the first quarter, of 2021, excluding Kuban, sets us up nicely to achieve our full-year gap and non-gap income goals in 2022.

Okay.

Brian Mueller: To elaborate upon one important comment from Jeff, while we expect Naglazine and Vimitim, orders to be weighted to the first half of 2022 based on the ordering patterns of select markets, we expect that our total revenues for the full year will be balanced out by growth in our other brands in the second half of the year, and that total BioMarin revenues will be roughly even between the first and second half of 2022.

Brian Mueller: Also, a comment on VoxOvo.

Chris I'll start off on the Boston Buffalo question.

Brian Mueller: While we are pleased to observe the early patient uptake trends for VoxOvo globally, which drove our increased expectations for the full year of 2022, it's important to note that even though we expect to continue to add new VoxOvo patients over the remainder of 2022, the mechanics of daily dosing mean that these new patients on therapy for just a portion of the year will contribute slightly less to full-year 2022 revenue.

Brian Mueller: Moving to Operating Expenses for the first quarter of 2022, both R&D and SG&A expenses, fell in line with our expectations.

Brian Mueller: R&D expenses for the first year were $161 million, a slight increase as compared to the first quarter of 2021, reflecting increased Roktavian development efforts and increased R&D on our early stage programs.

Brian Mueller: SG&A expenses for the first quarter of 2022 were $195 million, as compared to $174 million for the same period last year, and reflect the global VoxOgo commercial launch efforts since the European and U.S. approvals in the second half of last year, as well as the Roktavian commercial launch preparation costs.

So you mentioned in.

And confirming that.

We stated about a third of our revenues from the United States.

The balance ex U S, which ties up pretty closely to.

The patient numbers that we're reporting also.

In the United States early in Q1, we did have some.

Some specialty pharmacy, stocking, which was a one time event.

Not a huge number but but enough. So that there is a resting inventory in our specialty pharmacy network.

Brian Mueller: Moving to Bottom Line Results for the first quarter. As we shared in February, during the, first quarter of 2022, we sold the Priority Review Voucher received with the approval of VoxOgo in the United States. The transaction was recognized as a gain on sale of a non-financial, asset on our statement of operations and was the primary driver of Q1 gap net income of $120.8 million.

Brian Mueller: While gap profitability in 2022 will benefit from the PRV sale, we note that our business plan for the year and the related profitability expectations are not dependent upon the after-tax gain from the PRV sale.

That's kind of a one so as I say, a one time event.

Brian Mueller: With respect to non-gap income, Q1 2022 non-gap income of $105 million excludes the gain on the sale of the PRV and was relatively flat to 2021 first quarter non-gap income of $104 million, and represents a strong start to our expectation of earning between $350 to $390 million of non-gap income this year.

Brian Mueller: Turning the total cash and investments, we ended the first quarter 2022 with $1.5 billion, mostly flat to year-end 2021. While our total cash increased with the proceeds from the sale of the PRV, we also experienced, quarterly working capital timing differences during Q1 2022.

Brian Mueller: As we said when we provided 2022 guidance, we do expect positive operating cash flows for the full year.

Bye bye.

Brian Mueller: Briefly on the, Ukraine crisis, given our global footprint and commercial presence in this region.

March I would say, we were seeing reorders of our specialty pharmacy network in the U S.

On a consistent enough basis like you would conclude that there was no further.

Buying down of that inventory in the U S beans were essentially ordering to demand so that could be a little bit of a bump.

Brian Mueller: As we previously shared, the Russia and Ukraine markets represent approximately 2 to 3 percent of, BioMarin's total revenue. And based on what we know today, we expect that to be consistent in 2022.

Brian Mueller: Given the essential nature of our product, which treat underlying conditions for which no alternative, pharmaceutical treatments are available, we continue to serve our patients in the region and are working to minimize the treatment disruptions for Ukrainian patients. In fact, we have already fulfilled a significant portion of the expected 2022 supply to Ukraine and Russia.

Brian Mueller: In closing, 2022 is off to a great start, and we are on track to achieve our transition to sustainable profitability, with record first quarter revenues, driven by a strong global launch of Octogo and solid growth in the base business. Our plan to support both continued product approval and innovative pipeline growth, while at the same time generating sustainably increasing revenues, profits, and operating cash flows is being realized with an eye towards continued growth further into this decade.

In Q1, and more tilted towards the U S.

And you can follow along our pricing discussion as usual we have it.

Robust.

Particularly in the U S.

And so far we're managing it pretty tight price corridor.

So I'll go in other markets.

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

Does that cover your question.

Operator: Operator.

Yes.

So she is also going.

Going very well.

Both sides of the Atlantic.

<unk>.

And I.

I mean do you expect the difference you see elevated because we started selling in Germany actually.

Tomorrow, you still have the U S really started in January .

But.

Really what's happening is that the revenues are commensurate with the market the market size and.

And we are always saying that.

The largest opportunity was outside the U S and the numbers are confirming that.

So the good news here is that.

I think there was some anxiety that thread lenders reports about launching a product first in Europe and the U S. It's the first time, we do that then.

It was actually that we can be very successful launching of plaque in Europe ahead of the U S, which is likely to happen.

All of this is pretty good.

Thank you Ana.

I'm curious, though Chris the game plan is we've got to complete some additional preclinical studies.

Pertained to the findings that had been previously reported the agency we were hopeful that based on some early interactions with the agency that we would be able to remove the hole quicker.

But unfortunately with this requirement to conduct additional studies, we probably won't have any updates for you on that until we have the results of those studies, which are going to be several quarters from now so I would say unfortunately there'll be looking for near term updates on three of them.

Okay. Thanks, guys.

Operator: Ladies and gentlemen, if you would like to ask a question, please press star, then the number one on your telephone keypad. To withdraw a question, press the pound key.

Your next question comes from Robyn <unk>.

Operator: Your first question comes from the line of Salveen Richter

Hi, guys. Thanks for taking my question.

Just a quick one I guess for the EMEA discussion in the U S discussion given that you're adding with additional celebrate gland.

Data.

Is it possible that we could go into July I know, you're not on the docket. It looks like for April for EMEA and same for the U S. Do you think that this could take a little longer if the filing could be middle of the year like July August .

And then second question is on the block so ago. So it seems like you have the same number of patients in process that you did last quarter do you expect.

The addition of patients to be consistent or do you think this is more of a bolus upfront and then maybe you can comment on and it's a lot, but maybe you can comment on compliance.

Given the early and it's early but compliance with daily dosing.

I don't know and I think I'll take a shot at the first part of your question as to the timeline and the European Medicines Agency.

We're feeling pretty optimistic that all the information that we will be able to provide the MAA and the last night of review.

Enable them to make a decision in June but it's also a decent amount of information in the EMEA has.

Uh huh.

Based on the questions that they've asked that question a decent chunk of information center reviewed them in terms of risk management plans label first triple commitments and things like that so yes, if it could drip into July .

But we're working to be lined up with them and enable them to come to the positive opinion of course, that's the objective of all this.

And in regard to the U S. You're right to ask the question might be well certainly appreciate the nature of the question, which is that they're carrying a lot of water on the European application, but at the same time, we're finalizing the U S application. So can I ask with execution and that's really down to execution, yes, sure things may take a little longer we really want to make sure that we will submit an application.

So it's a.

So it doesn't affect a review by the U S, but that target again, it's in June .

Your uncle remaining on that track.

And regarding your question on box Sogo.

And then.

Jeff answers.

Personnel, whether it's fully sufficient over there.

The voice is going to be sustainable I believe it will be but just to elaborate in the compliant I think we must only one patient is that correct. All the pieces we saw it.

We have not one patient so far Jeff.

So extremely good compliance yeah. Thanks, Robert for the question, it's actually a par.

Positive sign of the launch trajectory in the United States, which is the one place in the world that we're able to track patient numbers and process. So.

The fact that that are in process is holding steady.

Compared to where it was a quarter ago is indicative of.

Getting a steady stream of both of new patients being enrolled and then also having the ability to pretty rapidly worked through those patients get.

Approved for treatment of gift products shipped out and first prescriptions fulfilled so I view that as a positive related to compliance.

J J noted.

Small number very small number on drop off so far we don't have at this stage I don't have a quantitative estimate of compliance other than the drop off figure, which is supportive of a high rate of compliance so far.

The other thing that we're doing is we're being very proactive with patients and their families about.

Training for this.

Daily injection and we've gotten.

Super feedback and in both Europe , and the United States. So that's been really helpful for Hamlin families, giving them the confidence to go out and begin the daily injection.

Routine them and I think that bodes well for compliance going forward. Thanks.

We have very good visibility just in the U S. Because this is basically first enroll.

Wendy.

They signify that he wants to be.

The families involved.

The kids should be treated with October . So so we have good visibility for the accretion rates and we have no insight and decided that it is.

There's a new fishers wanting to be treated at 90, he is slowing down and I think.

And then just you want to mention how long it takes to treat.

When a patient is going to be signed up in and when we start shipping on average in the U S.

Yeah. So so far it's pretty rapid our average is 23 days from a complete enrollment.

The prescription to shipment of that first prescription to patient with some variability around that.

Great. Thank you.

Your next question comes from Corey Passiveness of J P. Morgan.

Operator: of Goldman Sachs.

Operator: Your line is now open.

Hey, good afternoon, guys. Thanks for taking my questions two from me as well.

Operator: Good afternoon.

Both probably for Hank purchased a follow up on the on the U S rock cave in situations or anything specific that needs to be addressed in that pre BLA meeting that hasnt been dealt with already I guess just curious if this is standard operating procedure for a resubmission or if there were issues to still discussed and then the second thing I was just.

Operator: First, congratulations on turning GAAP profitable.

Wondering if you could set the stage ahead of the short stature update this weekend for a buck so go what would be compelling in your view or.

An investigator's view when you speak with them. Thank you.

Yes.

No I think.

Interaction with the FDA submission last baby and as more of the SLP, rather than necessarily particularly new information.

The agency's stance is likely to be you know these are all issues that have yourself during the review.

What's important for us to do is to make sure that we have clearer.

Clear eye view of the information that they're looking for we have we have all these data. So it's really just a matter of making sure. It's in the form of content of what they're looking for something more on the S&P side.

Far as a dog or presentation.

The expectation to have is that in the amalgam that sort of across a range of mutations, but I think a reminder is that these indicators that is accrued patients with six different types of mutations that there can be an improvement in stature syndrome as measured by the HEB and children, who have mutations that are different from the <unk>.

Contemplation of FGF our communication.

And he's got a lot of biology as to why he believes that to be the case, but of course the data itself themselves will be this positive towards what is underlying the topics that I would focus in on the age of the change from baseline across the different types of mutations that he is included and I think you know the the.

A good a good outcome would be similar or better than similar to what we've seen in achondroplasia is a great outcome.

And it might be mutation specific might be that's all mutations or even more responsive to the sort of tied so.

I think that's the stage is set for the data.

Great. Thank you.

Operator: Two questions for me.

Your next question comes from Tom <unk>.

T phone.

Sorry, we couldn't hear.

I think she said Palmer teeth at Stifel.

Operator: For Voxogo, in the US, how is outreach, and uptake progressing in pediatric endocrinologists?

Thanks, a lot for taking my question good to talk to you.

One box Doug a question on the commercial side I guess are you seeing physicians or do you think physicians will do anything to determine whether or not patients are benefiting them. Obviously you can look at growth natural history of every patient is different you kind of get into hypothetical. So maybe just comment on how you sort of verify efficacy what.

Operator: And then for Octavian, anything you can provide us, on how regulatory discussions are playing out in the US?

This drug and then to the extent you've seen any discontinuation so far.

What are the reasons, if you wouldn't mind clarifying thank you.

Operator: Thank you.

Thanks for your question Paul So.

In terms of attracting benefit.

That's not something that we guide specifically to but we would certainly expect.

We would certainly expect physicians to be following along the progress of their patients. There is a newly published guidance the management of <unk>.

Operator: Hi, Salveen.

All under pressure.

Which I think is helpful in providing those prescribers.

The guidance to do that.

Gross velocity and height would be.

Kind of a lowest common denominator, but could be expected.

Some some of the U S insurers are requiring.

Operator: I'll take the first question.

Evidence of benefit for renewable future renewal of prescriptions for example, which seems reasonable enough.

Operator: Yep, we're doing really well with outreach, to pediatric endocrinologists.

And back to the publication on management guidelines.

Operator: It is a new call point, and as we're emerging from the shutdown, our teams are establishing connections with this new call point in the United States and other markets where we're active, for example, in Germany.

You've heard me say before.

There was no medical home, particularly in the U S and our system no medical home for achondroplasia patients and I think part of the opportunity here.

As to establish a medical home for kids with Achondroplasia.

Two of them, including but not limited to the use of box ago as a part of that overall management scheme and I think that's going to be good for Biomarin, and Bob Togo, and it's going to be great for the kids with achondroplasia and their families.

So discontinuation, we don't really have enough data as J J mentioned and I think we have one discontinuation and I I don't have a stated.

Stated reasons for that one.

Okay. Thanks.

Just one.

Sorry go ahead.

Back to tracking.

So the as you can see.

Trying to keep what you could do it but just an anecdote.

When we tested the advertising campaign.

As European health care professionals and patients.

We actually haven't we haven't picture.

Young.

Now who have been treated with <unk> for I think over four years very close to five now.

And she is obviously, what she's equally impressive patient.

We actually from the panels of doctors and.

And probably the peak on patients with.

That said, we should be using we should be using really can do kind of sick patients for advertising.

But that's probably all the way to answer your questions.

Thank you J J and last just one quick thing any update on the path to full approval back again.

Not in particular other than the good news is that we're the data that's going to generate the full approval package is going to be.

You follow up these patients from the pivotal clinical trial.

As you just heard the compliance and the program overall is pretty excellent. So we do expect to be able to provide that in a timely fashion I don't know that we've got it to a specific submission date.

Understood. Thanks again.

Your next question comes from Gena Wang of Barclays.

Thank you for taking my questions I have two sets of questions. So the first one is regarding the rock TD and celebrate Glen last integration analysis. So you saw similar pattern.

Do you see any I wanted to cite does show up in this analysis and a related question for you all have to be Oh, seven PKU program.

This also shows the integration not to initiating event. The Ftes do you ask for data that require several quarters of work. So what makes you confident that similar situation won't happen here too.

And I have quickly.

So good question just wondering what is the price range for the ex U S different countries.

Full friends now you'll have it.

Like listing prices of 300000.

U S dollars, but since you expect future negotiating price will be lower how would you put the revenue here.

Yeah.

Hi, Gena.

As regards the pattern of integrations, there really was nothing particularly noteworthy about the pattern of integration and then I think it was.

Pieces to compare repetitive integration between the healthy tissue and the adjacent adjacent in the block to the tumor tissue and as has been previously described.

Or wild type <unk>.

Communist vectors have a relatively low propensity and integration and I think that's that has been foundational.

The regulatory perspective, you might remember there was an FDA guidance document on this and they referred to.

<unk> is having a low propensity for integration I think one of the great things about what we found so far is that it appears that the recombinant vectors saving similarly in terms of distribution integration patterns frequencies and sites of integration similar to the wildfire that is to say not binding prep.

Parental hotspots of particular relevance.

And so.

That's part of your question was the 307.

How does that read secondly, I understood. Your question would be how does it need on the 270 evaluation and why not imagine that there can be the similar requirements for two seven years. There have been four as there appear to be from three to seven I think the short answer to that is because the 270 vector has cleared its safety studies, so the adequate Saturday satisfaction of health space.

There have been there.

The only sort of suspicious signal that tourism in that 270 programs. What we just talked about which was the proud of tumor theres nothing unique, particularly as the findings in this individual.

And so I think having not seen us with neither by the preclinical data <unk> TV itself, nor with a vector that whose construction is very very similar Octavian and studied for a longer period of time, even the rotating some studies that similar similarly is not oncogenic and preclinical species. So I think all of these things take together taken together.

Other bodes quite well for the Octavian overall risk benefit evaluation, namely that in preclinical studies in humans.

No particular, confirming signal of oncogenic potential vector statistics.

Got it.

He was up.

To practically differently.

Although.

That is almost equal hole.

It's not some people hold we had awarded each of these studies as we see more as CMS once either also enrolling and therefore I think the agency is reacting to this isn't a vector specific indication specific decision.

And you had a question on the on the revenue and price range of OXXO in Europe and revenue recognition.

As always Jeff and Brian .

Okay.

Regarding the price range.

The prices are but we're anchoring too we've got the WAC price in the United States span on our approval call, we guided to our expectation.

Gross or WAC price to net realizable price for per patient I think thats, a pretty solid estimate we've got the list price.

You note in Germany, and France, and our expectation is that it's going to take about a year from product introduction.

To get to kind of negotiate it.

Prices for full reimbursement so that'll happen later this year and in the meantime, we're we're establishing pricing for our named patient sales markets.

R R right in a pretty tight corridor consistent with the U S French and German pricing and I'll, let Brian cover the.

The discount basic yeah. Thanks, Jeff Thanks for the question Gena.

This is Brian .

Theres nothing materially unique to speak about with respect to backfill the gross to net.

Our experience and our expectations are that the overall gross to net will be similar to our other products as well as our prior launches.

Not to get into each of the European country by country dynamics, but in some cases, you do start with an initial price.

And then there could be a claw back when you get to that final negotiated price lower but that were required under GAAP to make estimates at those and record those reserves. If you will so what youre, what youre seeing in our reported revenues would be a net net revenue.

Okay. Thank you.

Helpful.

Your next question comes from Geoff Meacham Bank Okay.

Hey, guys. Thanks, so much for the question.

A couple of long kind of the same themes as everyone has been asking.

Hank on <unk> I know, it's personally in our language a bit but it is the shift from <unk> to mid 2022 from the CH and Pete and that's just a normal fluctuation or was in fact there.

And impact to the review clock when you look at the the tumor analysis.

And then on the box sogo commercially I know, it's early but are there some themes in new patient starts in Europe , who weren't in the clinical studies in terms of.

Patient flows are awareness I'm, just trying to get a sense for what was working there. This early in the launch and maybe if that could be similar or different when.

When you look to the U S launch thank you.

Yeah.

Jeff on the earlier.

No.

Piece of information that is underneath the shifts.

The minor I was talking about it being June maybe shifting into the summer I think.

The only news here is that's not even use as we've been off except we just came off accelerated assessment and that was anticipated, but you never know at the beginning of the procedure or even in the bedroom. She Chris just sort of how their timelines lineup and when they want to receive information.

And so I think.

If anything we're just being a little.

Abundant caution here in terms of projecting Panama, because theyre not entirely in our control as a result of the fact that we're giving them a pretty big slug of data towards the tail end of the review that obviously you knew it was coming so that's why we're confident we can stay in the procedure and that we're going to have an opinion by the summer but it also is like that Apollo is their lead in terms of exactly.

When theyre going to take it to an opinion.

I think the most important thing is we believe we have the information that address questions they've issued to us and based on those questions. We believe that a positive benefit risk opinion can come but that happens after they've done their means for behind closed doors.

That's what we're working to support.

Yeah.

Okay.

Yes, so Jeff what I would what I would say about themes.

Is diversity of experience here.

With which points kind of away from common themes.

In an important way dive.

Diversity I would say diversity of age groups that were seeing starting therapy.

Operator: And we're seeing prescriptions coming in, from a mix of physician specialties, as I noted, but mainly from geneticists and pedendos, as we would expect.

One example diversity of.

Operator: So I would say it's going right on track, with nothing notable to describe that's kind of surprising or different than we expected.

Operator: And on regulatory discussions, again, the bulk of the conversations have been with European Medicines Agency, and we felt pretty good about the connection between the remaining questions they have and the information that we have to provide them, including the recently completed genomic analysis of the salivary gland tumor, which is favorable.

Operator: In regards to the U.S., we do plan to have even further discussions with the Food and Drug Administration in advance of our resubmission.

Prescribers specialty.

Seeing mainly genetics in pediatric endocrinologists, but also some <unk>.

Pediatric orthopedist and pediatricians.

Showing up here and also kind of a dive.

Diversity of approach so in Germany, we were essentially operating under a full price or reimbursement approval, even though we haven't negotiated a final price. They are kind of how the market behaves and so we're seeing pretty rapid uptake.

In France. In contrast, we're currently operating under a very structured.

<unk> expanded access protocol there.

So it's a more kind of structured approach to getting patients started from.

It's a relatively small network of clinics and in France as I've noted before the physicians there are actually starting older patients from working down of age.

Our biologics that they wanted to take full advantage of the <unk>.

When the window for treatment with their older Kids.

That's not really something that we've seen anywhere else in the smaller named patient sales markets I would say the theme. There is we're getting one or a couple of patients approved initially.

Her name patient sales approvals and our opportunity there has been to kind of build off that gets a third before in some cases, the fifth third bank.

<unk> treated and were working hard to do that so a lot of diversity actually experience.

Gotcha, Okay. Thanks, guys.

The next question, we have Phil Nadeau with Cowen.

Good afternoon, let me add my congratulations on a productive quarter just a couple of follow ups from us on flex. So go into Octavian first I'm not so ago, Jeff I think on the approval call you identified one of the challenges with the U S launch.

There's a lot of patients who are at an expert centers.

Are the expert centers reporting that patients are enquiring about being treated or because they were general flux of patients towards the expert centers with the availability of Mexico.

Second Hank just just briefly what are your expectations for an outcome.

One the first review do you.

Do you have to use all their critical amount com to review the productivity Resubmission.

Yes.

Doug.

I'll start on the box Togo experience in the United States, you're right when we.

On the approval call I noted that longer term, our big task was to establish a referral network.

And kind of get patients out of the random physician, which is not a medical home breakout replays are get them referred either genetics clinic, that's interested in achondroplasia or to a pediatric endocrinologist and.

And moments ago, I mentioned that that's an opportunity to create a treatment at home for achondroplasia.

And and also earlier I said.

Got a pretty steady.

The rate of patients coming in in the United States for referrals and in process with them and that's a good signal, indicating that we didn't just have a bolus of patients that.

More often it is slowing down over time, however, underneath that I think you're right.

A lot of our early patients were coming from the genetics and skeletal dysplasia clinics expert centers that have achondroplasia patients lined up.

So it's.

A lot of interest in referrals early on for Matt Channel and in the last couple of months than we've been able to get that referral network.

<unk> in the U S and start driving patients from random position that they're being seen by two pediatric endocrinologists. So that's picking up now and that I think that's gonna be the longer term driver of growth for the U S market.

Okay.

I mean, you show the AD Council I don't know that I have like meaningfully more information to add a dialogue since the agency won't really decide that.

Until they're in review.

I think if you would have seen personally what would you say it would be something like well the agency called and it comes generally for two purposes. One is when they wanted to approve something and they want to rally the troops around the decision they make and then the others when they want to kill something and they want to use the entercom to kill it.

Feels like you know.

Not a lot of info that they can show to an AD com to kill it because the efficacy profiles because the safety profile is good and.

And so what would you point to to be the motives for killing it. So I guess I could say I hope they do come on at a time because I hope that what they are doing is going to be serious about like how they regulate gene therapy products and use a fairly robust package breathtaking to establish standards for review.

But we will.

Yes.

That's helpful. Thank you.

Your next question is from Matthew Harrison of Morgan Stanley .

Okay.

Great. Good afternoon. Thanks for taking the question I just wanted to follow up on two things. One I think you talked about some inventory dynamics that help box out by this quarter at the specialty pharmacy could you or maybe you're willing to just quantify or give us some sense about how much that helped and then.

Secondly, just as you're preparing for rock caving in Europe can you give us some sense of how much work has been done so far.

And how much engagement, you've had with each of the countries around or if any engagement around.

Priced and and just sort of initial commentary there. Thanks.

Yeah.

Okay. Thanks, I'm asking the question so back on box logo in the U S and kind of arresting specialty pharmacy inventory.

You could judge from the mix of revenue ex U S and U S and say well Biomarin is guiding that $7 million of revenue with U S. I also said that by by March.

We were seeing orders.

Indicated to me that but.

But specialty pharmacies were not drawing down that resting inventory. We also in our specialty pharmacy and felt like the whole lot of.

Inventory and really they don't have to because we've got really good reorder dynamics for them. So.

Unlike my guide to a couple to several million dollars of <unk> inventory in the United States and then with respect to rock baby and in Europe , one of the things that I think the box I'll go launch in Europe is doing is validating that.

Where there is a large market opportunity and you have an experienced company with experienced teams that know what they're doing.

We can capitalize on that market opportunity and have successful launches.

In the EU in particular, we're leveraging all of the experience that we've gotten from the past launches.

As in the United States, we formed specialized team.

Teams to prepare for rock patheon, including seating our teams with people who have significant experience in the hemophilia business.

We're essentially ready to go in particularly in the markets, where we're expecting first revenues.

You might expect from the current and past experience that would be in places like France, and Germany, and Italy first.

And in places, where we get named patient sales uptake on a relatively rapid basis. So we've got people in those places yes, we've been doing.

<unk> research.

We have an active active program working with.

Market access.

Risers in Europe , we followed that practice for example, with with Baxalta, We're doing the same thing with rock gaming.

I'd say, we're really ready for this launch and we're excited about it and if we get us HIV positive opinion in EMEA approval here.

Let me add a few things.

So in Germany at least the last week being a price.

Obviously U S sites were around $2 million.

And we also have just done a lot for members for research.

There is major interest by driven tiers.

Outcome based agreements.

And we will be making those available because now we have great data showing that.

The majority of the patients do we fall through with David and very few of them.

Lewis did you start.

I had another responding or go back to.

Prophylactic effectively so that'd be another two years. So we can we can maximize the products launch.

Hi.

Offering a guarantee of success the figures.

And that's something that they understand very well and they're very interested in.

Considering that the they don't have much of a species that are causing that.

So that's kind of the plant.

Okay.

Your next question comes from Joseph Schwartz with SBC.

A lot of my questions have been answered so I'll ask some things about your mid stage pipeline I guess, it's been over a year since the <unk> was filed for <unk>.

$2 55, so I was wondering if you could give us an update on this program and I see you completed DSA D. We're.

Analyzing apps do you think you'll be advancing to the M D.

Portion and when can we expect to see some data there is it possible to see signal finding.

Travel, even though these are healthy volunteers.

Hi, Paul Good question, you know that it's early stages of small molecule development are the sort of the.

Often times.

<unk> is part of the roads.

I think all I can share with you now is that what you mean.

Putting your question, which is we've completed the single ascending dose portion of the study and.

And we're analyzing the results that I think.

China for 255, as its genetic enablement, namely that we understand there to be a molecular pathway. That's key to regulating oxalate excretion and you know theres a lot of oxalate excretion in recurrent some corners or people have chronic renal disease. So if we really figured out a way to open the tap on oxalate it should be.

<unk>.

It should be or I should say close to that it should be exciting for patients to stay tuned as we gather data in this particular twisty phase of the program.

Okay. Thank you.

Your next question is from <unk> with Guggenheim.

Hey, Thank you for letting me in just on box. So go on.

On the commercial loan so far upper age limit of patients who are currently getting prescribed and number two any clarity on the sleep apnea signal noted in the younger subjects in the.

Zero to five year old study and finally are you planning to advance the long acting version into the clinic. Thanks, so much.

Okay.

I did just I'll start with the question on the age range.

As noted earlier.

I've seen we've seen where we have the data to measure it.

Quite a lot of diversity.

In the age range, including teenagers being enrolled for pre spent as well as younger.

Young kids so.

Don't have a.

Ceiling.

Age, but what we know is that.

Kids that have.

Their phone place close will not benefit so.

We would expect that upper limit to be something plus or minus.

2018 years old plus or minus.

And I think the your second question was related to that sort of five year olds.

And then Archie.

Yeah. So biggest festival picture on those year to five year old is that.

In Europe first.

Our children lunch Europeans were compelled by the overall package of data in the Sentinel data that we've provided to them during the application, but I think we've talked about that.

I mean, we have the people who do we have a label what we can tell about that.

For the two to five year old population in the United States.

D a.

And a little bit more information on the results of 206 are going to inform that we've announced.

Positive trends were observed and I think in the in the.

Treatment of these young children and I think the next step therefore is to have conversations with food and drug administration about labeling requirements and we're going to pursue a similar pattern throughout the rest of the world. We believe that data support giving families treatment option for children, who are under five years of age with achondroplasia and working with health authorities.

Operator: Presubmission interaction is, in fact, scheduled with Food and Drug Administration. But we've also already had quite a bit of dialogue, since the CRL about information they'll want us to provide back to them when we do resubmit.

Operator: We also feel pretty good about the sufficiency of the data, that we have in hand for satisfying the concerns that were raised in the complete response letter.

Then the information that they need to come to that decision in different geographies make come to that decision at different time points based on our.

Emerging data so I'd say stay tuned for further updates from us on both regulatory plans as well as overall plans for <unk>.

Operator: So feeling pretty good about the regulatory situation, in both markets.

Address it and we are in.

Operator: Got it, thank you.

At this stage.

You in your backyard barbecue shouldn't it.

No.

The finding is 440.

Or any patients from birth to.

Exposure.

So and also if you wanted to do was about windows.

So what data would be presented some.

So the data we presented I think he said some are on the call or the middle of the year.

And then I think you also asked about long acting and long acting.

I think so far thought about it as not as much of an efficacy advantage and most children not much of a safety event, we've talked about all of the numbers behind all that.

But it is an interesting question as it pertains to the children who are under five.

No that Santos has in their phase two study enrolled some patients who are under five so there could be some data about the impact of long acting on overall growth, but again, a key reminder, about that as how far behind us as soon as really is in terms of spelling in pet food and this is a relatively small phase two studies. So I think we have some.

Room to both offer this option on a global basis for young children. Because there is nothing else in times of the essence as well as to further iterate our product offerings to continue building strengthen the Vauxhall brand.

Yeah.

Thank you good luck.

Operator: Your next question comes from Chris Raymond

Your next question is from Joel Beatty with Big.

Operator: of Piper Sandler.

Thanks for taking my questions.

First one is for about Togo.

Full of awareness of the drug among patients with achondroplasia and their families. And then also for $3 51 for DMD what will be learned from the initial studies starting later this year.

Maybe I'll start with a quick question about level of awareness.

That's something that we would typically be a market researching.

To get a quantitative estimate following launch in the B.

The answer on that one is we haven't yet gone out to market research that question, we will at some point during the year and we'll have to wait till we do that worked out estimate qual.

Qualitatively.

I would say it looks to be pretty high based on.

The level of patients that we see coming in for treatment.

And as regards but we will learn from the initial 351 study as I said.

Our our goal is to get into the treatment of DMD boys as quickly as we can hopefully by the end of the year and now of course, that's always subject to regulatory review of the IND.

But assuming that that's the plan I think and that should be the plan because the central question really is.

What's the relationship between that deliver dose its safety profile and the level of dystrophin.

The increase that you can achieve and.

Based on the biology of the compounds that we've developed we.

We believe that the nature of the chemistry being so similar to what we use what drives a person that we should be able to achieve tissue concentrations muscle tissue concentrations of our 351 compound that would produce skipping in a range of between 20 and 40%, meaning that the patients would have.

20, or 40% of this shorten dystrophin protein, which is a pretty high relative to what ambulatory patients with far less severe condition called becker's dystrophy muscular dystrophy app so quickly.

Quickly as possible the initiatives.

So you will gear itself towards demonstrating safety improvement.

A meaningful quantity of dystrophin protein and muscle.

Thank you the timeline, specifically for windows and it'll be available.

Sorry.

Thank you.

Your next question from Luca <unk> with RBC capital.

Oh, great. Thanks, so much for taking my question quick one on rocks.

I know you are ruling out AAV is the potential cause of the celebrate gland cancer, but can you actually share the integration frequency that you have observed in the surgical piece I know you mentioned in the past is 0.0% to 7% their cell showing evidence of AAV integrations, where there are some cell carcinoma case, so just wondering how you're none.

<unk> compares to that number and maybe also related I think asked by you and they reported a case of harmful cancer in their hemophilia B program. So I'm wondering if you know how you're thinking about read through for your program and then still involved rocks assuming it does get approved can you remind us what's the latest thinking on pricing strategy and still free to dichotomy.

The answer between the U S and the EU should that makes sense. Thanks, so much.

Yes.

I would say specifically as regards numbers coming to the presentations that are coming around the corner I thought it'd be a patient answers.

The way I think about it is that what we've seen so far is consistent with what's been previously described as low propensity for integration.

So qualitatively.

Qualitatively anyway, that's the frame take into your review of those presentations.

As regards the occurrence of other tumors I mean, I do think that over time, there are going to be patient.

Patients developing cancer I mean, that's.

Fact of getting older in life and I think that.

What we've seen to date doesn't really suggest that there's been particularly clustering.

Tumor types I think also one has to really consider sort of sector at a time, that's kind of what we've learned in Austria seven Giants were talking about earlier that is to say the agency is proceeding with <unk> three one and 370 enrolling clinical trials, it's only <unk> 307 in which the question is kind of race. So instead of.

Sort of lumping everything together I think the agency is taking each sector in each clinical situations sort of on its own face for the time being I think the data that we're talking about today are pretty encouraging as regards to reaffirming what we've known all along about AAV relatively low propensity for integration relatively low steps.

The city for integration events in particular spots in the genome.

And no reason to believe fundamentally that what's been observed with AAV.

People running around talking about the cancer risk of hepatitis C or hepatitis b.

These efficacy that people are running around talking about stomach cancer risks from so I think that low propensity and from a integration collaboration that we're talking about today is really a powerful sign that.

Just to see what happens.

Coffee is already the previous question the pricing in the U S or in Europe .

I don't think we need to go over that again, but you ought to see if it was about the U S. I think Jeff Yeah. So.

What you heard JJ said publicly a couple of years ago was probably not less than 2 million at whack, probably not more than 3 million.

But that's the range that the either.

I'll first review.

Showed roth KPN to be a dominant choice at a presumed price so two and a half million dollars.

Kind of worked up.

We'll announce the final price when we get an approval and.

In the launch, but I think generally those ranges look pretty solid to me, maybe just one other comment on pricing and our ability to capture a premium price J J mentioned outcomes based agreement.

Earlier that is crucial to our ability to capture value for rock Fabian Payors.

In addition to wanting their patients to do well.

Not lead to not have to infuse two and a half times a week on average payers are concerned financially about their risk of.

Of Nonperformance following administration and the risk of <unk>.

Durability of effect over time.

The data that we have so far would suggest risk of nonperformance. Following administration is very very low and the durability data that we've seen both out of the 201 study and that generates one study.

Putting the 17 patients that we have three years that is really encouraging about the durability of effect over time. So we think that we can largely take those risks.

Off the table for payers and that's one of the factors that will allow us to capture at high value initially.

Hugh.

Sure.

This concludes became too.

I will now hand, it over to J D.

Closing remarks.

Operator: Hey, thanks for taking the question.

Thank you operator, and thank you all for joining US today, we're pleased to begin 2022 with a record first quarter results.

Operator: Just on Doxogo, maybe just a couple questions, on the dynamic there.

The addition of OXXO goes to our commercial portfolio.

Operator: I think with the number you guys gave, about a third or so of revenue last quarter was in the U.S., and just a little less than a third of patients.

Operator: I know it's early, but is this maybe indicative, of more sort of parity pricing, or is there some sort of patient ad dynamic?

Operator: And then also just doing the math on the revenue, and then the patients, it seems to be a relatively high number for the quarter.

Definitely an important component of our growth story going forward and it paves the way for GAAP profit digitally.

Sustainable capital really beginning.

Beginning this year.

Operator: Is there anything you can add there, in terms of the pricing dynamic?

Operator: And if I can ask a pipeline question.

As we transition our focus to.

Operator: No mention of, I think I heard no mention of BMM 307.

Operator: Can you just give us a sense, of where that program sort of sits?

Hello fans crash commercialization of <unk>.

Yes.

A larger.

And we are.

Hopeful that 2020 would be the geofence.

Yes.

Would be approved in the U S in Europe , and we look forward to helping you.

We can keep you apprised of our progress over the coming weeks and months. So thank you all for it.

Operator: Thank you.

Operator: Hi Chris, I'll start off on the Bonsogo question.

Operator: So you mentioned and confirming that we stated about a third of our revenues from the United States and the balance XUS, which ties up pretty closely to the patient numbers that we're reporting also.

Operator: But kind of a one, as I said, a one-time event.

<unk> supports and Oh.

Operator: And by late March, I would say we were seeing reorders of our specialty pharmacy network in the U.S. on a consistent enough basis that you would conclude that there was no further buying down of that inventory and that the SPs were essentially ordering to demand.

We look forward to seeing you student.

Operator: So that could be a little bit of a bump in Q1, and we're tilted towards the U.S. And you followed along our pricing discussion.

Operator: As usual, we have a robust price, particularly in the U.S. And so far, we're managing a pretty tight price corridor for Bonsogo and other markets.

Operator: Does that cover your question?

Operator: If I may add, actually, the launch is going very well in both sides of the Atlantic.

Operator: This concludes today's conference call.

This concludes today's conference call. Thank you for participating you may now disconnect.

Operator: And the difference you see a little bit is because we started selling in Germany, actually, in October of last year, so a little ahead of the U.S. We really started selling in the U.S. in January.

Operator: But basically, what's happening is that the revenues are commensurate with the market size.

Operator: And we have always said that the largest opportunity was outside the U.S., and the numbers are confirming that.

Operator: Now, so the good news here is that, again, I think there were some anxieties I've read in some, you know, letters and reports about launching a product first in Europe and before the U.S. That's the first time we do that.

Operator: And it shows, actually, that we can be very successful launching a product in Europe ahead of the U.S., which is likely to happen for Octavio.

Operator: So all this is pretty good.

[music].

Operator: Hank, you want to answer?

Operator: Yeah, first, Chris, the game plan is we've got to complete some additional preclinical studies that pertain to the findings that had been previously reported to the agency.

Operator: We were hopeful that, based on some early interactions with the agency, that we would be able to remove the hold quicker.

Operator: But unfortunately, with this requirement to conduct additional studies, we probably won't have any updates for you on that until we have the results of those studies, which are going to be several quarters from now.

Operator: So I'd say, unfortunately, don't be looking for near-term updates on 307.

Operator: Okay.

Operator: Thanks, guys.

Operator: Your next question comes from Robin Karnoskas of Truist.

Operator: Hi, guys.

Operator: Thanks for taking my questions.

Operator: So just a quick one.

Operator: I guess for the EMEA discussion and the U.S. discussion, given that you're adding this additional salivary gland data, is it possible that we could go into July?

Operator: I know you're not on the docket.

Operator: It looks like we're April for EMEA.

Operator: And same for the U.S. Do you think that this could take a little longer if the filing could be middle of the year, like July, August?

Operator: And then the second question is on VoxOgo.

Operator: So it seems like you have the same number of patients in process that you did last quarter.

Operator: Do you expect the addition of patients to be consistent, or do you think this is more of a bullet up front?

Operator: And then maybe you can comment on — I know it's a lot — but maybe you can comment on compliance, given the early — I know it's early, but compliance with daily sub-keto things.

Operator: Thanks.

Operator: Hi Robyn, I think I'll take a shot at the first part of your questions as to the timeline in the European Medicines Agency.

Yes.

Operator: You know, we're feeling pretty optimistic that all the information that we said we'll be able to provide the EMA in the last leg of review will enable them to make a decision in June.

[music].

Operator: But, you know, it's also a decent amount of information, and the EMA has, based on the questions that they've asked, they've requested a decent chunk of information to review in terms of risk management plans, labels, post-approval commitments, and things like that.

Operator: So, yeah, it could drip into July, but we're, you know, we're working to be lined up with them and enable them to come to the positive opinion.

Operator: Of course, that's the objective of all this.

Operator: And in regards to the U.S., you're right to ask a question.

Operator: My team will certainly appreciate the nature of the question, which is that they're carrying a lot of water on the European application at the same time we're finalizing the U.S. application.

Operator: So, you know, as with execution things, and it's really down to execution.

Operator: Yeah, sure, things may take a little longer.

Operator: We really want to make sure that we'll submit an application that will facilitate an effective review by the U.S.

Operator: But that target, again, is in June, and we're remaining on that track.

Operator: And we got your question on VoxOvo.

Operator: I mean, I let Jeff answer the question of whether it's bullies of patients or whether the course is going to be sustainable.

Operator: I believe it will be, but Jeff can elaborate on the compliance.

Operator: I think we've lost only one patient.

Operator: Is that correct?

Operator: All the patients we saw, we have lost one patient so far.

Operator: So, extremely good compliance.

Operator: Yeah, thanks, Robin, for the question.

Operator: It's actually a positive sign of the launch trajectory in the United States, which is the one place in the world that we're able to track patient numbers in process.

Operator: So, the fact that our end process is holding steady compared to where it was a quarter ago is indicative of, you know, getting a steady stream of both of new patients being enrolled and then also having the ability to pretty rapidly work through those patients, get them approved for treatment, get products shipped out, and prescription fulfilled.

Operator: So, I view that as a positive.

Operator: Related to compliance, JJ noted a small number, very small number on drop-off so far.

Operator: We don't have, at this stage, I don't have a quantitative estimate of compliance other than the drop-off figure, which is supportive of a high rate of compliance so far.

Operator: The other thing that we're doing is we're being very proactive with patients and their families about kind of training for this daily injection.

Operator: And we've gotten super feedback in both Europe and the United States that that's been really helpful for families, giving them the confidence to go out and begin the daily injection routine. And I think that bodes well for compliance going forward.

Operator: Thanks.

Operator: And to summarize, too, we have very good visibility in the U.S, because patients basically first enroll kind of in the program.

Operator: They signify that they want to be, well, it's the family, that they want the kids to be treated with VoxOvo.

Operator: So, we have good visibility for the accretion rates, and we have no sign at this time that it is.

Operator: , Lt. Dean, Ross School of Medicine, White Houserophilic Administration Hoffman Thatzähidade's, , Dr. DEFRAAD, The

Operator: first question comes from Corey Kasimov of JP Morgan.

Operator: Hey, good afternoon guys.

Operator: Thanks for taking my question, too, for me as well.

Operator: Both probably for Hank.

Operator: First, just a follow-up on the U.S. Roktavian situation.

Operator: Is there anything specific that needs to be addressed in that pre-BLA meeting that hasn't been dealt with already?

Operator: I guess just curious if this is standard operating procedure for a resubmission or if there are, issues to still discuss.

Operator: And then the second thing, I was just wondering, Hank, if you could set the stage ahead of the short stature update this weekend for VOXOGO, what would be compelling in your view or an investigator's view when you speak with them?

Operator: Thank you.

Operator: Yeah.

Operator: You know, I think the interaction with the FDA pre-submission Roktavian is more of, the SOP rather than necessarily particularly new information.

Operator: You know, I think the agency's stance is likely to be, you know, these are all issues that are going to be resolved during the review.

Operator: What's important for us to do is to make sure that we have a clear-eyed view of the information that they're looking for.

Operator: We have all this data, so it's really just a matter of making sure it's in the form and content of what they're looking for.

Operator: So more on the SOP side.

Operator: As far as the Dauber presentation, you know, I think the expectation to have is that in the amalgam that sort of across a range of mutations, and I think a reminder is that he's indicated that he's accrued patients with six different types of mutations, that there can be an improvement in stature as measured by the AGB in children who have mutations that are different from the achondroplasia FGFR3 mutation.

Operator: And he's got a lot of biology as to why he believes that to be the case, but of course the data themselves will be dispositive for his underlying hypothesis.

Operator: So I would focus in on the AGB change from baseline across the different types of mutations that he's included.

Operator: And I think, you know, a good outcome would be similar or better than, you know, similar, to what we've seen in achondroplasia, a great outcome.

Operator: And it might be mutation-specific, might be that some mutations are even more responsive to the serotypes.

Operator: So I think that's the stage to set for the kind of data.

Operator: Great.

Operator: Thank you.

Operator: Your next question comes from Paul Matisse at CFL.

Operator: Sorry, we couldn't hear.

Operator: I think she said Paul Matisse at CFL.

Operator: Thanks for taking the question.

Operator: Good to talk to you.

Operator: Just one box logo question on the commercial side.

Operator: I guess, are you seeing physicians or do you think physicians will do anything to determine whether or not patients are benefiting?

Operator: Obviously, you can look at growth, natural history, but every patient is different.

Operator: You kind of can get into hypotheticals.

Operator: So maybe just comment on how you sort of verify efficacy with this drug.

Operator: And then to the extent you've seen any discontinuation so far, what are the reasons, if you wouldn't mind clarifying?

Operator: Thanks for your question, Paul.

Operator: So, in terms of tracking benefit, that's not something that we guide specifically to, but we would certainly expect, we would certainly expect physicians to be following along the progress of their patients.

Operator: There is newly published guidance on the management of achondroplasia, which I think is helpful in providing those prescribers the guidance to do that, and growth velocity and height would be, you know, kind of a lowest common denominator that could be expected.

Operator: Some of the U.S. insurers are requiring evidence of benefit for future renewal of prescriptions, for example, which seems reasonable enough.

Operator: And back to the publication on management guidelines, you know, as you've heard me say before, really there was no medical home, particularly in the U.S., in our system, no medical home for achondroplasia patients.

Operator: And I think part of the opportunity here is to establish a medical home for kids with achondroplasia, up to and including, but not limited to, the use of Boxogo as a part of that overall management scheme.

Operator: And I think that's going to be good for Biomarin and Boxogo, and it's going to be great for the kids with achondroplasia and their families.

Operator: In terms of discontinuation, we don't really have enough data.

Operator: As JJ mentioned, I think we have one discontinuation, and I don't have a stated reason for that one.

Operator: Okay, thanks.

Operator: And maybe just one...

Operator: Sorry, go ahead.

Operator: Back to tracking the efficacy, and this is not a scientific way to do it, but just an anecdote that when we tested the advertising campaign with European healthcare professionals and patients, we actually have a picture of a young girl who has been treated with Boxogo for, I think, over four years, probably close to five now. And she's obviously an achondroplastic patient.

Operator: And the reactions from the panels of doctors and families of achondroplastic patients were that we should be using really achondroplastic patients for advertising.

Operator: But that's my other way to answer your questions.

Operator: Thank you, JJ.

Operator: And last, just one quick thing.

Operator: Any update on the path to full approval?

Operator: Thanks again.

Operator: No, not in particular.

Operator: Other than that, the good news is that the data that's going to generate the full approval package is going to be if you follow up these patients from the pivotal clinical trial.

Operator: And as you just heard, the compliance and the program overall is pretty excellent.

Operator: So we do expect to be able to provide that in a timely fashion.

Operator: I don't know that we've got it to a specific submission date.

Operator: Understood.

Operator: Thanks again.

Operator: Your next question comes from Gena Wang of Barclays.

Operator: Thank you for

Operator: taking my questions.

Operator: I have two sets of questions.

Operator: So the first one is regarding the Roctavian

Operator: salivary gland mass integration analysis.

Operator: So you saw similar patterns, but did you see any unwanted sites that show up in this analysis?

Operator: And a related question for your 307 TKU program, your analysis also showed integration, not tumor initiating event, but FDA still asks for data that requires several quarters of work.

Operator: So what makes you confident that similar situation won't happen here to Roctavian?

Operator: And I have quickly on Voxogo question, just wondering, what is the price range for the ex-US different countries?

Operator: And for France, now you have like listing prices at 300,000 US dollars.

Operator: But since you expect future negotiating price will be lower, how would you book the, revenue here?

Operator: Hi, Gina.

Operator: So as regards to pattern of integration, there really was nothing particularly noteworthy about the pattern of integration.

Operator: And I think one of the keys is to compare the pattern of integration between the healthy tissue and the adjacent adjacent in the block to the tumor tissue.

Operator: And as has been previously described for wild type AAV, recombinant vectors have a relatively low propensity to integration.

Operator: And I think that's, that has been foundational in the regulatory perspective. You might remember there was an FDA guidance document on this and they referred to AAV vectors as having a low propensity for, integration.

Operator: I think one of the great things about what we've found so far is that it appears that the recombinant vector is behaving similarly in terms of distribution integration patterns, frequencies, and sites of integration, similar to the wild type. That is to say, not binding preferential hotspots of particular relevance.

Operator: And so the next part of your question was the 307, how does that lead effectively?

Operator: I understood the question to be, how does it lead on the 270 evaluation and why not imagine that there can be the similar requirements for 270 as there have been for, as there appear to be for 307?

Operator: I think the short answer to that is because the 270 vector has cleared its safety studies for the adequate satisfaction of health authorities to date. There have been the only sort of suspicious signal that's arisen in the 270 program is what we just talked about, which was the product tumor.

Operator: And there's nothing unique, particularly in the findings in this individual.

Operator: And so I think having not seen this with neither at a preclinical or Octavian itself, nor with a vector that whose construction is very, very similar to Octavian and studied for a longer period of time, even though Octavian's been studied, that similar vector similarly is not oncogenic in preclinical species.

Operator: So I think all these things take together, taken together, bode quite well for the Octavian overall risk-benefit evaluation, namely that in preclinical studies and in humans, no particularly confirming signal of oncogenic potential in the vector.

Operator: And clearly the FDA is seeing these two products very differently in this respect because although 307 is on clinical holds, Rokevin is not on clinical holds.

Operator: We are enrolling each of these studies as we speak.

Operator: Nor is CMS331 either also enrolling and therefore I think the agency is reacting to this as a vector-specific, indication-specific decision.

Operator: Any other questions on the revenue and price range of VoxPro in Europe and revenue recognition?

Operator: We will start with Jeff and then Brian.

Operator: Regarding the price range, Gina, the prices that we're anchoring to, we've got the wax price in the United States and our approval call we guided to our expectation of gross or wax price to net realizable price per patient.

Operator: I think that's a pretty solid estimate. We've got the list price, as you note, in Germany and France and our expectation is that it's going to take about a year from product introduction to get to negotiated prices for full reimbursement.

Operator: So that will happen later this year and in the meantime, where we're establishing pricing for our named patient sales markets are right in a pretty tight corridor consistent with the U.S., French, and German pricing and I'll let Brian cover the discount piece.

Operator: Thanks, Jeff.

Operator: Thanks for the question, Gina.

Operator: This is Brian.

Operator: There's nothing materially unique to speak about with respect to VoxOgo gross to net. Our experience and our expectations are that the overall gross to net will be similar to our other products as well as our prior launches.

Operator: Not to get into each of the European country by country dynamics, but in some cases, you do start with an initial price and then there could be a clawback when you get to that final negotiated price that gets lower, but we're required under a gap to make estimates of those and record those reserves, if you will.

Operator: So what you're seeing in our reported revenues would be the net net revenue.

Operator: Great.

Operator: Thank you.

Operator: Very helpful.

Operator: Your next question comes from Jeff Meechan of Bank of America.

Operator: Hey, guys.

Operator: Thanks so much for the question.

Operator: I just had a couple along kind of the same theme as everyone has been asking.

Operator: Hank on Roktavian, I know it's parsing the language a bit, but is the shift from 2Q to mid-2022 from the CHMP, is that just a normal fluctuation or was in fact there an impact to the review clock?

Operator: When you look at the tumor analysis.

Operator: And then on Voxogo, commercially, I know it's early, but are there some themes and new patient starts in Europe who weren't in the clinical studies in terms of patient flows or awareness?

Operator: I'm just trying to get a sense for what was working there this early in the launch and maybe if that could be similar or different when you look to the U.S. launch.

Operator: Thank you.

Operator: Jeff, on the earlier, you know, there's no concrete piece of information that is underneath the shift, the minor, you know, I was talking about it being June, maybe shifting into the summer.

Operator: I think the only news here is, or that's not even news, is we've been off, we just came off accelerated assessment, and that was anticipated.

Operator: What you never know at the beginning of the procedure or even in the middle of the procedure is just sort of how their timelines line up and when they want to receive information, and so I think, you know, as much as anything, we're just being a little abundant caution here in terms of projecting timelines because they're not entirely in our control as a result of the fact that we're giving them a pretty big slug of data towards the tail end of the review.

Operator: I think the most important thing is we believe that we have the information that addresses the questions they've issued to us, and based on those questions, we believe that a positive benefit-risk opinion can come, but that happens after they've done their meetings with non-closed doors, so that's what we're working to support.

Operator: Yeah, so, Jeff, what I would say about themes is diversity of experience here, which points kind of away from common themes in an important way.

Operator: Diversity, I would say, diversity of age group that we're seeing, starting therapy, one example, diversity of prescriber specialty that we're seeing, mainly genetics and pediatric endocrinologists, but also some pediatric orthopedists and pediatricians showing up here, and also kind of diversity of approach.

Operator: So, in Germany, we're essentially operating under a full price of reimbursement approval, even though we haven't negotiated a final price there, kind of how the market behaves, and so we're seeing pretty rapid uptake.

Operator: In France, in contrast, we're currently operating under a very structured expanded access protocol there, so it's a more kind of structured approach to getting patients started from a relatively small network of clinics.

Operator: That's not really something that we've seen anywhere else, and in the smaller named patient sales market, I would say the theme there is we're getting one or a couple of patients approved initially under named patient sales approvals, and our opportunity there has been to kind of build off that, get the third, the fourth, in some cases the fifth or the eighth patient treated, and we're working hard to do that.

Operator: So, a lot of diversity, actually, of experience.

Operator: Next question we have Phil Nadeau with Cowen.

Operator: Good afternoon.

Operator: Let me add my congratulations

Operator: on a productive quarter.

Operator: Just a couple follow-ups from us on VoxZogo and Roktavian.

Operator: First on VoxZogo, Jeff, I think on the approval call you identified one of the challenges of the, U.S. launch that a lot of patients weren't in expert centers.

Operator: Are the expert centers reporting that patients are inquiring about being treated, or is there a general flux of patients towards the expert centers with the availability of VoxZogo?

Operator: And then second, on Roktavian, Hank, just briefly, what are your expectations for an adcom?

Operator: I know there wasn't one in the first review.

Operator: Do you think the FDA is likely to hold an adcom to review the Roktavian resubmission?

Operator: Thanks.

Operator: So, Phil, I'll start on the VoxZogo experience in the United States.

Operator: You're right.

Operator: When we, on the approval call, I noted that longer term our big task was to establish a referral network and kind of get patients out of the random physician, which is not a medical home for achondroplasia, get them referred either to a genetics clinic that's interested in achondroplasia or to a pediatric endocrinologist and moments ago I mentioned that that's an opportunity to create a treatment home for achondroplasia.

Operator: And also earlier I said, you know, we've got a pretty steady rate of patients coming in in the United States for referrals and an in-process group and that's a good signal indicating that we didn't just have a bolus of patients that wore off and is slowing down over time.

Operator: However, underneath that, I think you're right, a lot of our early patients were coming from the genetics and skeletal dysplasia clinics, expert centers that had achondroplasia patients lined up.

Operator: So, a lot of interest in referrals early on from that channel and in the last couple of months then we've been able to get that referral network established in the U.S. and start driving patients from a random physician that they're being seen by to pediatric endocrinologists.

Operator: So, that's picking up now and I think that's going to be the longer-term driver of growth for the U.S, market.

Operator: On the issue of end counsel, I don't know that I have like needfully more information to add a dialogue since the agency won't really decide the ADCOM until they're in review.

Operator: I mean, I think if you were to ask Hank personally, what would he say?

Operator: It would be something like, well, the agency calls ADCOMs generally for two purposes.

Operator: One is when they want to approve something and they want to rally the troops around the decision they make and then the other is when they want to kill something and they want to use the ADCOM to kill it.

Operator: Feels like, you know, there's not a lot of info that they could show to an ADCOM to kill it because the efficacy profile is good, the safety profile is good, and so what would you point to to be the motives for killing it?

Operator: So, I guess Hank would say I hope they do call an ADCOM because I hope that what they are doing is going to be serious about like how they regulate gene therapy products and use a fairly robust package of

Operator: Octavian to establish standards for review.

Operator: Next question is from Matthew Harrison of Morgan Stanley.

Operator: Great.

Operator: Good afternoon.

Operator: Thanks for taking the question.

Operator: Geoff, I just wanted to follow up on two things.

Operator: One, I think you talked about some inventory dynamics that helped Boxogo this quarter at the specialty pharmacies.

Operator: Could you or maybe you're willing to just quantify or give us some sense about how much that helped?

Operator: And then secondly, just as you're preparing for Rokkavian in Europe, can you give us some sense of how much work has been done so far and how much engagement you've had with each of the countries around or if any engagement around price and just sort of initial commentary there?

Operator: Thanks.

Operator: OK.

Operator: Thanks, Matt, for the question.

Operator: So back on Boxogo and the U.S. and kind of arresting specialty pharmacy inventory, you could judge from the mix of revenue, ex-U.S. and U.S. and say, well, Biomarin is getting the $7 million of revenue, was U.S.

Operator: I also said that by March, we were seeing orders that indicated to me that specialty pharmacies were not drying down that resting inventory, which is a good thing.

Operator: We also know specialty pharmacies don't like to hold a lot of inventory and really they don't have to because we've got really good reorder dynamics for them.

Operator: So I might I might guide to a couple to several million dollars of inventory.

Operator: And then with respect to Rokkavian in Europe, one of the things that I think the Boxogo launch in Europe is doing is validating that where there is a large market opportunity and you have an experienced company with experienced teams, you can do a lot of things. Where there is a large market opportunity and you have an experienced company with experienced teams that know what they're doing, we can capitalize on that market opportunity and have successful launches in the EU in particular.

Operator: We're leveraging all of the experience that we've gotten from the past launches.

Operator: As in the United States, we formed specialized teams to prepare for Rokkavian, including seating our teams with people with significant experience in the hemophilia business.

Operator: We're essentially ready to go in particularly in the markets where we're expecting first revenues. And you might expect from the current and past experience that would be in places like France and Germany and Italy first and in places where we get named patient sales uptake on a relatively rapid basis.

Operator: So we've got people in those places.

Operator: Yes, we've been doing price research.

Operator: We have an active program working with market access advisors in Europe. We followed that practice, for example, with Boxogo.

Operator: We're doing the same thing with Rokkavian.

Operator: I think we're really ready for this launch and we're excited about it if we get a CHMP positive opinion and an EC approval here.

Operator: I may add a few things.

Operator: So in Germany, at least at large, we're seeing a price, you know, close to the US Fed price, around $2 million.

Operator: And we also have done a lot of preemptive research.

Operator: There's major interest by German payers about outcome-based agreements.

Operator: And we will be making those available, because now we have great data showing that, you know, the majority of the patients do, not respond very well to our payment, and very few of them, you know, lowest skill digits are either not responding or go back to prophylactic factory therapies after a few years.

Operator: So we can, we can maximize the price at launch by basically offering a guarantee of success to the payers.

Operator: And that's something that they understand very well, and they are very interested in, considering that they know how much the species are costing them.

Operator: So that's kind of the plan.

Operator: The next question comes from Joseph Schwartz with SBB Securities.

Operator: Hi, a lot of my questions have been answered.

Operator: So I'll ask some things about your mid-stage pipeline.

Operator: I guess it's been over a year since the IND was filed for BMIN 255.

Operator: So I was wondering if you could give us an update on this program.

Operator: I see you completed the SAD work and are analyzing that.

Operator: Do you think you'll be advancing to the MAD portion, and when can we expect to see some data there?

Operator: Is it possible to see a signal from the MAD trial, even though these are healthy volunteers?

Operator: Hi, Joe.

Operator: All good questions.

Operator: You know, the early stages of small molecule development are sort of oftentimes the twistiest part of the road.

Operator: So I think all I can share with you now is what you put in your question, which is we've completed the single ascending dose portion of the study, and we're analyzing the results of that.

Operator: So if we really figured out a way to open the cap on oxalate, it should be excretion.

Operator: It should be, or I should say close the cap.

Operator: It should be exciting for patients.

Operator: But stay tuned as we gather data in this particular twisty phase of the program.

Operator: Okay, thank you.

Operator: Your next question is from Dr. Tadopadhyay with Guggenheim.

Operator: Hey, thank you for letting me in.

Operator: So just on BoxerGo, on the commercial loan so far, upper age limit of patients who are currently getting prescribed?

Operator: And number two, any clarity on the sleep apnea signal noted in the younger subjects in the pre-0 to 5-year-old study?

Operator: And finally, are you planning to advance the long-acting version into the clinic?

Operator: Thanks so much.

Operator: I'll start with the question on the age range.

Operator: As noted earlier, we've seen where we have the data to measure it, quite a lot of diversity in age range, including teenagers being enrolled for treatment as well as younger kids. So don't have a ceiling on age, but what we know is that kids that have...

Operator: , and Mark Lowe.

Operator: We would expect that upper limit to be something plus or minus or 18 years old plus or minus.

Operator: I think your second question was related to the 0-5 year olds. Yeah, so the biggest possible picture on the 0-5 year old is that in Europe, the first territory we launched, Europeans were compelled by the overall package of data and the Sentinel data that we provided to them during the application.

Operator: I think we talked about that.

Operator: That means we have a label that we can sell the product to the 2-5 year old population.

Operator: In the United States, the FDA wanted a little bit more information, and the results of 2006 are going to inform that.

Operator: We've announced the positive trends were observed, and I think in the treatment of these young children, I think the next step, therefore, is to have conversations with Food and Drug Administration about labeling requirements.

Operator: We're going to pursue a similar pattern throughout the rest of the world.

Operator: We believe that the data support giving families a treatment option for children who are under 5 years of age with achondroplasia, and working with health authorities to provide them the information that they need to come to that decision.

Operator: Different geographies may come to that decision at different time points based on emerging data.

Operator: So I'd say stay tuned for further updates from us on both regulatory plans as well as overall plans for addressing this.

Operator: And we are in the late stage of a review in Japan for our application that the funding is for zero, that means for 80 patients from birth through big surgery.

Operator: So I don't know if you want to say a few words about when the data will be presented.

Operator: Yes, so the data will be presented, I think we said, summer on the call or middle of the year.

Operator: And then I think you also asked about lung acting.

Operator: Lung acting, I think, so far thought about it as not much of an efficacy advantage in most children, not much of a safety advantage.

Operator: We've talked about all the numbers behind all that.

Operator: But, you know, it is an interesting question as it pertains to the children who are under 5.

Operator: You might know that Ascendis has in their Phase 2 study enrolled some patients who are under 5, so there could be some data about the effect of lung acting on overall growth.

Operator: But, again, a key reminder about that is how far behind us Ascendis really is in terms of its development pathway, and this is a relatively small Phase 2 study.

Operator: So I think we have some room to both offer this option on a global basis for young children, because there is nothing else, and time is of the essence, as well as to further iterate our product offerings to continue building strength in the Voxezo brand.

Operator: Thank you.

Operator: Good luck.

Operator: Your next question is from Joel Beattie with Baird.

Operator: Thanks for taking the questions.

Operator: The first one is for Voxezo.

Operator: What's the level of awareness of the drug among patients with achondroplasia and their families?

Operator: And then also for 351 for DMD, what will be learned from the initial study starting later this year?

Operator: Maybe I'll start with the question about level of awareness.

Operator: That's something that we would typically be market researching to get a quantitative estimate following launch, and the answer on that one is we haven't yet gone out to market research that question, of 20 or 40 percent of this shortened dystrophin protein, which is pretty high relative to what ambulatory patients with a far less severe condition called Becker's dystrophy, muscular dystrophy, have.

Operator: So, as quickly as possible, the initial 3.5.1 proof of concept study will gear itself towards demonstrating safe improvement of a meaningful quantity of dystrophin protein in muscle.

Operator: Can't give you a timeline specifically for when those data will be available, as we're just getting started.

Operator: Thank you.

Operator: There are no questions from Luca Isi with RBC Capital.

Operator: Well, great.

Operator: Thanks so much for taking my question.

Operator: Quick one on Valrox.

Operator: I know you're ruling out AAV as the potential cause of the salivary gland cancer, but can you actually share the integration frequency that you have observed on the surgical piece?

Operator: I know Unicure mentioned in the past 0.027 percent of their cell, showing evidence of AAV integrations for their epithelial carcinoma case, so just wondering how your number compares to that number.

Operator: And maybe also related, I think Ask Bio and Bayer reported a case of tonsil cancer in their hemophilia B program, so wondering how you're thinking about read-through for your program.

Operator: And then still on Valrox, assuming it does get approved, can you remind us what's the latest thinking on pricing strategy?

Operator: And feel free to dichotomize the answer between the U.S. and the EU, should that make sense.

Operator: Thanks so much.

Operator: I think specifically as regards to numbers, coming to the presentations that are coming around the corner at both WFH and ASGC, the way I think about it is that what we've seen so far is consistent with what's been previously described as low propensity for integration.

Operator: So qualitatively anyway, that's the frame to take into your review of those presentations.

Operator: As regards the occurrence of other tumors, I do think that over time there are going to be patients developing cancer. That's just a fact of getting older in life.

Operator: And I think that what we've seen to date doesn't really suggest that there's been particularly clustering of tumor types.

Operator: I think also one has to really consider sort of vector at a time.

Operator: That's kind of what we've learned in our 307 journey, as we were talking about earlier.

Operator: I think the data that we're talking about today are pretty encouraging as regards to reaffirming what we've known all along about AAV, relatively low propensity for integration, relatively low specificity for integration events in particular spots in the genome, and no reason to believe fundamentally that what's been observed with AAV… People run around talking about the cancer risk of hepatitis C or hepatitis B. AAV is not the thing that people are running around talking about systemic cancer risks from.

Operator: So I think that low propensity of integration, corroboration that we're talking about today is really a powerful finding.

Operator: We covered already the previous question, the pricing in Europe, so I don't think we need to go over that again, but do you want to say a few words about the U.S. pricing, Jeff?

Operator: Yeah, so what you've heard JJ say publicly a couple of years ago was probably not less than $2 million at WACC, probably not more than $3 million, but that's the range that the ICER first review that showed Roktavian to be a dominant choice at a presumed price of $2.5 million kind of worked up.

Operator: Maybe just one other comment on pricing and our ability to capture a premium price.

Operator: JJ mentioned outcomes-based agreement earlier. That's crucial to our ability to capture value for Roktavian.

Operator: Payers, in addition to wanting their patients to do well, to not bleed, to not have to infuse two and a half times a week on average, payers are concerned financially about their risk of nonperformance following administration and the risk of durability of effect over time. The data that we have so far would suggest risk of nonperformance following administration is very, very low, and the durability data that we've seen both out of the 201 study and the Generate One study, including the 17 patients that we have three years at, is really encouraging about the durability of effect over time.

Operator: We think that we can largely take those risks off the table for payers, and that's one of the factors that will allow us to capture that high value initially.

Operator: Thank you.

Operator: This concludes the Q&A session.

JJ Bien-Aime: I will now hand it over to JJ Baname for closing remarks.

JJ Bien-Aime: Thank you, Operator, and thank you all for joining us today.

JJ Bien-Aime: We are, again, pleased to begin 2022 with a record first-quarter results.

JJ Bien-Aime: The addition of Oxogo to our commercial portfolio is definitely an important component of our growth story going forward, and it paves the way for sustainable gap profitability beginning this year.

JJ Bien-Aime: We have successfully transitioned our focus to the development of commercialization of therapeutic therapies for larger genetic conditions, and we are hopeful that 2020 will be the year that Rotarian will be approved in the U.S. and Europe, and we look forward to keeping you advised of our progress over the coming weeks and months.

JJ Bien-Aime: Thank you all for your continued support, and we look forward to seeing you soon.