Q3 2019 Earnings Call

All this last conference call.

Traci McCarty: Operating the conference call today from Biomarin is Traci McCarty, Vice President of Investor Relations. Please go ahead. Thank you, Grace.

The conference call to be from Biomarine, Mccarty, Vice President Investor Relations. Please go ahead Tracy.

Thank you great. Thank you everyone for joining us today to remind you. This non confidential presentation contains forward looking statements about the business prospects, the biomarin pharmaceutical inc., including expectations regarding fiber and financial performance commercial product potential future products in different areas of therapeutic research and development results may differ much.

Unknown Executive: Thank you everyone for joining us today. To remind you, this non-confidential presentation contains forward-looking statements about the business prospects of Biomarin Pharmaceutical Inc., including expectations regarding Biomarin's financial performance, commercial products, and potential future products in different areas of therapeutic research and development. Thank you, Tracy.

Really depending on the progress of vibrant product program actions of regulatory authorities availability of capital future actions in the pharmaceutical market developments by competitors and those factors detailed byron's filings with the Securities and Exchange Commission, such a 10- Q1 0-K, an 8-K report.

On the call today from Vibrance management team, our JJ piano named Chairman and Chief Executive Officer, and refuse President worldwide Research and development.

Spiegelman Executive Vice President and Chief Financial Officer, Rubber Baffi, President Global manufacturing checked the cooperation Jeff age or executive Vice President Chief Commercial officer.

Unknown Executive: Good afternoon, and thank you for joining us on today's call. We are proud to share our highest quarterly revenue results to date at Biomarin, a record $461 million in revenues in the third quarter, which represents an 18% growth over the third quarter of last year and demonstrates the increasing strength of our base business. And while we are excited about our next generation products, Phalrox and Rosoritide, we never lose sight of the importance of our existing products to both the people who rely on them to improve their health and to the In these unpredictable times, it is reassuring that, between our strong balance sheet and excellent commercial business, we are not reliant on the financial markets.

Consistent with the last two quarterly calls we intend to keep this call to one hour in like if we do not get your question. Please I mean email or give me a call we'll get right back to you. Thank you for your understanding now I'd like to turn the call over to our chairman and CEO JV enemy.

He is happening in thank you for joining us on today's call I'm here.

Share our highest quarterly revenue results to date and bomb run.

He record 461 million in revenues during the third quarter, which represents the.

10% growth over the third quarter last year.

Mr rates, increasing strength of our base business.

And why we're excited about our next generation products rocks and it was very tight.

We never lose sight, the importance of our existing products to boost the people.

And then to their health.

And to the financial health of our business.

These unpredictable times, if he is reassuring that between our strong balance sheet.

Commercial business, we are not reliance on the financials Mark.

As we rolled out you saw 19 copied US you know based business combined with our <unk> management.

Unknown Executive: As we round out 2019, confidence in our base business combined with R&D expenses management resulted in tightening of both gap and non-gap guidance to the top of the range for the full year. Our continued commitment to growth and profitability was demonstrated by cash generated in the third quarter, which was just over $70 million. In addition to our strong-based business, potential returns from our investments in Valrox and Vozori cards are on the horizon. Approximately three years ago, we laid out a five-year plan for the financial success of the business, and we remain on track. We say that R&D expenses as a percentage of revenues will peak and then come down.

We felt it is tightening up both GAAP and non-GAAP guidance to the couple of their range.

For the full year.

Our continued commitment to growth and profitability was demonstrated by cash generated in the third quarter, which was just over.

How do you mean.

In addition to our strong base business.

Potential returns from our investments in Boston was always cards are on the right.

Approximately three years ago, we laid out.

Five year plan for financial success of the business.

We remain on track.

We see the R&D expenses as a percentage of revenues with Pete and they've come down.

Unknown Executive: Over the last three years, it has come down from 60% to 43% of revenues and is on its way to our long-term goal of 25%, all while preserving a high level of productivity from our R&D engine. Meanwhile, our top line has grown 15% or more year-over-year with a $2 billion revenue target for 2020. Either Valvox or Rosario Tech could push revenue growth well beyond that after 2020. And, of course, we have been focusing on the bottom line as well in 2016.

Well, that's three years he has come down from 60%.

240% to 43% revenues and on its way through our long term goal of 25%.

While preserving our level of productivity from R&D engine.

Our topline Hasbro and 15% of more year over year with E $2 billion revenue target for 2020.

No of course, we have been focusing on the bottom line as well.

In 2016.

Unknown Executive: We said that we would be non-gap positive starting in 2017, and we were. Non-gap positive in 2017, and we have continued to grow each year. Our next target is GAAP profitability, and from here, the success we anticipate from VAROX overzoitized, rapid, and significantly profitable growth is on the horizon. We are all aware of recent market volatility and its negative impact.

We said that we would be nongaap holidays.

Got any 2017, we were.

No no positive in 2017, new we have continued to grow.

Each year.

Our next target is GAAP profitability and from here. The success, we anticipate homes. So there's always died rapid and significantly profitable growth is on the right.

Well, all aware, our research market volatility and the negative impact.

Unknown Executive: It's sent out to our shareholders in the short term, but with the potential business payoff of our strategies in full view. We remain steadfast in our focus to get Virox and Vazorita approved and launched. And with over $1 billion in cash and investments, our two potential blockbusters on the horizon, and a third already on the market, which is Palazik, we are poised to leverage the R&D, commercial, and manufacturing expertise and capabilities established over the last several years. At the heart of our business, and what creates our growth opportunities, is our R&D engine. And with that in mind, we look forward to hosting you at our annual R&D Day in New York on November 14, where we will provide updates on our late stage program as well as shine a light on the next potential growth drivers. Beale Barracks, and Missouri Tech.

Now on our shareholders in the short term.

However, with the potential business be off of our strategies in school you.

We remain steadfast in our focus to get boxes, it's always a cool handle.

And wheels, or when we didn't goes in cash and investments.

Two potential bulk purchases on the horizon. If there are many older markets.

Oh.

We are poised to leverage the R&D commercial and manufacturing expertise expertise and capabilities.

At least over the last several years.

At the heart of our business and what creates our growth opportunities is our R&D engine.

It was that in mind and look forward to Horsing you.

Our annual R&D day in New York on November 14.

Where we will provide updates on our late stage program.

There are lot shine a light on the next potential growth drivers.

Selling general and is there any time.

Jeff: We also have an interesting lineup of critical candidates to share with you as we consider which programs will be added next to our development pipeline. Please email the IR team for further details, and we hope you will be able to join us. Now I would like to turn the call over to Jeff, who will provide more details on the commercial business in the quarter and our expectations for the remainder of the year. Thank you, J.J. As J.J. mentioned, the third quarter was record-breaking in terms of revenue for Biomarin, driven by a strong quarter for Vemisim and $30 million in revenue growth from our newest brands, Palindik and Brnura. Globally, Biomarin commercial brands contributed $428 million, a 19% increase quarter-over-quarter, and $1.2 billion year-to-date, or 14% year-over-year growth.

We also have an interesting lineup of preclinical candidates to share with you as we consider which programs will be added next to our development pipeline.

Please email the IR team for further details and we hope you would be able to join us.

I would like to turn the call over to Jeff will provide more detail.

The commercial business in the core and our expectation.

Neither of the year Jeff.

Jay.

As Jay mentioned, a third quarter was record breaking in terms of revenue for both brands.

Driven by strong revenue quarter for Devon.

And $30 million in revenue growth from our newest brands, telling zinc and Bernard.

Globally, Biomarin commercial brands contributed $428 million, a 19% increase quarter over quarter and $1.2 billion year to date or 14% year over year growth I.

Jeff: I will detail the breakdown of individual product contributions, but I'll start with the positive development in Brazil, a major market for MPS brands. In the third quarter, we recognized the first installment of a 12-month supply agreement with the Brazilian Ministry of Health for both Vemizem and Aglozyme, which combined for a total contribution of $45 million. This new one-year supply agreement should result in more revenue predictability through Q2 of 2020, although there will still be uneven order patterns quarter to quarter. Importantly, under this new arrangement with the Brazilian Ministry of Health, we would expect the majority of the roughly $90 million contract to be applied in 2019. And now, a little more detail on VIMSIM globally.

I will detail the breakdown of individual product contribution.

Well start with a positive development in Brazil, a major market for MBS brands.

In the third quarter, we recognize the first installment of a 12 month supply agreement with the Brazilian Ministry of Health for book them, assuming that goes on.

Which combined for a total contribution of $45 million.

This new one year supply agreement should result in more revenue predictability through Q2 2020, although there will still be on even order patterns quarter to quarter.

Importantly, under this new arrangement with the Brazilian Ministry of Health, We would expect the majority of roughly 90 million dollar contract to be applied in 2019.

And now a little more detail on feminism globally quarterly revenue of $164 million represented a year over year increase of 33%.

Jeff: Quarterly revenue of $164 million represented a year-over-year increase of 33%. While a large Brazilian order was a major factor in the quarter, patient growth of 11% globally also contributed to the increase and will support long-term additional revenue growth. For the full year, we are tightening our guidance to between $540 and $570 million.

Well, a large Brazil order was a major back during the quarter patient growth of 11% globally also contributed to the increase and will support long term additional revenue growth.

For the full year, we're tightening our guidance to between 540 $570 million.

Jeff: For NAGLAZINE, revenues driven from Brazil were offset by decreases due to ordering patterns in the IUMEA region, and thus, Q3 revenue totaling $94 million was down 4% versus Q2. Despite the neutralizing effect of both favorable and unfavorable ordering in this quarter, overall patient growth remains steady, and we expect consistent annual revenue growth will continue. For the full year, we see revenues tightening to between $360 and $380 million, narrowing the range. Turning now to the PKU brands, starting with Palanzik.

Well that goes on the revenues driven from Brazil were offset by decreases due to ordering patterns in the EMEA region, and that's Q3 revenue totaling $94 million was down 4% versus Q2, despite the neutralizing effect of both the favorable and unfavorable.

During this quarter overall patient growth range study and we expect consistent annual revenue growth will continue for the full year, we see revenues tightening to between 360 and $380 million tightening the range.

Turning now to the PK, you brands and starting with Alan zinc and the U.S. July Mark the one your milestone of drug availabilities Whos, the FDA approval and the trajectory of patient referrals in correlating revenues are meeting expectations across all metrics.

Jeff: In the U.S., July marked the one-year milestone of drug availability post-FDA approval, and the trajectory of patient referrals and correlating revenues is meeting expectations across all metrics. Q3 revenues of $24 million, essentially all of which came from U.S. sales, were driven by a combination of the growing number of patients who have now achieved once-daily dosing and new patients initiating therapy. A reminder that it takes, on average, five months for a patient referral to get to commercial therapy and then to daily dosing, at which point that patient is a material revenue driver. At the end of Q3 in the United States, there were 670 patients on Pallanseed commercial therapy. 142 of those patients were from clinical studies and 528 patients formerly naive to Pallanseed. Additionally, there were an additional 153 enrolled naive patients who had not yet received their first commercial dispense.

Three revenues of $24 million essentially all of which came from U.S. sales were driven by a combination of the growing number of patients move now achieved once daily dosing and new patients initiating therapy. A reminder, that it takes on average five months for a patient referral to get to come.

Mercil therapy, and then to daily dosing at which point that patient is a material revenue driver.

The end of Q3 in the United States. There were 670 patients on Pellens eat commercial therapy 142, those patients from clinical studies and 528 patients formally naive dependency.

There were an additional 153 enrolled naive patients who have not yet received their first commercial dispense total of 823 adult PK you patients their bore either already being treated with commercial policy or well on their way that their first ship.

Jeff: A total of 823 adult PKU patients, therefore, either already being treated with commercial Palanzec or well on their way to their first shipment. Turning our attention now to the EU launch, in May 2019, we announced approval for Palanzec by the EMA, and since that time, we have engaged in very active education efforts, preparation of reimbursement dossiers, and promotional activities in first priority markets. I'm happy to share that physicians are treating patients now in Germany, the first EU country to market this medicine.

Turning our attention now to the you launch in May 2019, we announced approval propelling zig by the yeah may and since that time have engaged in very active education efforts preparation of reimbursement dossiers and promotional activities and first priority markets.

Happy to share the physicians are treating patients now in Germany. The first you country to market.

Jeff: Without the benefit of patients transitioning from clinical trials, in combination with the timing required to achieve reimbursement approvals, we expect that it will take time to realize material revenue contributions from Europe. We're very happy with the progress that we've made to date, and we reaffirm revenue guidance for Palanze, tightening the range. Shifting now to QVAN, global revenues in the third quarter totaled $121 million, representing a 6% increase year over year.

Without the benefit of patients transitioning from clinical trial in combination with the timing required to achieve reimbursement approvals. We expect that it will take time to really realize material revenue contributions from Europe , we're very happy with the progress that we've made today and we reaffirm revenue guidance for Pellens a tightening the range.

Shifting now to bad mobile revenues in the third quarter total $121 million, representing a 6% increase year over year. The majority of this was due to patient growth in the United States and achieved in parallel to changing patient demographics as more adult.

Jeff: The majority of this was due to patient growth in the United States and achieved in parallel to changing patient demographics as more adult PKU patients now have the option to treat with balance. We are adjusting our full year guidance for. Finally, an update on Bernoura.

PK new patients now have the option to treat.

We are adjusting up our full year guidance for Ku band.

Finally, an update on Bernard net product revenues were $20 million in Q3, driven by patient uptake and diverse global markets across all four regions. Our teams continue to focus our efforts on driving early diagnosis and identifying new patients who would benefit from therapy.

Jeff: Net product revenues were $20 million in Q3, driven by patient uptake in diverse global markets across all four regions. Our teams continue to focus their efforts on driving early diagnosis and identifying new patients who will benefit from therapy, coupled with unlocking reimbursement in countries around the world. As a result of these efforts, Bronura has exhibited steady growth over time and is now reaching the level of material revenue contributions on a quarterly basis.

Coupled with unlocking the reimbursement in countries around the world.

As a result of these efforts Bernard has exhibited steady growth over time and now is reaching the level of material revenue rec.

Contributions on a quarterly basis.

Hank: We expect continued growth going forward and reaffirm our guidance for Brunnera. In conclusion, I'm very pleased with the commercial team's execution and performance in the third quarter of 2019 in all four regions and excited to track and report the progress of the launch of Palanzec in the EU. For the remainder of the year, with our established commercial-based business, we are confident in our ability to achieve full-year revenue guidance of approximately $1.7 billion. So thank you, and now I'd like to turn the call over to Hank. Thanks, Jeff, and congratulations to you and your team. Starting with BALRCs for adults with severe hemophilia A.

We expect continued growth going forward and reaffirm our guidance for Bernard.

In conclusion, I'm very pleased with the commercial teams execution and performance in the third quarter of 2019 in all four regions and excited to track and report the progress of the launch of Palatins IEC and you.

For the remainder of the year without established commercial base business. We are confident in our ability to achieve full year revenue guidance of approximately $1.7 billion.

So thank you and now I'd like to turn the call over to Hank.

Thanks, Jeff and congratulations to you and your team.

Starting with Bell rush for adults with severe hemophilia a.

Hank: An exciting regulatory development has been announced today. We're pleased to share that the European Medicines Agency has recently granted our request for an accelerated assessment of Valrox. In its assessment report, the European Medicines Agency acknowledged Valrox's potential to address the existing unmet need by providing patients with a treatment option that only requires a single intravenous administration and subsequently is expected to provide steady levels of endogenously produced coagulation factor eight for a substantial amount of time.

An exciting regulatory development has been announced today, we're pleased to share at the European Medicines Agency has recently granted our request for accelerated assessment of Alex and their assessment report the European Medicines agency acknowledged dots has potential to address the existing unmet needs by providing patients for the treatment option that only require.

Just a single intravenous administration and subsequently is expected to provide study levels of endogenously produce coagulation factor for a substantial amount of time.

Hank: This decision is particularly important because, based on the data the EMA has already received, the EMA recognizes Valrox's potential as a product of major interest for public health and therapeutic innovation. This decision is also important as the accelerated assessment procedure reduces the time frame for the European Medicine Agency's Committee for Medicinal Products for Human Use, the CHMP, to review our planned marketing authorization application for Valrox on track for later this year. Needless to say, we are gratified to accept this recognition of Valrox given the impact it could have on patients with severe hemophilia A. Another positive development we want to share is the news that our Shambali facility has been successfully inspected by the Irish HPRA for testing and release of gene therapy products. These newly constructed laboratories are part of our overall strategy for meeting worldwide regulatory requirements for product distribution.

This decision is particularly important because it shows that based on the data. The EMEA has already received the M.A. recognizing its Alex as potential as a product of major interest from public health and therapeutic innovation.

This decision is also important to see accelerated assessment procedure reduces the timeframe for the European Medicines Agency commitment committee for medicinal products for human use cgmp to review our planned marketing authorization application for about right on track for later this year.

Needless to say, we're gratified to accept this recognition of how rocks given the impact half for patients with severe hemophilia.

Another positive dollar we want to shares news that our shambolic facility has been successfully inspected by the Irish H.P.R.A. protesting and release of gene therapy products. These newly constructed laboratories are part of our overall strategy for meeting worldwide regulatory requirements for product distribution.

Hank: This added capability prepares us to meet in-country testing requirements for the release of commercial product in the EU region. We continue to expect to submit marketing applications in both the United States and Europe in this quarter based on recent meetings with the FDA and the EMA, as we announced earlier this quarter. These submissions will be based on the recently completed Phase III Interim Analysis and the updated three-year Phase I-II data of patients treated with valactocagene roxiparvovac. Enrollment in the Generate One Phase 3 Open Label Study is expected to complete in mid-November, with the 52-week results anticipated in that study at the end of 2020. As we have said previously, although the trial is open-label, we have a data access plan in place that is designed to significantly mirror a blinded trial.

Capability prepares us to me in country testing requirements are the release of commercial caught in the region.

We continue to expect to submit marketing applications from both the United States in Europe , and this quarter based on recent meetings with the FDA on him a chance we announced earlier in this quarter.

These submissions we based on the recently completed phase three interim analysis and the updated three year phase one two data a patients treated with <unk> selected could gene rotce apartment back.

Enrollment in the generate one phase three open label study is expected to complete mid November with the 52 week results anticipated in that study at the end of 2020.

As we've said previously although the trials open label, we Havent data access plan in place, which is designed to significantly mirror a blinded trial.

Hank: This precludes anyone not directly monitoring the trial from accessing any emerging data from the study, and we are not updating any of our prior analysis. As for the ongoing Phase II study, we intend to share a four-year update with the 6E13 dose as well as a three-year update on the 4E13 dose in the middle of next year at an appropriate medical conference. Turning to our next late stage program, the sorotype of treatment for achondroplasia is nearing the finish line. Our global multi-pronged program has been designed to achieve maximum clinical benefit for infants and children with achondroplasia from newborns through growth plate closure.

Precludes anyone not directly monitoring the trial to access any emerging data from this study and we're not updating any of our prior analyses.

As for the ongoing phase two study, we intend to share a four year update with the 60 13 dose as well as a three year update on the 40 13 does at the Middle next year that appropriate medical conference.

Turning to our next late stage programs. So our type of treatment of a contra pager, it's finish nearing the finish line.

Our global multi pronged program has been designed to achieve maximum clinical benefit for infants and children with any contemplation from newborns true growth plant closure.

Beginning with the phase three program results from the large global study that includes children's for ages five to 18.

The data are expected by the end of the or Needless to say, we look forward to sharing all these top line results with you at that time.

Hank: Beginning with the Phase 3 program, results from a large global study that includes children ages 5 to 18, the data are expected by the end of the year. Needless to say, we look forward to sharing all these top-line results at that time. Another key component of our global program in achondroplasia is the Phase 2, a zero to five-year-old study.

Another key component of our global program and they constellation is the phase two zero to five year old study.

Given our conviction and the opinion stated that the ICANN AD com, meaning that the FDA held earlier in the year and last year triangle Sonatide, starting as early as possible may translate into the best results for children with a contra pleasure, we're thrilled with the progress of this ongoing study we've completed enrollment in the first couple of the study which includes.

Hank: Given our conviction and the opinion stated at the ACON ADCOM meeting that the FDA held earlier in the year and last year, treatment with mesorotide started as early as possible may translate into the best results for children with achondroplasia. We're thrilled with the progress of this ongoing study. We've completed enrollment in the first cohort of the study, which includes children from two to five years of age. The second cohort, which includes children from six months of age through two years of age, is expected to complete by year end. And the last cohort of the study, which includes newborns through six months of age, began earlier enrollment this month. Needless to say, the level of interest from families seeking treatment for their very young children is very consistent with our belief in starting treatment as early as possible.

Children from two to five years of age.

The second cohort, which includes children from six months of age through two years of age is expected to complete by the year end and the last kind of where the study which includes newborns through six months of age began earlier enrolling this month.

Needless to say the level of interest from families seeking treatment for their very young children is very consistent with our belief in starting treatment as early as possible. We hope to provide more insight on this program at R&D day.

Turning to BMN three of seven our investigational gene therapy for PK. You were pleased to have received orphan designation for B M. Three of seven this past Monday from the FDIC as you likely saw on our recent press release, we submitted a clinical trial application or Cts with a medicines and health care product regulatory agency in the United Kingdom or the Hbr right.

That's why the Emmy charting a for being on three of seven we expect to started enrolling patients with material manufactured whether commercial ready process to de risk. The program that facilitate rapid clinical development in a phase went to trial in early 2020, and we are actively preparing regulatory submissions for other countries. We're excited about the prospects.

Hank: We hope to provide more insight and detail on this program at R&D Day. Turning to BMN-307, our investigational gene therapy for PKU, we are pleased to have received orphan designation for BM-307 this past Monday from the FDA. As you likely saw in our recent press release, we submitted a clinical trial application, or CTA, with the Medicines and Healthcare Product Regulatory Agency in the United Kingdom for BMN-307. We expect to start enrolling patients with material manufactured with a commercial-ready process to de-risk the program and facilitate rapid clinical development in a Phase I-II trial in early 2020, and we are actively preparing regulatory submissions for other countries. We're excited about the prospect of BMN-307 as it represents a potential third PKU treatment option in our PKU franchise and a second gene therapy development program leveraging our learnings and capabilities from Valrox.

Mm 307, as it represents a potential third PK you treatment option in our PK you franchise and a second gene therapy development program, leveraging our learnings and capabilities from Alex.

A final note on pipeline changes, we announced today that we've entered into a licensing agreement with alleys Xtra Cal City days Alpha formally BMN to 50, and investigational enzyme replacement therapy for the treatment of sanfilippo syndromes high speed.

As we've stated previously our focus is shifting to larger indications, where we can have an impact with our highly engineered products. So we're thrilled to have alley backs now shepherding. The continued development of Trauson any itself.

We couldn't be happier for patients and their families. As we expect they will benefit tremendously from alley thats focused on treatments for rare nerd degenerative diseases.

Look forward to hosting you at our upcoming R&D day on November 14th in New York, where we will showcase our next potential commercial products, mainly valor absent the shorter time, including some baseline data never sure before another highlight will include an updated looked at the natural history information including trends.

So were tied treatment through 54 months as well as evaluation of untreated patients with any contemplation.

Hank: A final note on pipeline changes, we announced today that we have entered into a licensing agreement with Alivex for Tralicinidase-alpha, formerly BMN-250, an investigational enzyme replacement therapy for the treatment of Sanfilippo syndrome type B. As we have stated previously, our focus is shifting to larger indications where we can have an impact with our highly innovative products, so we are thrilled to have Alivex now shepherding the continued development We couldn't be happier for patients and their families.

With our earlier stage pipeline look forward to sharing a preview of the next potential Andy's we're considering for development. We hope you all intensive please reach out to our IR Department should you need more information.

Thank you for continued support and I'll now call I'll turn the call over to Dan to review the financial quarters Dan.

Thank you Hank.

Please refer to todays press release summarizing our financial results for full details on the third quarter.

First with respect them revenues, we reported total revenues in the quarter 461 million and are on track for full year 2019 revenues of approximately 1.7 billion thing and the expected range of 1.69 to 1.72 billion.

In addition to tracking towards the middle of the writing for full year total product revenues as Jay mentioned, we expect both GAAP and non-GAAP results to be at the top end of the ranges due to continued R&D expense management as we continue to improve overall margins.

Hank: As we expect, they will benefit tremendously from Alidex's focus on treatments for rare neurodegenerative diseases. We look forward to hosting you at our upcoming R&D Day on November 14th in New York, where we will showcase our next potential commercial products, namely Valrox and Vasoratide, including some baseline data never shared before. Another highlight will include an updated look at the natural history information, including trends of Vasoratide treatment through 54 months, as well as evaluation of untreated patients with Achondroma. With our earlier stage pipeline, we look forward to sharing a preview of the next potential INDs we are considering for development. We hope you will attend, so please reach out to our IR department should you need more information. Thank you for continuing to support us, and I'll now turn the call over to Dan to review the financial quarters. Dan?

An important item of note for the quarter is the impact of foreign exchange on our financial results.

Over the past year, the dollar has strengthened materially against the euro and the British pound and even more significantly against several of the Latin American currencies over.

Overall net of our hedging full year revenue is projected to be negatively affected by approximately 20 to 25 million, especially at our full year revenue would have been at the high end of our guidance instead of the mid range without these negative FX impact.

Thanks to our hedging contracts, which offset more than half of the potential revenue impact from a strengthening dollar.

And natural expense hedge offsets for your bottom line forecasted results are not materially impacted this year by exchange rates.

One specific revenue item that Jeff did not discuss downturns I'm revenue in the corner and increased by 17 million versus two Q due to delays in that quarter with Sanofi is two way release that has since been resolved.

Year to date algorithm is down 44 million due to a one time bolus of revenue in Q1 2018, no patients on therapy as reported by Genzyme continue to grow in 2019 versus 2018.

Dan: Thank you, Hank. Please refer to today's press release summarizing our financial results for full details on the third quarter. First, with respect to revenues, we reported total revenues in the quarter of $461 million and are on track for full year 2019 revenues of approximately $1.7 billion, being in the expected range of $1.69 to $1.72 billion. In addition to tracking towards the middle of the range for full year total product revenues, as J.J. mentioned, we expect both GAAP and non-GAAP results to be at the top end of the ranges due to continued R&D expense An important item of note for the quarter is the impact of foreign exchange on our financial results. Over the past year, the dollar has strengthened materially against the Euro and the British Pound, and even more significantly against several of the Latin American currencies.

Moving to operating expenses, both R&D and SGN expense.

Order roughly on track to previously provided full year guidance.

As Canada is expected to come in at the upper end in the range between 670 690 million SK expenses third quarter work impacted by the expansion of sales and marketing campaign for abilities. As we lost policy can New York and continue to prepare for our MSR.

Hi, an approval and launch.

And the third quarter R&D expenses reflected continued enrollment of additional patients in the global phase three.

Generate one study manufacturing of B M and three of seven our PK you gene therapy product ahead of clinical trials early next year and the children in the zero to five year old study with Sonatide.

However, despite the progress of these later stage development programs with the decision not to pursue development about them and to 70 for free to 90, I'm, sorry for Friedreichs ataxia, MBM and to 15, we now expect R&D expense for the full year to be lower than previously guided for the full year with.

Dan: Overall, net of our hedging, full year revenue is projected to be negatively affected by approximately $20 to $25 million, such that our full year revenue would have been at the high end of our guidance instead of the mid-range without these negative FX impacts. Thanks to our hedging contracts, which offset more than half of the potential revenue impact from a strengthening dollar and natural expense hedge offsets, full-year bottom-line forecasted results are not materially impacted this year by exchange rates. One specific revenue item that Jeff did not discuss was Alderazyme revenue for the quarter.

Now expect R&D expenses up between 710 and 740 million.

Turning to bottom line results GAAP net income in the third quarter was 55 million as compared to a GAAP net loss of 12.6 million a third quarter of 2018.

GAAP net income in the third quarter increased primarily due to that.

Net profit from operations and a benefit from income tax of approximately 45 million.

Four year, we expect GAAP loss.

To come in at the low end of our initial guidance range and now expect a loss of between 65 and 45 million.

Dan: It increased by $17 million versus 2Q due to delays in that quarter with Sanofi's QA release that have since been resolved. Year-to-date, aldorazine is down $44 million due to a one-time blip of revenue in Q1 2018, though patients on therapy, as reported by Genzyme, continue to grow in 2019 versus 2018. Moving to operating expenses, both R&D and SG&A expenses in the third quarter roughly matched previously provided full-year guidance. SG&A is expected to come in at the upper end of the range between $670 and $690 million.

As you know we also measure our performance on a non-GAAP basis, which is based on EBITDA and also excludes stock compensation contingent consideration and certain other specified items.

Our non-GAAP income in the third quarter was 78 million compared to non-GAAP income 61 million in the third quarter of 2018.

We are now narrowing the range for your non-GAAP income to be between 150 at 170 million.

In terms of cash cash equivalents and investments as of September 32019, We had 1.15 billion as compared to 1.1 billion on June Thirtyth 2019.

Finally, I know a cash flows for the third quarter.

Year to date cash used for operational activities totaled just about 9 million, whereas cash generated by operating that activities for the third quarter were just over 70 million.

Dan: SG&A expenses in the third quarter were impacted by the expansion of sales and marketing capabilities as we launched Pallanzic in New York and continue to prepare for Valox and Vasoratide approvals and launches. In the third quarter, R&D expenses reflected continued enrollment of additional patients in the global Phase III, generate one study, the manufacturing of BMN 307, our PKU gene therapy product, ahead of clinical trials early next year, and the children in the zero to five-year-old study with the sorotype. However, despite the progress of these later stage development programs, with the decision not to pursue the development of both BMN-270 and 290, I'm sorry, for Friedrichs Ataxia, and BMN 250. We now expect R&D expenses for the full year to be lower than previously guided.

Profitability and continued cash flow growth our expected as our revenues increase our piano structure is expected to be similar far larger biotech parents, we aspire to follow.

In closing Barbara's current commercial business remains on track to deliver roughly 1.7 billion in revenues this year and close to 2 billion next year with increasing GAAP and non-GAAP bottom line profitability.

The next 18 months well also expect to accelerate and then the next phase of higher revenue and growth from potential approval, Valtrex, MSR type, which could lead to approvals and revenue contribution starting before the end of 2020.

Thanks for your support and I will now open it to your questions operator.

Yes, that's right.

A question you want me to breast car went on your telephone.

<unk>.

Please standby will become kind of given a roster.

[noise]. Your first question comes from the lineup Salveen Richter from Goldman Sachs. Your line is open.

Thanks for taking my question so for sort of tied how should we think about the clinical meaningfulness up the phase three data. So while you showed about it to centimeter year benefit at the same dose and the phase two new clearly there was a range per various ratification measures that adds up here for gets you in our normal across the curve. So you could give us any.

Dan: For the full year, we now expect R&D expenses of between $710 and $740 million. Turning to bottom-line results, GAAP net income in the third quarter was $55 million as compared to a GAAP net loss of $12.6 million in the third quarter of 2018. GAAP net income in the third quarter increased primarily due to a net profit from operations and a benefit from income taxes of approximately $45 million.

Clarity, there and I have a follow up.

As having.

The clinical meaningfulness, just the phase three study I don't think can be considered in isolation because the phase three study is a relatively short duration one year.

In that it's placebo controlled and that was.

What we in our investigators agreed was feasible to study and generate high quality did I think the way to think about clinical meaningfulness of the sort of tied is in terms of cumulative effect over chronic therapy and to remind you we reported last year.

Dan: For the full year, we expect a gap loss at the low end of our initial guidance range and now expect a loss of between $65 and $45 million. As you know, we also measure our performance on a non-gap basis, which is based on EBITDA and also excludes stock compensation, contingent consideration, and certain other specified items. Our non-GAAP income in the third quarter was $78 million, compared to non-GAAP income of $61 million in the third quarter of 2018. We are now narrowing the range of full-year non-GAAP income to be between $150 million and $170 million. In terms of cash equivalents and investments, as of September 30, 2019, we had $1.15 billion as compared to $1.1 billion on June 30, 2019. And finally, a note on our cash flows for the third quarter. Year-to-date cash used for operating activities totaled just about $9 million, whereas cash generated by operating activities for the third quarter was just over $70 million.

On the accumulated benefit of a sore tide through 42 months of chronic therapy in our phase one two cohort of 10 patients. This year, we'll be giving you a another update on that which will now carry patients through 54 months of therapy and as I mentioned in my.

Talking points and we're now in a position to start addressing.

What the height gain over untreated patients can be expected to be given that we're now coming on line with our own contemporaneous natural history study.

So all that taken together says the value of the phase three trials to prove that sort of tied is effective compared to placebo, but the magnitude of the benefit should be wave in the context of longer term therapy.

Hopefully thanks.

Yes that was helpful. And then can you discuss the Ford trajectory and dynamics for two then do you expect the majority of patients here at your transition over to Palin seek prioritized the expiration.

I saw being that it is it is certainly our.

Goal to transition as many adult ku band patients do Palins IEC as possible before a loss of exclusivity in a year and we are making a lot of progress.

38% of our power on the referrals or naive pellens seek a patient referrals, our our ku band transition, so making a lot of progress there. It is also true but.

Dan: Gap profitability and continued cash flow growth are expected as our revenues increase. Our P&L structure is expected to be similar to our larger biotech peers, which we aspire to follow. In closing, Biomarin's current commercial business remains on track to deliver roughly $1.7 billion in revenues this year and close to $2 billion next year, with increasing GAAP and non-GAAP bottom line profitability.

No there remain a smaller now number of new adult patients that are being referred in core.

Ku band treatment and it is also true it particularly in the United States that are pediatric population is growing on on Ku band, So, but the truth. The trajectory I would think would be similar to what we are reporting year to date.

Dan: Over the next 18 months, we also expect to accelerate into the next phase of higher revenue and growth through potential approvers of Valrox and Vasoratide, which could lead to approvals and revenue contributions starting before the end of 2020. Thanks for your support, and I will now open it to your questions. Operator?

Patient growth of.

About 6% tied to continued revenue growth our focus both in Europe .

The United ebay to overwhelmingly now on adult patients gaining access to and benefiting from Pelosi therapy.

Operator: Yes, that's our inviter to ask. You will need to press star 1 on your... To submit your questions, press, Sponsored by Wabacom Cloud. Your first question comes from the line of Salveen Richter from Goldman Sachs. Your line, Thanks for taking my questions. So for Soratide, how should we think about the clinical meaningfulness of the phase three data? So while you showed about a two centimeters a year benefit at the same dose in phase two, you know, clearly there is a range per various stratification measures that adds up here or gets you on a normal growth curve. So if you could give us any more clarity there, and I have a follow-up. Hi Salveen.

Thank you tell me I'm, sorry, just to remind.

People on the line that.

Also exclusivity in Q4 of next year is only the U.S.

In Europe , we actually this week.

Yeah, if you know prediction until.

2024.

So the one point that maybe.

He's no different from probably your traditional generics.

Modeling is that when you were small molecule you lose protection.

Well market exclusivity generally when you lose a patient to generic they're very rarely come back to the Brian .

However, it okay.

You know what if we do study you for joining me in October and November 2020.

If we do lose a.

Unknown Executive: The clinical meaningfulness of just the Phase III study cannot be considered in isolation because the Phase III study is relatively short in duration, one year, and it's placebo-controlled, and that was what we and our investigators agreed was feasible to study and generate high-quality data. As I mentioned in my talking points, we are now in a position to start addressing what the height gain over untreated patients can be expected to be, given that we're now coming online with our own contemporaneous natural history study. So all that taken together says the value of the phase three trial is to prove that Vasorotide is effective compared to placebo, but the magnitude of the benefit should be weighed in the context of longer-term therapy. Hopefully, that was helpful. And then can you discuss the forward trajectory and dynamics for Kuven?

He did he grew last patient to a generic.

They are not lost forever to our business and this does that.

You can always go to probably antique down the road.

So the another whatsoever.

Thank you.

Your next question comes from the line up.

From Cowen and company your line is okay.

Great. Thanks for taking my question one on for search I for me also in the phase two data. It we saw a month 12, just below 50% increase in and always grow philosophy Pink is there any reason why we shouldn't expect that in the phase three are there any notable differences and the patient populations who are.

Enrolled that could.

Change the expected results.

Not really no we purposely kept the eligibility criteria fairly consistent and Oh to the outcome measures to say now come measure in the dosing regimen or the same so we should.

Expect a fairly similar result, now the one thing that we pointed out is that we've been doing those calculations compared to the baseline run EM.

Unknown Executive: Do you expect the majority of patients here to transition over to Palanzec prior to IP expiration? Hi Salveen, it is certainly our goal to transition as many adult QVAN patients to Palanzec as possible before loss of exclusivity in a year, and we are making a lot of progress. 38% of our Palanzec referrals are naive Palanzec patient referrals that have transitioned to QVAN, so we are making a lot of progress there. It is also true that there remain a smaller number of new adult patients that are being referred in for QVAN treatment, and it is also true, particularly in the United States, that our pediatric population is growing on QVAN. So the trajectory I would think would be similar to what we are reporting year-to-date with patient growth of about 6% tied to continued revenue growth. Our focus both in Europe and the United States is now overwhelmingly on adult patients gaining access to and benefiting from Palanzec. I just want to remind people on the line that the loss of exclusivity in Q4 of next year is only in the US. In Europe, next year, we have protection until 2024.

But as you as people have pointed out and as you noticed from public places natural history. Gross studies, there was a gentle negative slow so at one year there could be some.

Negative placebo effect, such that we underestimated at one year the magnitude of treating benefit from the sorts and I think where that's going to get to be more and more and more important as you go out farther and farther than time.

Because those those declines will start to add up.

And I was suggesting that the at R&D day will have an opportunity to look at those both of those phenomena the cumulative benefit from chronic treatment as well as contrast that to similar populations of patients who have not been treated with <unk>.

Got it okay, and even though the H five to 14 is exactly the same between phase two and fish Threed do you know whether the people who are actually enrolled have a similar page characteristics.

It was the phase two weighted towards younger patients and phase threes getting older patients or as far as you know that the age is in the trial are also identical.

As far as I know there are no major and substantive changes I think that I mentioned that we're going to talk a little bit more detail about the the sorts items out rocks programs.

And this is the kind of question that I think we can address it a little bit more detail at R&D day, but for today that the headliner is no. We're not aware of any differences that could come to a different result in phase three than in phase two.

Unknown Executive: And also, maybe one point that maybe is a little different from your traditional generic modeling is that, you know, when you have a small molecule, you lose protection or market exclusivity. And when you lose a patient to a generic, they very rarely come back to the brand. I don't know if you've ever, in our case... If we do, you know, starting in October or November 2020, if we do lose a Cuban patient to a generic... They are not lost forever to our business in the sense that they can always go back to Palenque down the road. To the end, Not will last forever.

Perfect and then one last housekeeping question on Brazil, I'm sorry.

I didn't hear what you said when you talked about the proportion.

Okay.

Yes, no no differences other than the inclusion of you'll see them.

Right right. Okay, sorry, there was asking about Brazil, just clarifying question. There was you mentioned I think 90 million in total in some portion of that was going to be 2019, I missed where you said about the proportion.

2019 from the Brazilian orders.

I felt so the comment was we expect greater than 50% of that 90 million dollar contract to be fulfilled in 2019.

Unknown Executive: Thank you. And your next question comes from the line of Philip Nadeau from Cullen & Company. Good afternoon, thanks for taking my question. One on Facertide for me, also in the phase 2 data, we saw at month 12 just below a 50% increase in annualized growth velocity. Hank, is there any reason why we shouldn't expect that in phase 3? Are there any notable differences in the patient populations who are enrolled that could change the expected results? Not really, no.

And the perfect less than half in 2021st half.

Perfect that's helpful. Thanks.

And your next question comes from the line of Cory Kasimov from JP Morgan. Your line is open Hey, good afternoon, guys. Thanks for taking my question I wanted to ask on the sore tied as well and with the progress you're making in children under the age of five when could we expect to maybe see a first kind of data from the initial cohort and then.

Maybe more importantly, do you think it's possible that you'd be able to submit some of that date as part of your initial application to potentially launch with a label, including younger children or is that something we should think of more as a it's a supplemental filing poster initial approval.

Unknown Executive: We purposely kept the eligibility criteria fairly consistent, and obviously the outcome measure is the same outcome measure, and the dose and regimen are the same, so we should expect a fairly similar result. Now, the one thing that we pointed out is that we've been doing those calculations compared to the baseline run-in, but as people have pointed out, and as you notice from Publishing Contemplation and Natural History Growth Studies, there is a gentle negative slope. So, at one year, there could be some negative placebo effects, such that we underestimated at one year the magnitude of treatment benefit from VASORTA, and I think that's going to get to be more and more and more important as you go out farther and farther in time, because those declines will start to add up, and I was suggesting that at R&D Day, we'll have an opportunity to look at both of those phenomena, the cumulative height benefit from I got it.

Supplemental funding for efficacy purposes post initial approval if things go well.

Initial application if anything will include safety data at most.

And as far as timing for completion of analysis of the under five study. It's obviously been depend on a finishing enrollment as I said.

We're projecting that will complete enrollment in the second cohort.

On the by the end of the year, but we're only just now beginning enrollment in the third cohort. So stay tuned for more clarity on timeline of expected enrollment completion. So you wouldn't show date until you had all three cohorts and is that correct.

Efficacy data I think.

Sure.

It's a blinded study so.

The benefit of waiting until the end is to protect the blood okay. Perfect I will stop there thanks for taking the questions.

Yes.

Your next question comes from the line of Jeff.

From Bank of America. Your line is open.

Afternoon, guys. Thanks, so much of the question I.

Just a couple unveil rocks I know you've been asked quite a bit about the reimbursement model.

Unknown Executive: Okay. And even though the age 5 to 14 is exactly the same between Phase 2 and Phase 3, do you know whether the people who are actually enrolled have a similar age characteristic? So was Phase 2 weighted towards younger patients, and Phase 3 is getting older patients? Or, as far as you know, are the ages in the trial also identical?

Over the past year, so, but just checking to see if theres at that has evolved over time, just given the success of Xeljanz. My for example.

From Novartis and in in terms of clinical updates on the sort taser trigger that regulators are looking for in terms of.

Any updates pipeline updates or clinical at that you're looking for beyond what you've released so far on things like duration of effect or exposure et cetera.

Unknown Executive: As far as I know, there are no major and substantive changes. I think that I mentioned that we're going to talk in a little bit more detail about the sort of details of DALROC's programs. And this is the kind of question that I think we can address in a little bit more detail at R&D Day, but for today, the headliner is no. We're not aware of any differences that could connote a different result in phase three than in phase two. Perfect. And then there is one housekeeping question on Brazil.

Thank you.

Mr., Jeff Jeff a weight, we continue to make progress with Val Ross reimbursement preparation, both from the United States and in Europe , and and it is a.

Ruminating to see other products begin to make it market and.

See how the market reacts to some bear the programs and pricing, including sole genzyme a.

Unknown Executive: I'm sorry, I didn't hear what you said when you talked about the proportions of what to expect in 2019. Yeah, no differences other than the inclusion of, Right, right. Okay. No, sorry, I was asking about Brazil.

I think Oh, we saw some some reported uptake of Xeljanz file in the United States with an implied growth than to that that was pretty high that was it both of those things were encouraging.

Unknown Executive: Just clarifying a question. There was, you mentioned, I think 90 million in total in some proportion that was going to be in 2019. I missed what you said about the proportion of 2019 from the Brazilian order. I can tell so the comment was we expect greater than 50% of that $90 million contract to be fulfilled in 2019. And that's less than half in 2020, first half. Perfect. That's helpful. Thanks.

The price level that we saw with Volte ends my was encouraging.

There's been a lot of discussion about different price models I think by now, it's becoming pretty clear that outcomes based agreements unless there's a legislative things are going to be limited to something like 23% of purchase price without triggering bake a government price.

Calculation.

And and resulting Bryce problems I think it's also clear that allows the installment payment method that.

People have been interested in and talked about for a while it's going be problematic in the United States.

Unknown Executive: And your next question comes from the line of Corey Casimo from J.P. Morgan. Your line: Hey, good afternoon guys, thanks for taking my question. I wanted to ask on Visorotide as well and with the progress you're making in children under the age of five, when could we expect to maybe see a first cut of data from the initial cohort and, maybe more importantly, do you think it's possible that you could submit some of that data as part of your initial application to potentially launch with a label including younger children, or is that something we should think of more as a supplemental filing post your initial Initial application, if anything, will include safety data at most.

All of those things are being reinforced in biomarin, one on one discussions with with payers to facilitate.

A potential launch in the United States discussions in Europe .

Continue Europe is substantially different situation with single National payer systems, essentially that have more latitude and don't.

Involve government price calculation problems.

It's also the.

The fact that that we don't see as much concrete a real development Oh.

Reimbursement models, yet in any use so that's more nascent situation. Jay did you want to add anything he would probably well and your resort type question as far as data triggers for next regulatory interactions are the big one is going to be the pivotal results of the phase three trial. The three other pillars of the program.

Unknown Executive: And as far as the timing for completion of analysis of the Under 5 study, it's obviously going to depend on finishing enrollment. And as I said, we're projecting that we'll complete enrollment in the second cohort by the end of the year, but we're only just now beginning enrollment in the third cohort. So stay tuned for more clarity on the timeline of expected enrollment completion. So you wouldn't show data until you had all three cohorts, then, is that correct?

Study in children under five the long term extension studies were going to give you a 54 month data as well as its comparison to natural history data those three elements are necessary, but not sufficient.

In the next meaningful milestone to occur in the sort of type program is going to be the unblinding. The phase three program at the end of the year.

Thank you.

Yep.

Okay.

Unknown Executive: Efficacy data, I think. Okay, we wouldn't be able to... it's a blinded study, so... The benefit of waiting until the end is to protect the blind. Okay, perfect. I will stop there.

So.

Your next question comes from the line as Chris Raymond from Piper Jaffray. Your line is open.

Hey, Thanks for taking for taking the question just a question on pounds. So you can have a follow up as well, but first pounds IEC I'm just looking at the U.S. patient dynamics.

Unknown Executive: Thanks for taking the time. Your next question comes from the line of Jeff Meacham from Bank of America. Afternoon, guys.

By our math it looks like there were about 120 or so maybe 118 naive patient adds in in the third quarter.

Unknown Executive: Thanks so much for the questions. I just had a couple on Valrox. I know you've been asked quite a bit about the reimbursement model over the past year or so, but just checking to see if that has evolved over time, just given the success of Zolgensma, for example, from Novartis, and in terms of clinical updates on basorotide, is there a trigger that regulators are looking for in terms of, Any updates, pipeline updates, or clinical updates you're looking for beyond what you've released so far on things like duration of effect, or exposure, Hi Jeff, we continue to make progress with Valron's reimbursement preparation, both in the United States and in Europe, and it is illuminating to see other products begin to make it to market, and to see how the market reacts to some of their programs and pricing, including Zolgensma.

And then just doing the same math and the second quarter I think that was about 130, so looks like there was a sequential decrease.

But you also supported a an increase in PK you clinics, so and I know this thing tends to see some chop and move around quarter on quarter in terms of naive patient adds but can you maybe talk about what you're seeing or we had a steady state in terms of new patient adds or is there any reason to think maybe Q4.

Our ads would be meaningfully different and I've got to have a problem.

Yeah, Chris so good observation.

If you look back to the numbers that we broke reported a close of each quarter.

We've seen patient growth going from hundred a high of 153, new patients on therapy at the end of the first quarter 130, 734 patients respectively. At the end of the fourth quarter last year in the second quarter.

Unknown Executive: I think we saw some reported uptake of Zolgensma in the United States, with an implied gross margin that was pretty high. Both of those things were encouraging. The price level that we saw with Zolgensmo was encouraging, and there's been a lot of discussion about different price models. I think by now, it's becoming pretty clear that outcomes-based agreements, unless there's a legislative fix, are going to be limited to something like 23% of the purchase price without triggering big government price calculations and resulting price problems.

This year and honored 19, new patients on therapy at the end of the third quarter. So there's there's some variability quarter to quarter and it is it is true that the third quarter was a little less than the previous several quarters. The other thing to note for the precursor.

On that is though the level of new patient referrals and so there is a little bit of variability there too, but new patient referrals in the third quarter were very strong so probably just a little bit of up on one.

Aspect in a down on another for total patients on therapy, and and nothing that I'm concerned about in fact.

Unknown Executive: I think it's also clear that the installment payment method that people have been interested in and talked about for a while is going to be problematic in the United States. All of those things are being reinforced in Biomarin's one-on-one discussions with payers to facilitate a potential launch in the United States. Discussions in Europe continue. Europe is a substantially different situation with single national payer systems, essentially, that have more latitude and don't involve government price calculation problems. It's also the fact that we don't see as much concrete, real development of reimbursement models yet in the EU, so that's a more nascent situation. JJ, did you want to add anything?

As I noted in my prepared remarks.

Following all of the the different parameters that we watch to see our we having a very successful problems IEC launch my my overall conclusion is vis vis looks like it's pretty much on on rails, right now without any yellow or or red flags to worry about so.

We're opening up new clinics were getting new patient referrals across the board from our existing clinics were getting reimbursement approvals and around 60 days on average for those patients they're going on the commercial therapy, there tight trading up to daily dosing.

Unknown Executive: No, I think that's probably enough. And your resort-type question as far as data triggers for next regulatory interactions, and the big one is going to be the pivotal results of the phase three trial. The three other pillars of the program, the study in children under five, the long-term expansion study that we're going to give you 54-month data as well as its comparison to natural history data, those three elements are necessary but not sufficient, and the next meaningful milestone to occur in the Sorotai program is going to be the unblinding of the Phase III program at the end of the year. And your next question comes from the line of Chris Raymond from Piper Jeffries. The line is open.

And then maintenance dosing.

We're not losing large numbers of patients. There's this is just a really solid story and all of that by the way is translating into a weekly syringe dispenses from our specialty pharmacy network and translating into increases and revenue is why at this point <unk>.

I would advise saying look follow the increase in revenues, which are pretty steady quarter to quarter to quarter. We think that's the best the best measure to watch.

Thanks for the color in.

Maybe just a quick one for Hank BMN Threeo seven so you filed the C.T. first up is there any gating factor anything different between Europe , you may and in the FDA.

Unknown Executive: Hey, thanks for taking a question. Um, just a question on Palanzik, and I have a follow-up as well. But first, um, Palanzik, you're just looking at the US patient dynamics. By our math, it looks like there were about 120 or so, maybe 118 naive patient ads in the third quarter. And then just doing the same math in the second quarter, I think that was about 130.

What's the gating issue in terms of filing would be lay in the U.S. Please thanks.

Oh.

It's.

Relatively simple thing we've got a lot of experience with the M. HR, a IND filing gene therapy applications first in man there.

And so we're starting with Oh, sorry, if I said in my prepared comments were preparing submissions and other regions.

Kurt Bristly thereafter, so there's nothing.

Going on there.

I did want to follow up out of questioning I spent less time, Chris just the five versus the one in the knowing a journal what we're reporting was related symptomatic high potential bats, and there was there has been only one and the ongoing phase one phase one to four and a half year study.

Unknown Executive: So it looks like there was a sequential decrease, but you also reported an increase in PKU clinics. So, and I know this thing tends to... Unknown Attendee, Dr. David Lugo, Unknown Attendee, Unknown Attendee, I'm going to have a follow-up. Yeah, Chris, so good observation.

Two things are supposed to lunch Chris.

Thanks.

Yep.

Moving on we have Joseph Schwartz from as the VB Leerink. Your line is open.

Thanks, very much I've a question on a bizarre tied and then.

Unknown Executive: If you look back at the numbers that we've reported at the close of each quarter, we've seen patient growth going from a high of 153 new patients on therapy at the end of the first quarter, 137 and 134 patients, respectively, at the end of the fourth quarter last year, and in the second quarter this year, 119 new patients on therapy at the end of the third quarter. So there's some variability quarter to quarter, and it is true that the third quarter was a little less than the previous several quarters. So we're opening up new clinics. We're getting new patient referrals across the board from our existing clinics.

So.

Hi, I'm wondering if you can expand on something that was asked earlier and that's how how do you expect the cumulative effect.

Chronic therapy for resort tied to compare to growth hormone, which seems to have a bigger effect upfront that wayne's over time, but it's still incremental so when you consider long term therapy for each treatment option, how much more impactful.

You expect the longer term treatment option to be for resort type.

The hi, Joe Thanks for the question.

Gross pharma in the non recurring deficiency syndromes and a little bit is a brother and diversity stared arena as well there is a big effect that initially and then there's no meaning in terms of an effect and we just don't see that with the started biology is very different in fact, what we reported through 42 months last year.

Unknown Executive: We're getting reimbursement approvals in around 60 days on average for those patients. They're going on to commercial therapy. They're titrating up to daily doses and then maintenance doses. We're not losing large numbers of patients. This is just a really solid story.

Every period in which we look at the rate of growth compared to pre trend baseline.

Rate of growth is on the store tide is in excess of what the pretreatment rate of growth was prior to taking sorts I'd. Now. We've also said that that growth philosophy of gently slowing down as you approach.

Unknown Executive: And all of that, by the way, is translating into weekly syringe dispenses from our specialty pharmacy network and translating into increases in revenue. That's why at this point I would advise saying, look, follow the increase in revenues, which are pretty steady quarter to quarter to quarter. We think that's the best measure to watch. Thanks for the color.

Adolescence, and and as we've said before also there's.

It does appear to be evidence of funeral spurred so our expectation is that as these children get older. Their untreated growth velocity would be decelerating. So that's why it's going to become initiatives was why the FDA asked us for this that in the absence of an ability to do it essentially a five or a 10 year placebo controlled trial the agency.

Unknown Executive: Maybe just a quick one for Hank. BMN 307, So you filed the CTA first. Is there any gating factor or anything different between EMA and the FDA? What's the gating issue in terms of filing the BLA and the EMA? It's a relatively simple thing.

He is going to be very keen to see the accumulated type benefit from our long term treatments contrasted with.

Long term.

Growth velocity outcomes in untreated patients and I think thats going to be up the best way to observe the cumulative benefit which we do expect to be fairly steady overtime and the other thing I want to make sure that everybody is clear about as sunsets in United States in Europe reform and it's not indicated for the treatment of a contra places so.

Unknown Executive: We've got a lot of experience with the MHRA and filing gene therapy applications for the first in man there. And so we're starting with the MHRA. As I said in my prepared comments, we're preparing submissions in other regions to occur riskily thereafter. So there's nothing unique going on there. I did want to follow up on a question you asked me last time, Chris. The five versus the one.

We have a careful when we talk about growth pharma.

Talking about growth from on a non a contra pleasure to source. This growth pharma does not have a favorable benefit risk as it's dean by U.S. and you regulators.

Okay, and then on Bauer off I was wondering if you have thoughts on why other gene therapies delivered via 85 may not require steroid prophylactic. So much so that patients. There are positive for 85 antibodies are not being excluded from other sponsors.

Unknown Executive: In the New England Journal, what we were reporting was related symptomatic hypotensive events, and there have been only one in the ongoing Phase 1, Phase 2, four and a half year study. Thank you. Moving on, we have Joseph Schwartz from SVB Learing. Thank you very much. I have a question on Zorotide and then on Valrock.

Ongoing study, but they'll rocks expression does seem to be sensitive to that's now so and whether steroids are used I was just wondering if you know you've been able to determine why that might be.

Unknown Executive: I'm wondering if you can expand on something that was asked earlier, and that's how do you expect the cumulative effect of chronic therapy for Visoratide to compare to growth hormone, which seems to have a bigger effect up front that wanes over time, but it's still incremental, so when you consider long-term therapy for each treatment option, how much more impactful do you expect the longer term treatment option to be for Visoratide? Hi Joe, thanks for the question. You know, growth hormone in the non-growth hormone deficiency syndromes and a little bit in the growth hormone deficiency arena as well, has a big effect initially, and then there's a waning of the effect. And we just don't see that with the sort of type of biology; it's very different.

Well, let me just remind you know that although we acknowledge that number of the result at the end of the 20 to 26 week period for the Phase. One two study is numerically higher than the result at the end of 20 326 weeks in the phase three study.

There are substantial that variability in patient response, such that we can't conclusively say that there's a difference in the phase one to result in a phase three results.

And then to further speculate that that due to steer as a causal explanation is a hypothesis that rather than necessarily a fat.

And as to the optimal steroid regimen for use with Alex.

Unknown Executive: In fact, what we've reported through 42 months last year is that every period in which we look at the rate of growth compared to the pre-treatment baseline, the rate of growth on the sort type is in excess of what the pre-treatment rate of growth was prior to taking the sort type. Now, we've also said that growth velocity is gently slowing down as you approach adolescence, and, as we've said before, also, there does appear to be evidence of puberal spurts.

As I said, a couple of months ago, we in our investigators are intrigued by the result of the interim analysis and we are tightening per the protocol the use of on demand serious let's see where that gets to us to as a result, we've also talked about potentially doing a prophylactic steroid company.

And study, but as yet we haven't initiated that study.

So our plan is to finish the present study as designed burden the hand winner independent data monitoring Committee say, we have positive benefit risk, we're very confident that we're going into bleeding outcomes in the phase three trial.

Unknown Executive: So our expectation is that as these children get older, their untreated growth velocity will be decelerating. And so that's why it's going to become, and this is why the FDA asked us for this, that in the absence of an ability to do essentially a five or a 10-year placebo-controlled trial, the agency is going to be very keen to see the accumulated height benefit from our long-term treatments contrasted with long-term growth velocity outcomes in untreated patients. And I think that's going to be the best way to observe the cumulative benefit, which we do expect to be fairly steady over time. And another thing I want to make sure that everybody is clear about is that, in the United States and Europe, growth hormone is not indicated for the treatment of achondroplasia. So we've got to be careful when we talk about growth hormone that we're talking about growth hormone and non-achondroplasia disorders because growth hormone does not have a favorable benefit risk as it is deemed by U.S. and EU regulators. Okay.

We're going to put a lot of the details at substantiate. These statements stop in front of you at R&D day. So you can see why we're so keen to get cross the finish line as directly as we could.

As far as what other companies are doing and what read to make from that it's a little hard to speculate because we don't have the same access to their data.

One thing I would say a subset of the published information from other companies invest getting 85 gene therapies and treating patients who are so called antibody positive. There actually is a transduction inhibition neutralizing antibody assay, which doesn't necessarily always correlate with pre existing immunity and we presented some several posters about.

That and various health started conferences, so I'd say.

Lets gather more data from before we make any conclusions about whether steroids are required how their acquired and what the role of pre existing immunity. If any there is in a need for steroid therapy My management.

Thanks, a lot.

Yes.

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

Unknown Executive: And then on Valrox, I was wondering if you have thoughts on why other gene therapies delivered via AV5 may not require steroid prophylaxis. So much so that patients that are positive for AB5 antibodies are not being excluded from other sponsors. Unknown Speaker Unknown Speaker Unknown Speaker Unknown Speaker, Well, first of all, let me just remind that, you know, that although we acknowledge the number of the result at the end of the 23 to 26 week period for the Phase I-II study is numerically higher than the result at the end of 23 to 26 weeks in the Phase III study, there's substantial amount of variability in patient response such that we can't conclusively say that there is a difference in the Phase I-II result and the Phase III result.

Hi, This is close to us on for Matthew I have a question on B M. N C O seven and specifically, let's assume that Youre CPH approved soon can you talk about a the starting dose that you I concede that inc. and about the efficacy that you are expecting to see with these starting dose Oh. So it can you discuss how quickly would you.

We expect to see the clinical effect, which is there any lending that did not getting patients. Thank you.

Yep.

So.

Based on preclinical studies, we expect to see efficacy in FY learning from an active does within just a few weeks and as far as starting dose dose.

One of the things that are that is a very strong positive is our collaboration with damage. Our day Nimish arrays belief is that in gene therapies that considering the fact that they're essentially one and done that the starting this has to be also informed by the prospect of benefit for patients.

Unknown Executive: And then to further speculate that that's due to steroids as a causal explanation is a hypothesis rather than necessarily a fact. And as to the optimal steroid regimen for use with Valrox, as I said a couple of months ago, we and our investigators are intrigued by the results of the interim analysis, and we are tightening, per the protocol, the use of on-demand steroids. And let's see where that gets us as a result.

So were specifically they don't really want to see a lot of patients dusted in active doses, which is very different than development of drugs and other indications as to the actual number of the starting dose. The that's not been finalized because we're still in the process of a review with the health authority and obviously, we have a point of view.

Unknown Executive: We've also talked about potentially doing a prophylactic steroid combination study, but as yet, we haven't initiated that study. So our plan is to finish the present study as designed, bird in the hand, winner, independent data monitoring committee, saying we have a positive benefit risk, we're very confident that we're going to hit the bleeding outcomes in the Phase 3 trial, and we're going to put a lot of the details that substantiate these statements up in front of you at R&D Day so you can see why we're so keen to get across the finish line As far as what other companies are doing and what we can learn from that, it's a little hard to speculate because we don't have the same access to their data. The one thing I would say is that in the published information from other companies investigating AB5 gene therapies and treating patients who are so-called antibody positive, their assay is a transduction inhibition neutralizing antibody assay, which doesn't necessarily always correlate with pre-existing immunity.

You about where that should start but until that Cts is activated I think it'd be premature to talk about what the specifics are.

Thank you very much.

Yes.

Your next question comes from the line up.

From Cantor Fitzgerald Your line is open.

Hey, guys. Thanks for taking my question Congrats on all the progress.

Another one on but for me I'm, just thinking about the potential you said and other indications beat on 800 plays out and if you have sort of any plans to develop that said he doesn't other indicates that and then.

Hi.

I know you mentioned sort of collecting the data on that the cumulative height, but just.

From a payer perspective, given that's not a fatal disease sort of what other data.

Other morbidities, Ralph and I think a matter to the tires.

Unknown Executive: And we have presented several posters about that at various health authority conferences. So I'd say let's gather more data before we make any conclusions about whether steroids are required, how they're required, and what the role of pre-existing immunity, if any, there is in the need for steroid therapy management. Thanks a lot. Hi. This is Kostasson for Matthew.

Do you think about Frank Thanks.

Yes.

So congrats potentially using other indications of we forgot to mention that summarizing our quarter that we publish the phase two data known internal medicine.

In early July .

And.

Subsequent to that there was a a letter to the editor written to the authors exactly on this topic speculating that because of the genetics of growth and have to serotype may be indicated in other.

Unknown Executive: I have a question about BMN 307. Specifically, let's assume that your CTA is approved soon. Can you talk about the starting dose that you are considering and about the efficacy that you are expecting to see with this starting dose? Also, can you discuss how quickly you expect to see the clinical effect, which is phenylalanine reduction in patients? Thank you. Yes.

Growth disorders.

The genetic data that people are talking about what's actually cited by us at our last R&D day, where we illustrated that there are conditions in which loss of function on either the like inside of the receptor side or gain a function. Unlike intercepted side are associated with stature deficiency or stature.

Excess.

Respectively, and Ah that suggests that the addition of CNP in patients with other mutations that cost actual impairment may also be amenable to the store type therapy at this year's R&D day, we're going to provide you an update on the progress of our.

Unknown Executive: So based on our preclinical studies, we expect to see efficacy and fee lowering from an active dose within just a few weeks. And as far as the starting dose goes, one of the things that is a very strong positive is our collaboration with the MHRA. The MHRA's belief is that in gene therapies, considering the fact that they're essentially one and done, the starting dose has to be informed by the prospect of benefit for patients. So more specifically, they don't really want to see a lot of patients dosed at inactive doses, which is very different than developing drugs and other indications. As to the actual number of the starting dose, that's not been finalized because we're still in the process of reviewing it with the health authority, and obviously, we have a point of view about where that should start. But until the CTA is activated, I think it would be premature to talk about what the specifics are. Thank you very much.

Thinking.

About whether that's attractable target for new indication development.

And so I'd say come to a theater near you.

As regards no information for payers and Jeff can certainly chime in as well but.

Yeah, We've said all along that generating.

Definitive proportionality did it will take longer time than we expect to be able to obtain in the pivotal clinical trial and would really require starting much earlier at a much earlier point in time. So we don't expect to see dramatic changes in proportionality in our favor and Moreover, functional benefits in short.

Term sites can be very difficult to come by in the stature deficiency.

Unknown Executive: The next question comes from the line of Eliana Merle from Cantor Fitzgerald in Illinois. Hey guys, thanks for taking the question and congrats on all the progress. Another one on the sortit- How should we think about potential usage and other indications beyond achondroplasia and if you have any sort of any plans to, you know, develop this or study this and other indications? And then second, on viscera type, you know, I know you mentioned sort of collecting the data on the cumulative height benefit, but just, you know, from a payer perspective, given this is not a fatal disease, sort of, what other data are you collecting, and other comorbidities beyond growth and height will matter to the payers, sort of as you think about pricing.

Kick start we're going to measure patient reported outcomes such as quality of life by several different measures.

But another big element that payers will be considering and we've done a lot of work in this area is to characterize the burden of illness, because the burden of illness is not as neatly summarized in the condition of they contemplated as simply how color you and how much deficiency in your stature do you have.

The burden of the condition.

Is measured in lots of different ways, and so I think the strategy that we've employed and these kinds of context previously as to make sure payers really understand what it's like and that's very important in these rare disease areas because for the most part pairs are not going to be seeing patients with rare diseases on any kind of regular basis. It will have no reference.

Unknown Executive: [inaudible] So, as regards potential use and other indications, we forgot to mention that, in summarizing our quarter, that we published phase two data in the Nona Journal of Medicine in early July, and subsequent to that, there was a letter to the editor written to the authors, exactly on this topic, speculating that, because of the genetics of growth, basortide may be indicated in other growth disorders. The genetic data that people are talking about was actually cited by us on our last R&D day, where we illustrated that there are conditions in which loss of function on either the ligand side or the receptor side, or gain of function on either the ligand or the receptor side, is associated with stature deficiency or stature excess.

Standard so want to educate them well about the condition of of study and then educate them well about the outcomes that have been demonstrated and so far that's been a pretty successful strategy for biomarin.

Your next question comes from the lightest Tim.

Yes.

No.

Thanks for the question another all the Sarah tide going back to the newborn to under five year old trial, Yeah. The growth velocity is so.

Pronounce between especially new born after one year old can you talk maybe about the unique safety efficacy concerns around these patient population.

Maybe more so than the over five year olds.

Yeah, well, so though we define the study into three different age cohorts. This we had a reason to at least hypothesize that by distribution of the drug would be different as a function of age and it turns out that's likely to be true.

Hank: And that suggests that addition of CNP in patients with other mutations that cause statural impairment may also be amenable to SOAR-type therapy. At this year's R&D Day, we're going to provide you an update on the progress of our thinking about whether that's a tractable target for new indication development. And so I say, come to a theater near you.

And so three different cohorts.

That would be.

That's a really important consideration is actually quite an advantage of a short acting.

For the short acting drug in the sense said it doesn't take you months to adjust that doses assorted if there's a problem you know the half life being what it is pretty much. The next day you concerned it's different dose safely.

So that's actually quite an interesting advantage that we have and.

Hank: As regards, you know, information for payers, and Jeff can certainly chime in as well, but, you know, we've said all along that generating definitive proportionality data will take a longer time than we expect to be able to obtain in the pivotal clinical trial and would really require starting much earlier, at a much earlier point in time. So we don't expect to see dramatic changes in proportionality in our favor, and moreover, functional benefits in short-term studies can be very difficult to come by in the statutory deficiency kinds of cases, but we're going to measure patient-reported outcomes, such as quality of life, by several different measures. But another big element that payers will be considering, and we've done a lot of work in this area, is to characterize the burden of illness. Because the burden of illness is not as neatly summarized in the condition of achondroplasia as simply how tall you are and how much deficiency in your stature you have.

And interpretation of.

Of of safety therefore.

Is going to be to what extent if there are safety sequentially can they be addressed with simple does not application. So when we get to the end of the say that will stack up all that information for you.

I would say after he already we have no real hypotheses about there being incremental differences and safety in this population compared to the older population and finally in regard to efficacy. The critical consideration us is that breadth velocity is declining quite rapidly over that age period. So it's going to be much more difficulty would be much more difficult to compare these patients who a natural history control.

For that reason so that that's the reason that we chose to blind. This study and randomized to placebo comparisons that will give us a healthy assessment of the treatment effect in this age group.

Interesting. Thank you for the color.

Hank: The burden of the condition is measured in lots of different ways. And so I think the strategy that we've employed in these kinds of contexts previously is to make sure payers really understand what it's like. And that's very important in these rare disease areas because, for the most part, payers are not going to be seeing patients with rare diseases on any kind of regular basis. They will have no reference standards.

Your next question comes from the line of attached to marry from Wolfe. Your line is open.

Hey, Thanks for taking me on so talking to investors there seems to be a large variation and how the store type data will be perceived whether you show 151.75 or to even though I think I feel like statistically could totally being in that range. So what will be the data release procedure for store type well, we just get a topline.

Hank: So we want to educate them well about the condition of study and then educate them well about the outcomes that have been demonstrated. And so far, that's been a pretty successful strategy for bottom right. And your next question comes from the line of Tim Lugo from William Blair Clinic. Thanks for the question. Another on the serotide. Going back to the newborn to under five-year-old trial, you know, the growth velocity is so pronounced between, especially the newborns to one-year-olds. Can you talk maybe about the unique safety, efficacy, and concerns around this patient population, maybe more so than the over five-year-olds? Yeah, well, so we divided the study into three different age cohorts because we had reason to at least hypothesize that biodistribution of the drug would be different as a function of age. And it turns out that it's likely to be true.

Average growth Laci number or will there kind of be a call and we'll be able to age match patient populations from phase two versus phase three and in that kinda like are you targeting an average age of patient similar to what was in phase II for your phase three trial.

And then.

Maybe on your PK Eugene therapy, I think if you look at your competitor homology at least it preclinically and mouse models, they weren't able to show feed normalization.

Until they hit a threshold of about 30 viral genome copies Purcell in order to do you get feed normalization. How do you think about the translate the ability of these like PK you mouse models into humans, specifically on what dose.

Yes, certainly they cannot go on Oh, sorry that.

Hank: And so, three different cohorts that would be evaluated. So that's a really important consideration and is actually quite an advantage of a relatively short-acting drug in the sense that it doesn't take you months to adjust the dose of sorotide. If there's a problem, the half-life being what it is, pretty much the next day, you can start a different dose safely. So that's actually quite an interesting advantage that we have.

No I'll get resign I'll get back Okay anyway, I see way so thanks for taking on your questions.

And I appreciate the opportunity to address investor variability [noise].

Right, that's supposed to any other kind of variability.

So the target population for the phase three trial should be fairly similar to the phase two trial. So there should see some opportunity for for since comparison, but again. These are not side by side trials and they're not identical a patients that are being randomized between phase two in phase three so interpretation could be difficult.

Hank: And an interpretation of safety, therefore, is going to be to what extent, if there are safety sequelae, can they be addressed with simple dose modification. So when we get to the end of the study, that will stack up all that information for you. I would say, a priori, we have no real hypotheses about there being incremental differences in safety in this population compared to the older population. And finally, in regard to efficacy, the critical consideration is that growth velocity is declining quite rapidly over that age period.

I think the principal point of interpretive emphasis is going to be either met or didnt meet the primary endpoint for statistical sat testing because in this condition as I said before the what it adds up to won't be is uniquely understood from just the phase three data.

And so I think the the key thing to focus on that topline resolved in the first instance is going to be met or Didnt meet the primary endpoint.

As far as what the contents of the press release our.

Very premature I mean, we I don't even think we've had less patient out of the study yet and so therefore, we have an UN blinded and therefore, there is nothing really to talk about just yet so stay tuned hang in there we'll try to give you the salient perten information only unblind, just the right amount not too much.

Hank: So it's going to be much more difficult, and it would be much more difficult to compare these patients to a natural history control for that reason. So that's the reason that we chose to blind this study and randomize it to placebo. That will give us a healthy assessment of the treatment effect in this age group. Interesting. Thank you for the color.

Thank you want to add something about the.

The other fees to the phase two trial the ongoing phase two trial in under five patients and he is actually a randomized controlled trial definitely space, we'll get that yep Yep Yep. So that trials I said, we're stuck in the three cohorts three cohorts are two to five years old six months to.

Unknown Executive: Your next question comes from the line of Akash Tewari from Wall Street. Hey, thanks for taking me on. So talking to investors, there seems to be a large variation in how the Visorotide data will be perceived, whether you show 1.5, 1.75, or 2, even though I feel like statistically, it could totally be in that range. So what will be the data release procedure for Visorotide? Will we just get a top-line average growth velocity number? Or will there kind of be a call, and we'll be able to age match patient populations from phase 2 versus phase 3? And in that light, are you targeting an average age of patients similar to what was in phase 2 for your phase 3 trial?

Two years old zero months to six months of age a patients are randomized well actually each cohort has three sentinel subjects.

And the purpose of the set goals are to obtain initial pilot safety data as well as well for initial PK data for the purpose of dose adjustment.

Theres going to be in their randomized one to one drug to placebo within each of the three cohorts.

There are 30 patients in the first hub, where they're completed enrollment there are to be 10 patients 20 patients sorry, 20 patients in the second to or 20 patients in the third code again randomized one to one and the comparisons going to be hi, Z scores standard deviation scores.

Active versus placebo.

Unknown Executive: And then maybe on your PK eugene therapy, I think if you look at your competitor homology, at least pre-clinically in mouse models, they weren't able to show phenormalization until they hit a threshold of about 30 viral genome copies per cell in order to get phenormalization. How do you think about the translatability of these PKU mouse models into humans, specifically what dose levels are needed to get phenormalization?

Each individual cohort is.

Powered to detect trends, but study in aggregate is powered to detect an improvement in growth velocity.

So little more information about the design of the two six trial.

You also asked about 307 and Translatability.

Let me just take a little bit of the step back we have an internal saying Biomarin mouse nice lie in monkeys don't always tell the truth and that's actually a reference to the history and of gene therapy in which nearing experiments didnt necessarily predict what would happen in prime made experiments or what happened in human experience as it turns out 85 tends to be rally.

Unknown Executive: I see why you said thanks for taking on your questions, and I appreciate the opportunity to address investor variability, as opposed to any other kind of variability. So the target population for the phase 3 trial should be fairly similar to the phase 2 trial, so there should be some opportunity for some comparison. But again, these are not side-by-side trials, and they're not identical patients that are being randomized between phase 2 and phase 3. So interpretation could be difficult. And I think the principal point of interpretive emphasis is going to be whether or not the primary endpoint for statistical testing is met. Because in this condition, as I said before, what it adds up to won't be as neatly understood from just the phase 3 data.

Simply predictable I don't know that I would say the same thing necessarily for different capsense, and particularly novel Capsids for which there is hardly any preclinical data.

But I think with 85, what we have observed is this a preclinical murine data and the preclinical from non human primate data, it's actually pretty reflective of what have you know if you look at the right time points pretty reflective what happens in humans and that I think gives us a lot of confidence that we'll be able to see that relatively rapid result, once we get to an active dose and whether there's really.

Yes threshold or it's just a stick dose response curve.

Stay tuned let's see what they are.

Your next question comes from the line.

Your line is okay.

And then just where the man this is paid on for Paul.

Just to go back to pound take real quick that I hope it doesn't take too long to answer one I think more than 500 of your 800 patients ontology were previously on coupon are there any differences and.

Unknown Executive: And so I think the key thing to focus on in that top line result in the first instance is whether or not the primary endpoint is met. As far as what the contents of the press release are, it's very premature. I mean, I don't even think we've had the last patient out of the study yet. And so, therefore, we haven't unblinded them. And therefore, there's really nothing really to talk about just yet. So stay tuned. Hang in there. We'll try to give you the salient, pertinent information when we unblind. Just the right amount, not too much.

Underlying agent.

What's that.

People can here's what we're having technical difficulties.

Hi can you hear me.

The him aboard.

Do you guys still there.

Okay.

And so operator, we'd like to do that how some of the two and a portion of the call and let our chairman and CEO provide closing comments.

Unknown Executive: I mean, Hank, you want to add something about the other phase 2 trial, the ongoing phase 2 trial, in under five patients, that is actually a randomized controlled trial. Yeah, to explain a little bit about the design there.

No.

As you.

Herds are becoming 18 months will be transforming need for the company.

Which we'd expect to drive.

You need even growth beyond our existing commercial business.

Nothing growth continued R&D expense management and cash generated by offering a TV will continue to increase in parallel investment.

Hank: Yep, yep, yep, yep. So that trial, as I said, was split into three cohorts. The three cohorts are two to five years old, six months to two years old, and zero months to six months of age. Patients are randomized with, well, actually, each cohort has three Sentinel subjects. And the purpose of the Sentinels is to obtain initial pilot safety data, as well as pilot, as well as initial PK data for the purpose of dose adjustment. There's gonna be a randomized one-to-one dose of drug to placebo within each of the three cohorts. There are 30 patients in the first cohort. They've already completed enrollment. There are to be 10 patients, 20 patients, sorry, 20 patients in the second cohort, 20 patients in the third cohort, again, randomized one-to-one.

And what kind of its already tight our cities transition to larger multi indication is now on track with the Outlicensing up 20 meters on top and the pursuit of new potential product.

You will hear about all these R&D day next month.

We can't do get taken together, we believe I'm going is poised for significant commercially expansion over the coming quarters and we are preparing for success.

Thank you for your continued support than.

See all of your most of you in New York.

Thanks.

Ladies and gentlemen that concludes today's conference call. Thank all for joining you may now disconnect.

Hank: And the comparison's gonna be height Z scores, standard deviation scores, active versus placebo. Each individual cohort is powered to detect trends, but the study in the aggregate is powered to detect an improvement in growth velocity. So a little bit more information about the design of the 206 trial. You also asked about 307 and translatability.

Hank: Let me just take a little bit of a step back. We have an internal saying at Biomarin: mice lie, and monkeys don't always tell the truth. And that's actually a reference to the history of gene therapy in which murine experiments didn't necessarily predict what would happen in primate experiments or what would happen in human experiments. As it turns out, AAV5 tends to be relatively predictable. I don't know that I would necessarily say the same thing for different capsids and particularly novel capsids for which there is hardly any preclinical data.

Hank: But I think with AAV5, what we have observed is that the preclinical murine data and the preclinical non-human primate data are actually pretty reflective of what, you know, if you look at the right time points, it's pretty reflective of what happens in humans. And that, I think, gives us a lot of confidence that we'll be able to see that relatively rapid result once we get to an active dose. And whether there's really a threshold or it's just a steep dose response curve, stay tuned, and let's see what the data is.

Unknown Executive: Your next question comes from the line of Paul Matteis from Stateho. Your line is open. Hey, thanks for squeezing me in. This is Nadon for Paul.

Unknown Executive: Just two, going back to Palanzik real quick, that I hope it doesn't take too long to answer. One, I think more than 500 of your 800 patients on Palanzik were previously on Kuvan. Are there any differences in those underlying patient populations?

Unknown Executive: What's that? I don't know if people can hear us, but we're having technical difficulties. Hey, can you hear me? Yeah, I can hear you. But I don't think that works.

Operator: Are you guys still there? Operator, we'd like to now conclude the Q&A portion of the call and let our Chairman and CEO provide closing comments. So, as you have heard, the coming 18 months will be transformative for the company, which we expect will allow us to drive significant growth beyond our existing commercial business. Top-line growth, continued R&D expense management, and cash generated by operating activities will continue to increase in parallel with the investment in Valerox and Vazoritide. Our strategic transition to larger offering indications is now on track, with the out-licensing of 20Cm Alpha and the pursuit of new potential products. A few of you will hear about all this at R&D Day next month. Taken together, we believe Biomarin is poised for significant commercial expansion over the coming quarters, and we are preparing for success.

Operator: So thank you for your continued support, and we hope to see all of you, or most of you, in New York next month. Goodbye. Ladies and gentlemen back... Thank you all for joining, ??? ??? ??? ??? ??? ??? ??? ??? ??? ??? ??? ??? ??? ??? ??? ??? ??? ??? ??? ??? ??? ??? ??? ??? ??? ??? © BF-WATCH TV 2021