Q2 2020 Ultragenyx Pharmaceutical Inc Earnings Call

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Operator: Ladies and gentlemen, thank you for standing by, and welcome to the Ultragenyx second quarter of 2020 financial results and corporate update conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 1 on your telephone. As a reminder, we ask that you limit yourself to one question and one follow-up. If you require any further assistance, you can press star zero, and without further ado, I would like to hand the conference over to Mr. Joshua Higa. Thank you.

He gem gentlemen, thank you for standing by welcome to the Ultragenyx second quarter up from 20, <unk> financial results and corporate update conference call.

At this time all participants are in the missing only about.

So just because the presentation there will be a question answer session.

The asked a question during this session you want me to press Star one on your telephone.

Mining, we ask that you limit to one question one follow up.

If you require any further system you can press far easier and read out far they do who like to Kinda conference over to Mr., Josh and Workiva. Thank you. Please go ahead Sir.

Good afternoon, and welcome to the Ultragenyx financial result in corporate update conference call for the second quarter 2020.

Joshua Higa: Good afternoon, and welcome to the Ultragenyx financial results and corporate update conference call for the second quarter of 2020. We have issued a press release detailing our financial results, which you can find on our website at ultragenyx.com. I am Joshua Higa, Director of Industrial Relations. Joining me on this call are Emil Kakkis, Chief Executive Officer and President, Shalini Sharpe, Chief Financial Officer, Camille Bedrosian, Chief Medical Officer, and Erik Harris, Chief Commercial Officer.

We had issued a press release detailing our financial results, which you can find on our web site at Ultragenyx Dot com.

I am Josh when he got director of Investor Relations. Joining me on this call Im Okay, I guess, Chief Executive Officer, and President Shalini Sharp Chief Financial Officer, Camelback drug in Chief Medical Officer, and Air carriers, Chief Commercial officer.

Joshua Higa: I'd like to remind investors that this call will include forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, the types of statements identified as forward-looking in our 2019 annual report on Form 10-K filed on February 14, 2020, our quarterly report on Form 10-Q that will be filed soon, and our subsequent periodic reports filed with the SEC, which will all be available on our website in These forward-looking statements represent our views only as of the date of this call and involve substantial risks and uncertainties, including many that are beyond our control. Please note the actual results could differ materially from those projected in any forward-looking statements. For a further description of the risks and uncertainties that could cause actual results to differ materially from those expressed in the forward-looking statements, as well as risks related to our business, see our periodic reports filed with the SEC. I will now turn the call over to Emil.

To remind investors that this call will include forward looking statements within the meaning of the safe Harbor provisions of the private Securities Litigation Reform Act of 1995, including but not limited to the types of statements identified as forward looking in our 2019 annual report on form 10-K that was filed on February 14th.

2020.

Quarterly report on form 10-Q that will be filed soon and our subsequent periodic reports filed with the FCC, which will all be available on our web site can be investors section.

These forward looking statements represent our views only as of the date of this call and involve substantial risks and uncertainties, including many that are beyond our control.

Please note the actual results could differ materially from those projected in any forward looking statement.

For further description of the risks and uncertainties that could cause actual results to differ materially from those expressed in the forward looking statements.

Well those risks related to our business. She our periodic reports filed with the FCC I will now turn the call over to anymore.

Good afternoon, and thank you everyone for joining us on today's call I'll start with our recall with general update or progress then turn it over to Eric shortly and can be able to drive more detailed update so their respective areas.

Emil D. Kakkis: Good afternoon, and thank you, everyone, for joining us on today's call. I'll start our call with a general update on our progress, then turn it over to Erik, Shalini, and Camille to provide more detailed updates on their respective areas. The second quarter was highly productive for Ultragenyx. In the span of just two weeks in June, we received our third and fourth FDA approvals in our first 10 years as a company. The first was CRIZVITA for tumor-induced optimulation, or TIO, which is now the second indication of the product after its approval for XLH in 2018. The second was Dojolvi for long-chain fatty acid oxidation defect, or LC-FAOD. A group of six distinct inborn errors of metabolism.

The second quarter with highly productive rural Ultragenyx instead of just two weeks in June we received our third and fourth ft approval.

Emil D. Kakkis: These are the first approved treatments for either of these debilitating diseases. In both cases, we were able to secure full FDA approval based on our Phase 2 studies, supplemented by data from expanded access programs. This significantly reduced the time to develop these therapies for patients with no other FDA option. Our established FDA-approved products continue to perform well.

First 10 years as a company.

The first with crispy tipper tumor induced osteomalacia or T O because now the second indication where the product after approval for Exelon, which in 2018.

The second was still Jovi core long chain fatty acid oxidation be pick or L. C D.

The group of six distinct inborn errors of tablets.

These are the first approved treatment for either of these debilitating diseases.

In both cases, we're able to secure pool at the approval based on our phase two studies supplemented by data from expanded access program.

[laughter] significantly reduced the time to development for these therapies.

For patients with no other up the auction.

Our established approved products continued to perform well because feed in Xalatan met SEBI continued to grow as we enter the third year post approval.

Emil D. Kakkis: QRISFEDA and XLH and MetSavvy continue to grow as we enter the third year post-approval. We've developed a great team and strong relationships in both medical genetics and in endocrinology fields with these early launches, and this will enable efficient launches in both TIO and LCFOD, despite some expected impact from COVID-19. Moving to our gene therapy platform and programs, there have been significant recent clinical data updates for all three programs, and ASGCT presented data on both our GSD-1A and OTC deficiency programs. For GSD-1A, all patients across all three cohorts in the Phase 1-2 study have responded to DTX401 gene therapy, with the patients in the latest cohort more rapidly tapering their use of cornstarch and oral glucose replacement therapy that is enabled now by the expression of the transgene in our vector.

We've developed a great team and strong relationships in both medical genetics, and then indicates an all endocrinology field with either launches.

This will enable efficient launches in book T O L C or D. Despite some impact from coded team.

Moving to our gene therapy platform and programs. There has been significant recent clinical data update for all three program.

Emil D. Kakkis: For OTC, we've now confirmed that six out of nine patients in the study are responders to DTX301 gene therapy, including all three of the patients in the highest dose cohort. These updates further solidify our confidence in both programs as phase three planning continues. The third gene therapy update was for the hemophilia A program led by our partner Bayer. As with prior cohorts, these latest data show a sustained and clinically meaningful factor 8 increase competitive with other CMA programs and a near-complete reduction in spontaneous bleeds. As a reminder, the B.A.R.E.

It is TCT were presented data on both our GFT wanting and ODC deficiency program.

Or just even when they all patients across all three cohorts in the people to study have responded to be tier four one gene therapy with the patients in the latest cohort were rapidly tapering their use of corn starch and oral coax replacement therapy that has enabled now by expression of the transient or a vector.

Grow T. C was now confirmed that six out of naive patients in the study are responding to the tier three or one gene therapy, including all three of the patients in the highest dose cohort.

These updates further solidify our confidence of both program.

The three planning continue.

The third gene therapy update with for Hemophilia a program led by our partner fire.

Appear on the ongoing phase one two presented data at <unk> T. H on the third cohort from the study.

As with prior cohort these latest data show sustained and clinically meaningful factory, increasing competitive with other he may program.

And the near complete reduction spontaneous bleeds.

As a reminder, that bear programs, our first partner gene therapy program and first to use material from our large scale, if you love producers selling system.

Emil D. Kakkis: The program is our first partner gene therapy program and the first to use material from our large-scale HeLa producer cell line system. In the first quarter of this year, we initiated the Gene Therapy Platform Partnership with Daiichi Sankyo, in which they have non-exclusive access to our HeLa and HK293 manufacturing system. Technology transfer related to that license has since been initiated, and we will receive $25 million in milestone payments when it is complete. So with multiple collaborations in place, three products demonstrating positive clinical results, our gene therapy platform is on very solid footing as a source of multiple potentials. I'll now turn the call over to Erik to go into more detail on the launches of Dojoldi and LC Epi.

The first quarter. This year, we initiated a gene therapy platform partnership Daiichi Sankyo in which they have now it's good access to our HILA, an 8-K to any green manufacturing system.

Technology transfer laid that out license has since been initiated and we will receive 25 million and milestone payment plan. It is complete.

So with multiple collaboration in place three products demonstrating positive clinical results are gene therapy platform as I'm very solid footing as a source of multiple potential treatment.

Erik Harris: WD

I'll now turn the call over to Eric to go to more detailed the launches of Dolby and L.C. at the end crispy the in T O as both progress with our other commercial program.

Erik Harris: and Chris Vita in TIO, as well as Progress with our other commercial programs.

Thank you animal.

Erik Harris: Thank you, Emil. I will start by recapping our launch plans for De Jovi and covering Chris Fito. As you saw last week, Dijoby is now commercially available to U.S. patients with LC-FLD. Yogi is the first approved therapy for LC-FLD, which is a severe, lifelong, and life-threatening disease. We have initiated the process of working with commercial and government payers to ensure that Djovah is accessible to all LC-FAOD patients as indicated in the broad FDA label. In the first week of launch, we received star forms from multiple doctors and centers of excellence, and we shipped commercial therapy to our first patient just this week. First reimbursements were approved for patients. We also had one newborn already prescribed to Joby, whose older sibling had died at a very young age with FAOD.

Let's start with recapping, our launch plans for the Joby thin cover Chris feeder.

As you saw last week. The Jobin is now commercially available to us patients with LCR D.

You always the first approved therapy for LCR facility, which is a severe lifelong in life threatening disease.

We have initiate the process of working with commercial and government payers to ensure that the job is accessible.

The all LCR failed the patients indicated in the broad FDA label.

In the first week of launch we receive star forms from multiple doctors centers of excellence and we have shipped commercial therapy to our first patients.

Just this week.

The first reimbursements were approved for patients.

We also had one newborn already prescribed to Joby, whose older siblings has died at a very young age with FHLB.

It is important to recognize that the reimbursement process does take time as various payers established a new market policies.

Erik Harris: It is important to recognize that the reimbursement process does take time as various payers establish their new market policies. As a result, we expected the Joby launch to build gradually over time and most of our revenue for the product to come from EU named patient sales. In the early stages of the U.S. launch, we are focused on transitioning the approximately 80 patients currently on clinical drugs in the U.S. to reimbursed commercial therapy. Our team has started conversations with these physicians at our clinical sites to provide information about these transitions, which we expect to complete in the upcoming months, dependent on payers' new-to-market coverage policies. Overall, we estimate that there are approximately 2,000 to 3,500 patients with LCFAOD, and the vast majority of these patients are seen at approximately 160 metabolic genetic centers. We are very familiar with these centers and their positions based on our experiences with MEVSEVI, CRISPIDA, and our OTC and GSD-1A programs. As a result, our incremental commercial investment will be minimal for this new launch.

As a result, we are expected to adobe launch to build gradually overtime and most of our 2020 revenue for the product to come from you named patient sales.

And the early stages of the U.S. launch we are focusing we're focused on transitioning the approximately 80 patients currently one clinical drug in the U.S. to reimburse commercial therapy.

Our team has started conversations with these physicians at our clinical sites to provide information about these transitions, which we expect to complete in the upcoming months dependent on payers news to market coverage policies.

Overall, we estimate that there are approximately 2000 to 3500 patients with LCFS LT.

The vast majority of these patients are seen at approximately 160 metabolic genetics centers.

We are very familiar with the centers and their physician is based on our experiences with met savvy, Chris via and our LTC and GST when a programs.

As a result, our incremental commercial investment will be minimal for this new launch.

And while launching in the midst of the coven 19 pandemic if not ideal the work that we have done to adapt to the current situation form that's being cressida will be extremely helpful. As we launched the joking.

Erik Harris: And while launching in the midst of the COVID-19 pandemic is not ideal, the work that we have done to adapt to the current situation for MEVSEV and CREFETA will be extremely helpful as we launch JOVI. These adaptations, coupled with the patient's ability to take Jovi at home since it is an oral therapy, along with a high unmet need, give us confidence that we will be able to have a successful launch. Turning now to Chris Vita, which we are also currently launching in the U.S. for tumor-induced osteomalacia, or TIO, and have begun to treat our first commercial TIO patient. Many of the potential prescribers are the same group of endocrinology specialists that have become familiar with CRISPR for XLH over the last couple of years, so we are able to leverage our current commercial infrastructure. PIO, however, is much less common than XLH, affecting about 500 to 1,000 Americans, and it can take a long time to diagnose.

These have that patients coupled with the patience ability to take the joke here at home since it is an oral therapy, along with a high unmet need give us confidence.

And we will be able to have a successful launch.

Turning now to Chris feedback.

Which we are also launched currently launching in the us for tumor induced osteomalacia for T. Io and have begun to treat our first commercial T O patients.

Many of the potential prescribers, how the same group of endocrinology specialists that has become familiar with Chris feeder for XL age over the last couple of years. So we are able to leverage our current commercial infrastructure.

T. Io however, as much less Commons in Echo Lake.

Affecting about 500 to 100 to 1000 Americans.

And it can take a long time to diagnose.

Our initial focus is on conversion of clinical trials and compassionate use patients.

Erik Harris: Our initial focus is on conversion of clinical trials and compassionate use patients. Similar to Dojovi, we expect payers to update their policies for CRISPR to add the TIO indication over time. The good news is that the J-code for CRISPR remains the same for both XLH and TIO indications, which will simplify the buy and build process for payers.

Similar to the Jovi, we expect payers to update their policies for Chris FIDA to add the CIO indication overtime.

Good news is that the J code for Chris feet of remains the same for both XL late in T. idle indications.

Which will simplify the buying bill process for payers.

To date.

We have had multiple starts and patient reimbursements for Chris feed anti up.

Shalini Sharpe: We have had multiple starts and patient reimbursements for CRISPI and NTIO. We expect a gradual and steady revenue build in this new approved indication. Chris Vita, CEO of XLH, continues to do well in spite of COVID-19-related challenges. Our patient support services team has reached out proactively to all of our existing patients individually to ensure continuity of care. Since the COVID-19 pandemic, we continue to receive new star forms and increase the number of patients on reimbursed therapy. Our field teams have done a noteworthy job of adjusting to this environment with our HCPs and have started to effectively use virtual platforms to engage with them. We expect to further build momentum as the country begins to reopen. Across Latin America, there is a strong patient community that has driven a lot of awareness and demand for CRISPR-Vita.

We expect the gradual steady revenue growth in this new approved indication.

Chris feeder for EXL H. continues to be well in spite of cobot 19 related challenges.

Our patient support services team has reached out proactively to all of our existing patients individually to ensure continuity of care.

Just a cobot 19 pandemic, we continue to receive newstar forms and increase the number of patients on reimburse therapy.

I feel teams have done a noteworthy job and adjusting to this environment with our HCP and have started to effectively use virtual platforms to engage with them.

We expect to further build momentum as the country begins to reopen.

Across Latin America, there's a strong patient community that has driven a lot of awareness and demand for Chris FIDA.

In Brazil, the regions largest market. This is seen in the steadily growing numbers of injunctions that are being granted and funded by both state and federal government.

Shalini Sharpe: In Brazil, the region's largest market, this is seen in the steadily growing numbers of injunctions that are being granted and funded by both state and federal governments. Similarly, in Colombia and Argentina, the number of patients on reimbursed named patient treatment increased. Over time, we expect Life in America to provide a more meaningful contribution to revenue as the launch in this region progresses because of the team's efforts to maintain continuity of care while also finding new and creative ways to reach patients. Chris Vita's performance through the second quarter of 2020 has been strong. We are maintaining our revenue guidance of $125 million to $140 million for Crisp Vita revenue in the Ultragenyx Territory. As a reminder, this range includes CRISPR and XLH and TIO and covers both profit share and revenue in North America, as well as product sales in other regions. With that, I'll turn the call over to Shalini, who will walk through our financial results.

Similarly.

In Colombia, and Argentina, the number of patients on reimburse named patient treatment increases.

Overtime, we expect Latin America to providing more meaningful contribution to revenue as we launch in this region progresses.

Because of the team's efforts to maintain continuity of care, while also finding new and creative ways to reach patients for sweetest performance through the second quarter of Twentytwenty has been strong.

We are maintaining our revenue guidance of 125 million to 140 million for Chris Peter revenue and the Ultragenyx territories.

As a reminder, this range includes Kristina and XL age anti IL and covers both profit share revenue in North America as well as product sales in other regions.

With that I'll turn the call over to Shalini, who will walk through our financial results.

Thank you Eric and good afternoon, everyone.

Shalini Sharpe: Thank you, Erik, and good afternoon, everyone. We issued a press release earlier today that included a financial update, which I will briefly summarize. Total revenue for the three months ending June 30, 2020 was $61.7 million. For the quarter ending June 30, 2020, Krispita revenue in the Ultragenyx territories was $32.4 million. This includes $29.8 million in collaboration revenue in the North American Profit Share Territory and net product sales in other regions of $2.5 million. Total royalty revenue related to the sales of Kris Vita in the European Territory was $5 million, which includes $1.5 million for sales in the region prior to January 1, 2020, from a change in estimate and release of reserves by our collaboration partners.

Issued a press release earlier today that included a financial update recalibrate only sunrise.

Shalini Sharpe: The Metsevi product revenue for the second quarter of 2020 was $4.2 million, and UX007 named patient revenue was $1.3 million. We also recognized $18.9 million of revenue related to the collaboration and license agreement with Daiichi Sankyo that was executed in March of 2020. Our total operating expenses were $124.8 million for the second quarter of 2020, which included research and development expenses of $80.7 million and SG&A expenses of $42.3 million.

Total revenue for the three months ending June Thirtyth 2020 was $61.7 million.

The quarter ended June Thirtyth 2020, Kristina revenue in the Ultragenyx territory for $32.4 million.

This includes $29.8 million and collaboration revenue in the North American profit share territory.

And to net product sales in other regions of $2.5 million.

Total royalty revenue related to the sales of Kristina and the European territory was $5 million, which included $1.5 million for sales in the region. Prior to January one 2020 from a change an estimate and releasing reserves by our collaboration partner.

Lets heavy product revenue for the second quarter 2000, $24.2 million and do you like seven named patient revenue with $1.3 million.

We also recognize $18.9 million and revenue related to the collaboration and license agreement with Daiichi Sankyo that was executed in March of 2020.

Our total operating expenses were $124.8 million for the second quarter 2020, which included to research and development expenses at $80.7 million and SGN expenses and $42.3 million.

We expect our R&D costs to continue increasing overtime as we advance additional product candidates from preclinical development into early and pivotal clinical studies.

Shalini Sharpe: We expect our R&D costs to continue increasing over time as we advance additional product candidates from preclinical development into early and pivotal clinical studies. We also expect SG&A to modestly increase over the coming quarters as we support the expansion of our existing commercial programs and the launch of Dijolvi for LCFAOD and Crispito for TIO. We expect the split of R&D versus SG&A expense to remain fairly consistent.

We also expect SDMA to modestly increase over the coming quarters as we support the expansion of our existing commercial programs and the launch of digital they for LCR sanity, and Christiana for T.O. Wayne.

We expect the split of R&D versus SGN expense remained fairly consistent.

In 2020 today, approximately 17% of our operating expenses are noncash.

Shalini Sharpe: In 2020 to date, approximately 17% of our operating expenses are non-cash. In the second quarter of 2020, we reported net income of $25.3 million, or $0.42 for the basic share and $0.41 per diluted share. This compares to a net loss of $93.7 million, or $1.59 per share basic and diluted for the second quarter of 2019. The net income for the second quarter of 2020 includes a $95.2 million unrealized gain from the Fair Value Adjustment on the investment in Arcturus Equity and $18.9 million of collaboration revenue related to our agreement with Daiichi Sankyo. These were partially offset by $8.4 million in non-cash interest expense on the liability related to the sale of future royalties.

In the second quarter 2020, we reported net income of $25.3 million for 42 cents per basic share and 41 cents per diluted share.

This compares to a net loss of $93.7 million or $1.59 cents per share basic and diluted for the second quarter of 2019.

The net income for the second quarter of 2020 includes 95.2 million dollar unrealized gain from the fair value adjustment on the investment in the Arcturus equity.

And the $18.9 million of collaboration revenue related to our agreement with Daiichi Sankyo.

These were partially offset the $8.4 million and noncash interest expense on the liability related to the sale of future royalties.

Recall in the second quarter, we exercise our option to purchase 600000 shares of Arcturus common stock at $16 per share.

Shalini Sharpe: Recall, in the second quarter, we exercised our option to purchase 600,000 shares of Arcturus common stock at $16 per share. Upon completion of the additional equity purchase, Ultragenyx owns 3 million shares and continues to be Arcturus's largest shareholder. For the first half of 2020, cash used in operations was $7.8 million, which included $134.9 million of operating cash received from Daiichi Fankio related to the collaboration and license agreement. We ended the second quarter of 2020 with $817.5 million in cash, cash equivalents, and available for sale in Beth. Moving to our guidance for 2020, we are currently maintaining the guidance range that we shared at the beginning of the year and affirmed in our first quarter earnings

Upon completion of the additional equity purchase Ultragenyx on 3 million cherries and continues to be Arteris is largest shareholder.

For the first half of 20 to 20 cash used in operations was $7.8 million, which includes the $134.9 million operating cash received from Daiichi sankyo related to the collaboration and license agreements.

We ended the second quarter of 2020 with $817.5 million in cash cash equivalents and available for sale investments.

Moving to our guidance for 2020, we're currently maintaining the guidance range that we shared at the beginning of the year and affirmed our first quarter earnings call.

We anticipate cristeta revenue to Ultragenyx NR territories to be between $125 million and $140 million those territories, including North America, Latin America, and Turkey and exclude the European royalty as this was monetized in the transaction that was completed before healthy pharma that was announced in December of 2019.

Shalini Sharpe: We anticipate Crispida revenue to Ultragenyx in our territories to be between $125 million and $140 million. Both territories include North America, Latin America, and Turkey and exclude the European royalty as this was monetized in the transaction that was completed with Royalty Pharma that was announced in December of 2019. We continue to monitor the situation as the COVID pandemic persists. I would now like to turn the call over to Camille, who will provide an update on our clinical program. Thank you, Shalini. And good afternoon, everyone.

We continue to monitor is situation as the Covance pandemic persist.

I would now like to turn the call to Camille who will provide an update on our clinical programs.

Thank you Charlotte and good afternoon, everyone I will review, our two new FDA approvals and progress with our annual than syndrome program before handing back to ammo to provide more detail on our recent gene therapy clinical updates.

Camille L. Bedrosian: I will review our two new FDA approvals and progress with our Angelman syndrome program before handing back to Emil to provide more detail on our recent gene therapy clinical updates, starting with Dojovi for Long-Chain Fatty Acid Oxidation Disorders, or LCF-AOD, a devastating disease with significant morbidities despite newborn screening and use of available management options. On June 30, we received the first ever FDA approval of a treatment for patients with LCSAOD. The approval spans all six types of LCSAODs and applies to both pediatric and adult patients. As Eric's team works to make doldrovi broadly available to patients living with this debilitating and dangerous disorder, the clinical and regulatory teams will be focused on two areas of next steps for the program.

Starting with Dolby for a long chain fatty acid oxidation disorders, or Lcs sale D. A devastating disease with significant morbidities, despite newborn screening and use of available management options.

On June 30, we received the first ever FDA approval of a treatment for patients with Lcs Seo D.

The approval stands all six types of LCFS, LDL and applies to both pediatric and adult patients.

As Eric's team works to make don't drill the broadly available to patients living with this debilitating and dangerous disorder, the clinical and regulatory teams will be focused on two areas of next steps for the program.

First we are seeking approval for don't told me in other regions around the World. We had previously submitted a marketing application to Anvisa in Brazil.

Camille L. Bedrosian: First, we are seeking approval for DoDolvi in other regions around the world. We have previously submitted a marketing application to Anvisa in Brazil and, more recently, made a new drug submission in Canada, where we have been granted priority review. Our discussions with the European Medicines Agency are ongoing, and in the meantime, we will continue to make the product available to the more than 70 7-0 patients with LC-FAOD who are receiving it based on requests from physicians seeking the product for reimbursed named patient treatment in France and Italy. The development team's other area of focus going forward for DoDrovi is the implementation of our Disease Monitoring Program, or DMP. As a reminder, the DMP is a long-term, fully-sponsored observational study of DoDrovi and LC-FAOD in at least 300 patients for a target of 10 years. The DMP will encompass all post-marketing requirements from the FDA in a single study.

More recently made a new drug submission in Canada, where we had been granted priority review.

Our discussions with the European Medicines agency are ongoing.

And in the meantime, we will continue to make the product available to the more than 77, Oh patients with LCFS L.D., who are receiving it based on request from physician seeking the product for reimbursed named patient treatment in France and Italy.

The development teams other area of focus going forward for Dolby is the implementation of our disease monitoring program or DMP.

As a reminder of the DMP as a long term fully sponsored observational study until Jovi, and Lcs L.D. and at least 300 patients for a target of 10 years.

The DMP low encompass all post marketing requirements from the FDA in the single study.

Disease monitoring programs or just one development innovation, we are implying it Ultragenyx for example, the dam T., we initiated for accelerates in 2018 has enrolled very rapidly.

Camille L. Bedrosian: Disease Monitoring Programs are just one development innovation we are employing at Ultragenyx. For example, the DMP we initiated for XLH in 2018 has enrolled very rapidly. As a reminder, patients in the LCFAOD DMP may or may not be receiving dodrovia. Those patients who receive therapy in our DMPs all receive commercially reimbursed drugs.

As a reminder, patients in the LCFS Cody DMP may or may not be receiving don't drill the those patients who received therapy NRT MPS all receive commercial reimbursed drug.

This enables us to minimize post marketing requirement costs, while generating robust high quality data from these very large and very long term studies.

Camille L. Bedrosian: This enables us to minimize post-marketing requirement costs while generating robust, high-quality data from these very large and very long-term studies. Moving on, to Quesida for tumor-induced osteomalacia, or TIO, a rare debilitating disease for which approximately half of patients have tumors that cannot be surgically removed, leaving them with no other current treatment options. We received FDA approval of the Crisvita Supplemental BLA less than two weeks before the DoDrovi approval. FDA approval for both pediatric and adult patients was based on data from two single-arm phase 2 studies that followed 27 patients with TIO for up to 144 weeks. In these studies, CRISPR was associated with increases in serum phosphorus and improvements in osteomalacia and healing of bone lesions.

Moving onto Cressida tumor induced osteomalacia or T O a rare debilitating disease for which approximately half of patients have tumors that cannot be surgically removed, leaving them with no other current treatment options.

We've received FDA approval of the could feed a supplemental B.L.A. less than two weeks before they'll Jody approval.

The FDA approval for both pediatric and adult patients was based on data from two single arm Phase two study that follow 27 patients with T O for up to 144 weeks.

In May studies, crispy was associated with increases in serum phosphorus and improvements and osteomalacia and healing of bone lesions.

Similar to our other approved therapies, we will be implementing a long term fully sponsored observational DMP that will enroll at least 20 patients and who will be followed for over a 10 year period.

Camille L. Bedrosian: Similar to our other approved therapies, we will be implementing a long-term, fully-sponsored observational DMP that will enroll at least 20 patients and who will be followed for over a 10-year period. Shifting to CRESCITA for X-linked hypophosphatemia, or XLH, which is approved by the US FDA and Health Canada for the treatment of adult and pediatric patients six months of age and older with this rare bone disease. Recall also that CRESCITA is approved in Brazil with a slightly different indication. Our partner Kiowa Curin recently announced a positive opinion from the Committee for Medicines for Human Use, or CHMP, in Europe to expand the XLH European approval to now include adults, and therefore, it is labeled now for all patients at least one year of age. The initial EU approval only covered pediatric and adolescent patients who are still growing. Kira Karan expects a final European Commission decision in the second half of this year.

Shifting to Cressida for excellent type of foster teammates or XL age, which is approved by the U.S.F.D.A. and health, Canada for the treatment of adult and pediatric patients six months of agent older. With this we are bone disease recall also that could see the is approved in Brazil with a slightly different indication.

Our partner Akila, Karen recently announced a positive opinions from the committee for medicine products for human use foresee HMP in Europe to expand the Exelate European approval to now include adults and therefore is labeled now for all patients or at least one year of age.

The initial eagle pool, only covered pediatric and adolescent patients who are still growing.

Cuba, Karen expects a final European Commission decision and the second half of this year.

Our first approved therapy MEP study, which is approved for the treatment of Mucopolysaccharidosis type seven a slice syndrome occurring in approximately 200 pediatric and adult patients around the world recently received a positive opinion from the CHF <unk> on the tied to variation.

Camille L. Bedrosian: Our first approved therapy, MEPSEVI, which is approved for the treatment of mucopolysaccharidosis type 7, or SLY syndrome, occurring in approximately 200 pediatric and adult patients around the world, recently received a positive opinion from the CHMP on the type 2 variation. This variation would expand the EMA approval information to include long-term effects of Mepceti on the reduction of urinary glycosaminoglycans, or UGAGs, and improvements in the Multi-Domain Clinical Responder Index, as well as six-minute walk-throughs. We anticipate a formal decision from the European Commission in the second half of 2020.

This variation will expand the M&A approval information to include long term effects in that study on the reduction of urinary glucose immuno gleick hands or you guys and improvements in a multi domain clinical responder index as well as six minute walk test.

We anticipate a formal decision from the European Commission in the second half of 2020.

I will now turn to our program with genetic Sarah Biotherapeutics to advance Gtx, one or two and antisense oligonucleotides for the treatment of Angelman syndrome, Angelman syndrome. As you know affects approximately 60000 patients worldwide and is a devastating neuro genetic disorder with abroad.

Camille L. Bedrosian: I will now turn to our program with Genetics Biotherapeutics to advance GTX-102, an antisense oligonucleotide for the treatment of Angelman syndrome. Angelman syndrome, as you know, affects approximately 60,000 patients worldwide and is a devastating neurogenetic disorder with a broad spectrum of disease manifestations including Speech and Cognitive Impairment, Ataxia or Balance Issues, Sleep Dysfunction, and Seizures

From a disease manifestations, including speech and cognitive impairment ataxia or balance tissues sleep dysfunction and seizures.

There are no approved treatment options this diseases that neuro developmental disorder, and not neuro degenerative. So there is a possibility to reverse some of the manifestations.

Camille L. Bedrosian: There are no approved treatment options. This disease is a neurodevelopmental disorder and not neurodegenerative, so there is a possibility to reverse some of the manifestations.

Our partners genetics initiated the phase one two study of Gtx, one or two earlier this year, marking the first azo to move into the clinic for agents syndrome.

Camille L. Bedrosian: Our partners, Genetics, initiated the Phase 1-2 study of GTX-102 earlier this year, marking the first ASO to move into the clinic for Angelman's Syndrome. The first two cohorts have been fully enrolled, and patients have received multiple doses. Safety and efficacy data from the first two dose escalating cohorts are currently being evaluated, and enrollment and dosing at the next dose levels are expected to resume shortly. All we have achieved so far in 2020, and we will drive continued progress of the programs going forward. I want to commend our internal teams for successfully pushing through two concurrent FDA reviews, as well as the joint team with Genetics for its impressive progress with a potential therapy for Angelman Syndrome. And importantly, I want to again thank the patients, families, caregivers, and physicians who participated in the clinical program at LCFAOD and TIO and those currently participating in the ANGEL1 program, particularly in light of COVID-19. I will now turn it back to Emil, who will provide more detail on our gene therapies in development.

The first two cohorts had been fully enrolled and patients who received multiple doses.

Safety and efficacy data from the first two dose escalating cohorts are currently being evaluated and enrollment and dosing at the next dose levels are expected to visit shortly.

Two.

All we have achieved so far in 2020, and we will drive continued progress of the program's going forward.

I want to commend our internal team successfully pushing through two concurrent FDA reviews as well as the joint team with genetics fourth impressive progress with a potential therapy for any human syndrome.

And importantly, I want to again, thank the patients families caregivers and physicians who participated in the clinical program at LCFS Seo D. N T O and those currently participating in the Angel and program, particularly in light of Cobot 19.

Well now turn it back to ammo, who will provide more detail on our gene therapies in development.

Thank you Camille as mentioned in my opening remarks, we had important data readouts from all three critical to their program during Q2.

Emil D. Kakkis: Thank you, Camille. As mentioned in my opening remarks, we had important data readouts from all three clinical team therapy programs during Q2, starting with DTX-401 proglytion, storage disease type 1A. GSC-1A is a life-threatening disease that requires patients to take cornstarch every 3-4 hours to avoid severe hypothermia and the risk of death, as well as long-term complications. We presented at ASGCT the first data from the confirmatory cohort 3 as the 6012 dose, as well as longer-term data from the early cohort. All Cohort 3 patients responded to DTX-4.1 as we saw in the earlier cohorts. However, Cohort 3 patients, though, reduced their corn starch usage at a faster rate by an average of 57% at Week 12, versus 38% and 14% at the same time point for the other two cohorts. Looking at the longer-term data from cohorts 1 and 2, these patients reduced corn starch use by an average of 83%, with 4 of 6 patients discontinuing daytime corn starch use altogether. Additionally, two patients have completely terminated all corn starch use.

Starting with the tier four one production store disease type one a.

Do you see one is a life threatening disease the requires patience to take corn search every three to four hours to avoid severe hypoglycemia and the risk.

As well as long term complication.

We presented at his TCT first data from a confirmatory coordthree 60 called dose as well as longer term data from the early cohort.

All coordthree patients respond to detect for one as we saw the earlier cohorts.

Core three patients so reduced the corn starch usage at a faster rate quite an average of 57%.

We 12 versus 38% in 14% the same time point for the other two cohorts.

Looking at the longer term data from cohorts one into these patients produce corn George.

Use by an average of 83% with core of six patients discontinued daytime course or excuse altogether.

Two patients have completely terminate all courts searches.

These results suggest a de kits for one is dramatically changing lives of these patients who prior to joining therapy has been at risk for death with such significant reductions in court searches.

Emil D. Kakkis: These results suggest that DTX-401 is dramatically changing the lives of these patients who, prior to gene therapy, would have been at risk for death with such significant reductions in corn starch use. We continue to follow all patients in the study and expect to put out additional data on Cohort 3 in the second half of this year. We plan to have an end of Phase 2 meeting with FDA in the same timeframe as we gear up for a Phase 3 study in early 2021, depending on the impact of COVID-19. Moving on to DTX-301, a gene therapy for the treatment of orensine transcarpamylase deficiency, or OTC. OTC is the most common of the urea cycle disorders caused by an inability to detoxify ammonia into urea, and OTC patients can experience metabolic crises that can result in neurologic issues, hospitalizations, and comas, sometimes resulting in death.

We continue to follow all patients the study expect to put out additional data on cohort three second half year.

We plan to have an end of phase two meeting with FDA and the same timeframe as we get report phase three study in early 2021, depending on the impact of Coca 19.

Moving onto TTX real Wanna gene therapy for the treatment warranty transfer bandwidth efficiency or PC.

Oh do you see is most common other recycled disorders caused by an inability to the takeaway ammonium into urea Lucy patients can experience, but about crisis that could result in neurologic issues hospitalizations and coma.

Sometimes result and up.

The FCC to get it was an update to the initial cohort three data from January.

Emil D. Kakkis: The ASGCT data was an update to the initial cohort 3 data from January. It included three major updates. First, patient nine is now confirmed as a responder to DTX-31 following multiple sustained urea genesis increases, and it is one of the levels that remain stable at normal age over that time. Six of nine patients in the study are now confirmed respondents, including all three patients in the highest-dose cohort three. Second, patient A, the previous responder, is now along the path of becoming a complete responder after discontinuing scavenger therapy and starting a relaxer diet. Third, all three of the previously disclosed complete responders remained stable through up to two years of follow-up. They reigned well despite discontinuation of alternative therapies and a restricted diet for more than one year now.

As GCT included three major updates first patient nine is now confirmed as a responder to Detroit three one following multiple sustained regenesis increases is really levels have remained stable normal range over that time.

Six nine patients in the study confirmed responses, including all three patients in the highs this cohort three.

Second patient Ada previous responders now along the path to become a complete responder after discontinuing scavenger therapy is very relaxed or diet.

Third all three of the previously disclose complete responders remain stable through up to two years, a follow up the rain well despite discontinuation of alternative therapies and the restricted for more than one year now.

The next there for this program to treat three more patients at the cohort three dose with prophylactic steroids.

Emil D. Kakkis: The next step for this program is to treat three more patients at the cohort three dose of prophylactic steroids. Due to COVID-19, we have not yet dosed patients into the prophylactic steroid cohort, but we are aiming to have data by the end of 2020. In addition to these ASGCT updates, data was presented at the recent ISTH meeting on the hemophilia aging therapy developed by our partner FHIR. The new data covered the third dose cohort of 2E13Gc per kilo in two patients in the Phase 1-2 study. 201 led to factored expression levels of 72% and 12.9% of normal at weeks 28 and 26, of note, there were no spontaneous bleeds after reaching peak expression, including discontinuation of prophylaxis. One of the patients experienced a traumatic bleed but without the need for Factor VIII replacement therapy.

Due to cope with 19, we've not yet dose patients the prophylactic steroid cohort, but we're aiming to have data by the end of 2020.

We tend to hold it into phase two meeting with you at the end plan in terms of 83 in the first top 2021.

In addition to these areas GCT updates data was presented at the recent I.S.T.H. waiting on the hemophilia aging therapy in developed by our partner buyer.

The new data covered third dose cohort of 213, GC C low and two patients in the phase one two study.

Dietrich to a one led factory expression levels of 72% and 12.9% of normal at week 28 and 26.

Of note there were no spontaneous bleeds after reaching peak expression, including discontinuation of property taxes.

One of the experience patients experienced the dramatically, but without the need for factory replacement therapy.

An update of the first for patients treated the lower dose cohort showed stable factor it expression after up to 60 month a follow up.

Emil D. Kakkis: An update on the first four patients treated at the lower-dose cohort showed stable Factor VIII expression after up to 16 months of follow-up. This provides further validation of Bayer's hemophilia program, including at relatively low doses, as well as the Ultragenyx HeLa production system. The Safety Advocacy is competitive with other HEMA programs with good safety so far. To close out the prepared remarks, as you can see, we have made substantial progress so far in 2020 and expect the same through the second half of the year. I'm proud that the company has been able to make all of this progress in the midst of the ongoing COVID-19 pandemic. The team has adapted and found creative ways to continue working with and supporting patients, their families, and their healthcare providers, with four approved programs, a strong balance sheet, one of the most experienced rare disease development organizations and an exceptional commercial team globally.

Provides further validation of buyers hemophilia program, including a relatively low doses as well so trajenta you up production system.

The safety efficacy is competitive with other he may programs with good safety so far.

To close out the prepared remarks as you can see we made substantial progress a barn 2020 and expect the same through the second half of the year.

I'm proud of the company has been able to make all this progress limits to the ongoing covered by 19 pandemic teams adapt inbound creative ways to continue working with the sporting patients their families and their health care providers.

With for crude program strong balance sheet and one of the most experienced rare disease volatile organization and the exceptional commercial team globally.

Objects is poised for substantial progress and our development goals as a next generation rare disease company.

Emil D. Kakkis: Ultragenyx is poised for substantial progress in our development and commercial goals as a next-generation rare disease company. While we have accomplished a great deal in our first decade, we will continue to pursue smart, efficient, effective development, setting the bar for effective rare disease development and commercialization using the exceptional team and company we've built to bring even more therapies to patients. And we will do so with great urgency and dynamic development. Commercialization is required to overcome inevitable challenges, especially in the first-ever treatments for rare diseases. Thank you for joining us today, and let's move on to your questions.

While we have accomplished a great deal. Our first decade, we will continue to pursue smart efficient effective all and setting the bar for effective rare disease development and commercialization using exceptional team and company, we've built to bring even more therapies to patients.

We will do so with greater in seems inevitable <unk> the commercialization as required to overcome the inevitable challenges, especially in the first ever treatments for rare diseases.

Thank you for joining us today, and we'll move onto your question.

[noise] [noise], ladies and gentlemen, we will now begin the question answer session. Thank you asked a question you will need to press star one in your Tulsa.

Operator: Ladies and gentlemen, we will now begin the question and answer session. And to ask a question, you will need to press star 1 on your telephone. If your question has been answered and you wish to remove yourself from the queue, you can press the contact button. Please limit yourself to one question and one follow-up.

If your question has been answered on you wish to remove yourself from the key Tempress Dick on key.

I'm pleased that limit to one question and one follow up.

Operator: Please stand by while we compile the Q&A roster. Our first question is from Tazeen Ahmad of Bank of America. Your line is open. Hi, good afternoon. Thanks so much for taking my questions. Um, Emil, just a little bit of color on Chris Vito for the quarter. I think that KRK has provided some commentary that, Transcripts provided by Transcription Outsourcing, LLC.

Hi, My will be compiled the kinnear off [noise].

Our first question is from dizzying almond.

Bank of America. Your line is open.

Hi, good afternoon, so much for taking my questions I'm, just I'm a little bit of color encore developed for the quarter I think I can't recall will provide some commentary that.

Well done a lot of some sort of back.

On location lives in light of those I'll have a little corruptions Perkins locations give us a little bit of color on on pretty funky can on the level of impacts part with schools, who clue on them as it relates to Hello, how are you talking more about the initial ramp or how should we be thinking about expectations as it would still be.

He Mcdonald's recall that environment.

Hi, good so on Kristina in the U.S.

Emil D. Kakkis: Very good. So on Clifida in the U.S.

I think we've been managing it very well we did you talk a little book, a proactive effort and I'll, let her Erica finished at that moment, a little bit about the impact.

Emil D. Kakkis: I think we've been managing it very well. We talked a little about the proactive effort, and I'll let Eric finish with that in a moment, a little bit about the impact. We are probably not seeing the same impact they're seeing, but our territories are different. And so I think that has to be a factor in thinking through. T.O.

We are probably not seen same impact their thing, but our characters are different and so as it could have to be a factor in the coming through.

T O is a relatively small indication was slow will fully diagnose we expect it's going to take time gold slowly as we continue that patient Eric maybe you can add a little bit on the crispy to impact in our management.

Erik Harris: is a relatively small indication that's slowly diagnosed. We expect it's going to take time and build slowly as we continue to add patients. Erik, maybe you can add a little bit on the CRISPR-Vita impact and our management of it in the second quarter.

Second quarter.

Yes, so the.

Erik Harris: Yeah, so. The majority of CRIFIDA patients in the U.S. are receiving care at home, and we've been able to ensure the continuity of that care by working closely with the patients and the providers, where there was concern with having a home health nurse. Enter due to the COVID. Concerns. We were able to arrange for self-administration, and that's been the exception in that continuity of care has continued, and where there were concerns about sites of care where patients had to go into the clinic. We've been able to arrange for at-home administration and work with the payer as well as the provider. With regard to the impact on new patient starts, there has been a ramp-up has dampened a little bit as it takes longer to identify, diagnose, and initiate treatment as healthcare providers are, you know, seeing lower volumes of patients and certainly even less in their clinics. So the way I would think of this is it's not, It's not a demand issue; it's really more of a capacity issue, which is why we're confident Thanks, Eric.

The majority of the Chris feeder patients in the U.S. are receiving care at home.

And we've been able to ensure the continuity of care by working closely with the patients in the providers.

Where there was concern if with having a home health nurse.

Enter due to the cobot.

Concern.

Concerns.

We were able to arrange for self administration and that's been the exception.

And there were also continuity of care has continued.

And where there were concerns about.

Sites of care, where patients had to go into the clinic, we've been able to arrange for at home administration in working with the Payara as well as a provider.

With regards to the impact on new patient starts.

There has been a ramp has dampened a little bit as it takes longer to identify diagnose and initiate treatment.

As healthcare providers are seeing lower volumes of patients is certainly even less in their clinics. So what I would think of this is Matt.

It's not a demand issue, it's really more of a capacity issue, which is why we're confident as the country because they open up that there will have a rebound.

Thanks, Eric.

Next question.

Operator: Next question.

The next question is from.

Operator: The next question is from Gena Wang, Barclays, Yolani Loving. Thank you.

General you want a Barclays. Your line is open.

Thank you for taking my question question, one team sequence origination a very strong quarters. Despite the coping cheap so I'm I've two questions. The first one is the Guardian.

Operator: Thank you for taking my questions. First, I want to say congratulations on a very strong quarter despite COVID-19. So I have two questions. The first one is regarding Joby. I'm not sure if I missed it. Did you mention star swarms?

Jody I'm not sure if I missed it did you mention I'll stop swaps and if so you know what these across all different genetic backlogs and the second question has only gotten the onto my Angel.

Operator: And if so, you know, was this across all different genetic backgrounds? And the second question is regarding Andrewman syndrome. How has the safety been so far from the first two cohorts? And how would you decide on the third dose?

Uh Huh safety, so far from the first two coupons and how would you decide the third dose.

Oh, Okay, let's start with I'll start with the interim partly middle it Eric talk about the to drill the launch question.

Emil D. Kakkis: I'll start with the engineering part and then I'll let Eric talk about the Dujulby launch question. First of all, Angelman, the program is managed by Genetics, and we're encouraged by the results so far, but we're not disclosing information yet on the conduct of the study. We'd want to maintain the study integrity and not discuss both.

First of all usually in the program is managed by genetic and we're encouraged are the result, both so far but we're not disclosing information yet on the concrete study we'd want to maintain the.

The.

The studies integrity not discussing both.

Erik Harris: You know, Epstein Safety, since it is open label, but it's really up to genetics to manage it, but as I said, we're encouraged with the results so far and we expect to resume dosing shortly. Eric, I think the question on Dojoba related to stocking, is that what you said?

We have seen safety.

So there is open label, but it's really up to genetics.

Managing it but as I said for crews results both growth so far and we expect to resume dosing shortly.

Eric I think I think the question when Theres overlay to stockings that which said that Gina.

Erik Harris: A big start for them.

Thanks to our for.

<unk> sarcoma didn't start here. So we didnt provide any specifics with regards to star phones as we did with our other products will.

Erik Harris: The Air Force

Erik Harris: We didn't provide any specifics with regard to Starforms as we did with our other products, but we will begin to provide specific launch metrics, most likely in the next quarter, and it will probably be similar to what we did for CRISPR-Vita. But with regard to performance in the early days, we're very pleased with the interest that we received from health care providers and patients. Shortly after approval, we started receiving Star forms from multiple centers and prescribers, and that number continues to grow. And it includes a mix of patients that were in our clinical trials and receiving clinical drugs for compassionate use, as well as naive patients that, you know, that are new to...

Begin.

Provide launch specific launch metrics most likely in the next quarter.

And it will probably be similar to what we did well with Vito.

But with regards to the performance in the early days were very pleased with interest that we receive from healthcare providers and patients.

Shortly after approval, we started receiving star forms for multiple centers and prescribers and then number continues to grow and includes a mix of patients that were in our clinical trials and receiving clinical drug for compassionate use as well as naive patients that.

There are new to the joking.

So it was 91 doesn't matter a lot quicker.

Erik Harris: Regarding the genetic background,

Just background of the patients.

Erik Harris: Jet background of the patient being created.

Being treated.

Yes, well I don't vote, we would it be refinanced or the stuff ones.

Erik Harris: I don't think we would have provided that normally.

Emil D. Kakkis: [inaudible] I don't think we would normally provide that breakdown, but obviously, you know, VLCAT is by far the most common, and CPV2 and LCHAT are two others. Those three are, incumbent on most of the patients, and You know, the TFP and CACT are much less common. So it'll be those three, the majority of them, but I don't know that we'll be breaking up Starform by type. And I don't think there would be that much enlightenment there based on the clinical trial data, which I think showed an effect across all patient types.

I don't think we would normally provide that breakdowns, but obviously you know deal CAD is by far the most common is easy to an l. chat or two others those really come.

We can put most of the patients then.

Yeah. The teeth PMTCT are much less common so it'll be those three the majority of them, but I don't know that will be breaking out star form by tight, but I don't think there would be that much and lighting that they're based on the clinical trial data, which.

I think showed effect across all patient type.

Yes.

Okay. Thank you very much.

Erik Harris: Okay, thank you very much.

Our next questions from yarn werber.

Operator: Our next question is from Yaron Werber of Collin, Illinois.

Calling your line is I think.

Erode.

Yes can you hear me okay.

Operator: Yes, can you hear me okay?

Operator: Now I can, yes.

Now I can yeah, okay excellent. So I've a question on the also on Gtx, one no true and so the study a sikhism coming to enroll 20 patients in five cohorts. So is it is that magic mass and it's sort of four patients per cohort and then secondly, I think you you mentioned that some patients got multiple dose.

Operator: Okay, excellent. So I have a question also on GPX 102.

It is in effect or you're supposed to get those to sort of.

A four doses the so every 28 days and so I.

Just wanted to confirm that you you can dose them sequentially that way each patient can get a those doses and its sequential that everybody has to go through one dose look at safety and then go to the mix dose.

Thanks, so much yes, good so the dosing even more magical than what you propose it's actually.

Emil D. Kakkis: And so the study, I think, is intended to enroll 20 patients in five cohorts. So is it magic math, and it's sort of four patients per cohort? And then secondly, I think you mentioned that some patients got multiple doses, and I think they're supposed to get those to sort of four doses or so every 28 days. And so I just want to confirm that you can dose them sequentially, that way, each patient can get those doses. And it's sequential that everybody has to go through one dose, look at safety, and then go to the next dose. Thanks so much.

Two in the first cohort two in the second core and it goes before.

And then a larger amount last cohorts for it so the first cohort started at much lower dose.

And tight traded each dose.

But we're reaching therapeutic doses by the time they've got to the third report those we would expect.

And just starting dose for each tow trading cohort would start a little higher each time.

So that's the basic design and that.

But even the first two course would be expected to get to therapeutic dosing range at least from our expectation projecting from animal.

So the two cohorts have been receiving multiple doses and that's what we've said.

And there were always managing safety, okay, because its dose cohort I mean, each dose stepping up until the continuously monitoring and then there are DMC reviews that occur all filtering process. So that's basically the structure.

Up to two cohorts of two patients each have received multiple doses so far.

We're only so we're encouraged but we haven't said anymore and we're trying to protect the integrity of the study.

Got it so when you say two cohorts are fully enrolled is it fully enrolled sort of four patients. Each of them are really there were two patients. It. So for thank you to peach in the two eight patients in cohort one and two in core too.

Emil D. Kakkis: Yes, good. So the dosing is even more magical than what you propose. It's actually two in the first cohort, two in the second cohort, then it goes to four, and then a larger amount in the last cohort, right? So the first cohort started at a much lower dose and titrated at each dose. Up, but we're reaching therapeutic doses by the time they got to their third or fourth dose, we would expect, and just the starting dose for each toe tracing cohort would start a little higher each time. So that's the basic design of it.

Emil D. Kakkis: But even the first two cohorts would be expected to get to therapeutic doses, at least from our expectations observing from animals. So the two cohorts have been receiving multiple doses, and that's what we've said. And there we're always managing safety and efficacy because it's a dose cohort. It means each dose is stepping up, and so they're continuously monitoring. And then there are DMT reviews that occur also during the process. So that's basically the structure. Two cohorts of two patients each have received multiple doses so far. We're only saying that we're encouraged, but we haven't said any more, and we're trying to protect the integrity of the study.

Go ahead, Camille am I incorrect.

Okay.

Yes, that's correct you're correct okay.

Right and and they'll continue to enroll each cohort to up to four patients thereafter, yes, the next cohorts get bigger.

Three years or I got here during the course get bigger.

The idea is they wanted to have the cohorts that were further early safety very low doses were smaller because they weren't starting at a very little doubt, but once you know the low doses. Fine then you can start Kirk the next cohort started a little bit higher level instead is very low.

I think the great thing is that the clinical trial has proceeded particularly the one center despite kobin.

Kudos go to the Doctor.

Fighting for patient care acute we're seeing going.

Okay.

Next question.

The next question is from more of a cost of Jefferies. Your line is open.

Hi, Thanks for taking my question. This is something along for Maury.

Operator: Got it. So when you say the two cohorts are fully enrolled, is it fully enrolled sort of four patients each, or there are really, there were two patients each so far? Thank you.

Emil D. Kakkis: Two patients in Cohort 1 and two in Cohort 2. Do I have... Camille, am I incorrect?

Camille L. Bedrosian: UK.

So can you provide a going into the Jovi launch under Hubert of more perspective in terms of dynamics related to editor courses pediatric ratio reimbursement and then looking migrates will you be providing going forward and then I was wondering.

Sure. So I'll touch on the adult versus P.'s Lin Eric Chris you can talk about the dynamics going forward.

Camille L. Bedrosian: Yeah, that's correct.

I think one of things you have to understand about the dosing of drill Joby is that it's based on a percentage calories and what that means that.

So by the time, you get the like seven or eight years old you reach kind of the peak level and you're the cost per patient from late school age two adult is actually the same.

So I'm, making that point to that they actually the number of adults or the number 10 year old doesn't really matter the actual.

Revenue per patient is almost the same does it clear it's not like other drugs that are weight based it's a little bit different.

It so it's a much flatter top curve on revenue for the patient if that's what your question that we expect to see adult impedes involved and there's just different patterns of of disease that you see in adult and pediatric patients and.

Patients have different manifestations of peace later have different types of problems adult so, but we expect to see adult impedes.

I would say overall, probably there's more kids with it mainly because.

Maybe the kids are dying so naturally the number of patients are younger or whether it be more than.

Because of the loss of patient overtime.

Any other than another the Rootmetrics book I think you asked about the metrics going forward.

Eric maybe can touch on what we will do for metrics in digital thing for the coming quarters.

Most likely that coming quarter, we plan to provide some on for Matt metrics to help characterize the strength and momentum as the launch.

We haven't determined exactly what those metrics will be.

But from Kristina, we provided number prescribers patient star forms and patients on reimburse pier therapy. So I would think we would do something similar to that.

And I think you did you ever question with regards to the payer landscape. So what you were asking.

As anything no I think I think this is no I think this is good I just had a follow up questions. So this is regarding clinical trials website. So just great recently.

Camille L. Bedrosian: Right, and they'll continue to enroll each cohort to up to four patients.

That does expansion for the number of patients for food away from nine to 18.

So for feel when that it looks like the amendment of protocol in steadily to use so can you provide some towards.

The changes to the protocol.

Well in you're talking about Dts real one is that correct and TTX or one.

Camille L. Bedrosian: Yes, the next cohorts get bigger. 3 and 4, the cards get bigger. The idea is that they wanted to have the...

Camille L. Bedrosian: Very low doses. We're smaller because they were starting at a very low dose.

Camille L. Bedrosian: I think the great thing is that the clinical trial has progressed, particularly at one center, despite COVID. Kudos go to the doctor for fighting for patients there and keeping the thing going.

Yes.

Yes, so strategic three one we have said we're going to treat three more patients in a prophylactic steroids or to that would.

Operator: Next question.

We're already been nine treated we'd have three more.

Core GFT, one we would we may do another cohort with.

Earlier Steri treatment.

But it's not a.

Those patients would not be limiting toward our progression to phase three.

That would be the other three patients.

Okay, Okay got it got it thanks.

Our next question is from Chris Frank.

Operator: The next question is from Maury Raycroft of Jeffrey's. Your line is open.

Chris Raymond of Piper Sandler Your line is open.

Hi, This is the alley Brasil on for Chris. Thanks for taking my question. So one on and on did you actually I want him for a lot I know you've been talking about building and the phase two meetings with D.A. and the second half tend to discuss a day after those programs for a while now.

So just wondering how are those meetings officially on a calendar got or is that something that that could be pushed back due to cold better or maybe other gating factors any color on the the status of those discussions and just your confidence on the authority to start phase three on the expected timeline first half 21.

Be helpful. Thanks.

Yeah, we normally don't talk about when meetings are scheduled with just not something you normally disclose but we don't anticipate having a problem having meetings.

For end of phase two between now and the second half asleep disclose them getting started.

In 2021, so at this point to see a problem I think the FDA.

Maybe not because of covert just because of how many gene therapy probes are definitely burden lot of applications. The question that is putting a strain on them, but but at this point, we don't see a problem with getting into phase two done.

But we will.

Certainly provide updates when we've had meetings and decision's been made and work plan is but.

When we've had this meetings and we know what's going forward basis.

Okay. Thank you.

Ladies and gentlemen, just sort of money. Please limit your questions one and one follow up your next question from Cory Kasimov JP Morgan Your line is open.

Operator: Hi, thanks for taking my question. This is Swapnil on for Maury.

Emil D. Kakkis: Can you provide, going into the Dojovi launch, a little bit more perspective in terms of dynamics related to adult versus periodic ratio reimbursement? And then what metrics will you be providing going forward? And then I have a follow-up.

Hi, this is going on for Corey I wish I had a quick one on the Wilsons program.

Wondering well getting softer demand for the I.M.D. submission later.

Later this year.

Sure the.

Erik Harris: Sure. So I'll touch on DALT versus PIS, and then, Erik, perhaps you can talk about the dynamics going forward.

Emil D. Kakkis: I think one of the things you have to understand about the dosing of Diljovi is that it's based on a percentage of calories. And what that means is that by the time you get to like seven or eight years old, you reach kind of the peak level, and the cost per patient from late school age to adult is actually the same. So, I'm making that point to you that the actual number of adults or the number of 10-year-olds doesn't really matter; the actual... revenue per patient is almost the same. Is that clear? It's not like other drugs that are wheat-based.

We have already run that I've noted this before the GMP production line that we need to get through the tipping fleets that product.

Emil D. Kakkis: It's a little bit different. So it's a much flatter top curve on revenue for the patient, if that's what your question is. We expect to see adult MPeds involved, and there's just different patterns of disease that you see in adults.,,,,,,,,,,, I would say overall, probably there are more kids with it, mainly because many of the kids are dying. So naturally, the number of patients that are younger is going to be more because of the loss of patients over time. Any other dynamics or metrics? I think you asked about the metrics going forward.

Erik Harris: Eric, maybe you can touch on what we will do for metrics in Djolby for the coming quarter.

Erik Harris: We haven't determined exactly what those metrics will be. But for Chris Vita, we provided a number of prescribers, patient start forms, and patients on reimbursed therapy. So I would think we would do something similar to that. And I think you, did you have a question with regard to? Repair landscape? Is that what you were asking? Was there anything else? No, I think, I think this is it.

We have been running some lin on clinical work so for the lab doing OCO work have meant.

Good question that the most manufacturing local growth had some impact of coded, particularly workers the ticket SV Kipp home, but so far we look what those key activities are looking ahead.

We're also.

Have been discussing the program with the agency in coming up with our our plan is for developing it. So so far we looked like we're moving along well, but there's clearly some impact going on in in the vendors, but we right now we don't see and.

An obvious impact yeah, let something became clearer than we would let people know.

Next question.

Your next question is from Laura Chico of Wedbush. Your line is open.

Hey, good afternoon, guys. Thanks for taking my question I Wonder if we could go back to the Christina revenue guidance and I apologize if I missed it but wondering if we how should we be thinking about the impact of any Latin America, South American countries for Christina and kind of what assumptions are embedded in the guidance at this.

Point and maybe just longer term does does this silverman of I will region free to pursue orphaned treatments any color there. Thanks.

Well I'll answer the first part for but I I mean, the last part first we strongly believe in Latin America region for rare disease treatment and weeks that that there will be always political and economic challenges at time, there, but we think that theres a lot of patients in a way.

Willingness to support treatment in Latin America.

We will continue to pursue treatment. So we feel as part of our own ethic as a company to treat people where they need to be treated.

And we think that by direct who will be reasonable.

In the past, we haven't broken out country by country and I don't know as.

Obviously majority of what's happening is in the North America territory, but it did note some improvement in Latin America.

Eric I don't know if you want everything about Latin America, we haven't really disclose those specific numbers yet.

And just to reinforce that we take us a significant ER has significant potential and we see increasing demand across multiple countries.

In the region.

And you can see that our revenue is steadily growing so we're picking up momentum.

As we work through the named patient sales.

Process, which which take some time.

As we continue positive discussions with health authorities for formal reimbursement across multiple countries.

Good Thanks, Eric.

Thanks.

Your next question is from Eagle Mitchell move it from Citi. Your line is open.

Hi, Bill Harley.

Emil D. Kakkis: I think this is good. I just had a follow-up question. So this is regarding a clinical trials website. So we just recently saw that there is an expansion for the number of patients for 401 from 9 to 18. And also, for 301, there is a slight amendment of the protocol regarding steroid use. Can you provide some thoughts on the changes to the protocol?

Hi, This is Charlie I think all thanks for taking our clash here just on ATX oral one in three outline on finalizing endpoints for that for the planned phase threes will clearly be a key topic on the upcoming into phase two meetings that we just wanted to get your thoughts on what you would view is kind of the best case scenario in terms.

Yes, Hey street endpoint heading into that meeting.

Great well, yeah. So I guess you that's one of the reasons, we like these two disease areas frankly, because they are biochemical genetic disorders. Therefore, the biochemical endpoint RFS measuring the disease.

Emil D. Kakkis: Well, in that case, you're talking about DTX 301. Is that correct? And DTX 401? Yeah.

Emil D. Kakkis: Yes, so for DTX 301, we have said we're going to treat three more patients in a prophylaxis steroid cohort. So that would, there have already been nine treated, and we'd have three more. For GST-1, we may do another cohort with earlier steroid treatment, but it's not a those patients would not be limiting toward our progression to phase three. That would be the other three patients.

Operator: Okay, I got it, I got it, thanks.

Otcs a disease of urea Genesis ammonia is obviously the thing that the cumulative built habit well described in literature. So we'd expect them only be part of it and we will look to try to supplement the biochemical primary endpoints with secondary endpoints would give some measure of clinical efficacy, but we do.

Expect to have a biomarker primary endpoint ammonia in some form.

Now for for TST one a.

Good coasts is just a well accepted by our mark of met the implications of its level or well accepted well known and cornstarch. In this case, it's being used as a treatment is essentially oral glucose replacement therapy. So if you don't give course first glucose go because low.

And what we're seeing very clearly here is that the amount of corn search required is highly dependent on how much the gene therapies, releasing glucose itself sort of obviating the need for the oral glucose replaced but so we think that anything that matches glucose.

Removal of the treatment only corn search reduction or monitoring glucose in some form time, the hopeless senior or.

Maintenance of glucose is in the normal control region. For example, you can get to cope with marketing would all be wins for us because all those are easily determine biomarker based employees I think those are the ones that would be well powered and trial. We will of course look at cognizant other types of outcome.

But we'd look at those the secondary tertiary outcome.

And we would not expect them to be part of the partner.

Okay. Great. That's helpful. Thank you and then just a quick follow up could you talk a little bit more specifically about TTM and how that can be utilized that that potential primary or secondary endpoint wireline.

Operator: Our next question is from Chris. Chris Raymond of Piper Sandler, Yalini. Hi, this is Allie Braptalon for Chris.

Sure well.

The challenge with glucose monitoring this is very good for diabetes, but until the dot com fix.

It wasn't they weren't the best for GFT, one specifically because of a particular challenge with measuring lactate Black kids very high and Lucas.

And GFT, one and so that okay that interfere that would create problems that the dexcom six now I'll give you very accurate glucose even in the presence of lactate. Therefore, that's why the step forward and GST. One is that you do pro.

When you have continuous monitoring it allows you to walk her in real world setting what patients are doing at home.

And what we're learning from that what we've shown to patients that are further down more than 24 weeks is it you can watch them all through the night many nights in a row right with that and see that they're glucose as they're not going low that theyre managing without starch Tonight, the middle the night.

And then.

So you can oh.

So I'll have to capture so much more data on the into real world environment that it's far I think more powerful.

Then in hospital assessment trying blood for patients to the very artificial setting.

So I think it gives us a massive data it gives us highs and lows that manage that in a repeat this national allow us to both demonstrate the improved efficacy and safety and better controls Lucas spoke high or low as important measures of glucose control so well.

We think it is powerful part of the story.

And something that will really help but.

Demonstrate improved efficacy of using gene therapy versus.

Elkhorn carriage.

Great. That's helpful. Thanks, almost equal.

Okay.

The next question is from Jeff from Morgan Stanley. Your line is open.

Operator: Thanks for taking the question. So one on on DTX 301 and 401. I know you've been talking about holding end of phase two meetings with FDA in the second half to discuss data for those programs for a while now. So just wondering, are those meetings officially on the calendar yet? Or is that something that could be pushed back due to COVID? Or maybe other gating factors? Any color on the status of those discussions and just your confidence in the ability to start phase three on the expected timeline, first half of 21, would be helpful. Thanks.

Thanks for taking the questions offer convenient g. I owe you indicated there are 502000 American can you remind us how many patients in the U.S. have already been identified and what kinds of efforts you're planning to identify additional patients and then I've a follow up.

Yeah, we haven't really put out for any of our programs identified patient numbers. So we're not disclosing that we are.

Emil D. Kakkis: Yeah, we normally don't talk about when meetings are scheduled; it's just not something I do. Maybe not because of COVID, just because of how many gene therapy programs are definitely burdened.

We're continuing to get up by patients, but tio patients are definitely can be more challenging the fine because they're often because there are a nuance that problem and that could take several or many years effective diagnosed.

We need to work on helping people diagnosis quicker, but we're not going to be disclosing patient numbers at this point, we haven't for other programs either.

Okay Paul's question.

Yeah, and inferred for Toby you mentioned that there were some naive patients with the start forms.

Any comment on how the proportion of start forms from naive patients compared to your expectations.

Well I don't think that that proportion. So early launch is gonna be all that lightning obviously, the doctors that are trials are.

The watching and waiting a ready to go so I think you'll take a little time to kind of set out how much naive and how much start corn, but I don't think it's going be that lightning, but what.

Because already said is that there were many now you patients and clinical trial patients already described and I think most impressive the authority was a newborn.

Diagnose newborn.

Treated allocate which I think is.

An important part of the future of the product is actually having newborns diagnosed get put on it early in life instead of waiting for later when they have a crisis and then switching so we think thats an important part of the story about naive, but right now it could be pretty early to talk in detail about ratios make any conclusion.

Thank you.

Sure.

The next question is from salaries being richer of Goldman Sachs. Your line is.

Thanks for taking your questions Andrew on for something you now and maybe a fresh swine and if you could you speak on how you're focusing your efforts and allocating resources for your gene therapy program versus the other technologies under development catches your eye.

Operator: Transcripts provided by Transcription Outsourcing, LLC. But we'll certainly provide updates when we've had meetings and decisions have been made on what the plan is. But when we've had those meetings, and we know what's going forward with Datestream.

I think well.

The gene therapy program involved.

Essentially multiple programs three program can there be in the clinic.

But the fourth burden, which is buyers plus early stage. So the gene therapy franchise and the team or burn is clearly a substantial part of R&D investment in these added a number of people and built out the platform there and so is there really substantial investment there.

Our air so deal with genetics that is the one area. So we're working on its using standard is so technology contract manufactured and so it's a relatively focused choice and in that situation.

Range them in there so strategy eliminating the regulatory Arnie, we think is the best strategy for treating Andrew on and that's why we opted to go in that direction, because our goal to complete the folks on the right drug for the right because these.

And not get hung up on.

Our our mechanism we happen to have inside the house. So right now gene therapy took big investment area is though is the very targeted investment.

Okay.

Got it and then maybe just another strategy question. We recently saw that agreement Mike Daiichi is this something that we should expect that you might pursue more collaboration like that in the future.

Yes, we expect to do another such collaboration in the future.

We think that the he'll tell platform current version and the new version, which was which was presented at the half GCT.

Our vendor substantially improved the.

Productivity and cost of goods for gene therapy programs and scale and we think that that's going to be an increasingly important point of focus.

More important than trace a capsids and other things.

So we do think that the dates you deal will be something that we expect to do other deals on.

They maybe not quite the same but I think people will want to have access to large scale a million 80 production system and the he'll have platform. We think is the best one out there.

Great. Thanks, so much.

I know last question is from Vincent Chen of Bernstein. Your line is open.

Operator: Okay, thank you. Ladies and gentlemen, just a reminder, please limit your question to one and one follow-up. Your next question is from Corey Casimov of J.P. Morgan. Your line is open.

Operator: All right, this is Gavin on for Corey.

Operator: We just had a quick one on Wilson's program, wondering what gating factors remain for the IND submission later.

Thank you very much for taking the question or just one quick question on the Gtx to a one data analyzed G.H. I recognize it's still early days, but the longer term data from the earlier cohorts shows very sustained factory expression out to nearly a year and a half in one patient without any any seeming lost expression and I guess, if it holds up well this would potentially look a little different.

Emil D. Kakkis: Later this year. Sure, the... We have already run, and I've noted this before, the GMP production line, and we need to get through the testing release of that product. We have been running some of the non-clinical work. So far, the labs doing non-clinical work have, There's no question that most manufacturing in the world has had some impact of COVID, particularly if workers get sick and have to be kept home. But so far, we look like those key activities are moving ahead. We've also been discussing the program with the agency and coming up with our plan for developing it. So, so far, we look like we're moving along well, but there's clearly some impact going on in the vendors, but we right now don't see any obvious impact. Yeah, and if something became clear, we would let people know.

Operator: The next question is from Laura Chico of Wetbush. Your line is open.

Operator: Hey, good afternoon guys. Thanks for taking the time to answer the question. I wonder if we could go back to the CRISVITA revenue guidance, and I apologize if I missed it, but I'm wondering how we should be thinking about the impact of any Latin America and South American countries for CRISVITA and kind of what assumptions are embedded in the guidance at this point, and maybe just longer term. Does this still remain a viable region for you to pursue orphan treatments, any color there? Thanks.

Emil D. Kakkis: Well, I'll answer the first part first. But I mean, the last part first. We strongly believe in the Latin American region for rare disease treatments. And, you know, we expect that there will always be political and economic challenges at times there. But we think that there are a lot of patients and a willingness to support treatment in Latin America. And we will, we will continue to pursue treatments. And we feel it's part of our own ethic as a company to treat people where they need to be treated.

Erik Harris: And we think that Latin America will be reasonable. In the past, we haven't broken out country by country, and I don't know if obviously, the majority of what's happening is in North America, but we did note some improvement in Latin America. Erik, I don't know if you want to add anything about Latin America. We haven't really disclosed those specific numbers yet.

Erik Harris: And just to reinforce that we think there is significant potential and we see increasing demand across multiple countries in the region, and you can see that our revenue is steadily growing, so we're picking up momentum as we work through the name patient sales process, which takes some time, as we continue positive discussions with health authorities for formal reimbursement across multiple countries.

Erik Harris: Pretty good. Thanks, Erik.

From what we're seeing with others hemophilia agent therapies I'm curious how confident are you that factor it expression will indeed be sustained overtime, especially as you look to some more patients and higher doses and higher levels and I guess, what gives you confidence and the second cover laid in one quickly would just be.

Would you be hypothesis as to what might drive what looks to be kind of late spike in factual levels. After a week 24 in the six patient those treated.

Sure well talk about the stable question issue I think one of things important factor Ace it's not fully appreciate that.

Operator: Thanks.

Operator: The next question is from Yigal Nochomovitz from City. Your line is open.

Dr. Eight as a protein is very hard to synthesize.

In manufacturing factory companies, they make milligrams per liter type of quantities because itself just can't make it it's a very hard to fold protein.

It's important that is when you're doing in vivo gene therapy, you are really doing battery replacement therapy with cells expressing their manufacturing side the body.

The key thing there they understand as if you make a sell expressed too much individually you'll end up putting he trucks are asking myself. They may not lets say last long term. So optimal factory therapy, our mine would be achieved by having a larger number of self producing a small amount of factory in the you would end up with a more stable.

Producing sell rather than an over express sell that can't actually continue doing that.

With the Aviate, it's you 30.

EG 37 capsid.

We believe we get a more prevalent wider array of river another cells expressing.

A factory and by having more expression across many itself, we think that that could potentially give you a more stable type of phenotype.

We didnt do the hottest expressing promoters and things because in fact I think that is what create more stress that I think the team and good choices and finding a good expression clone, but assuring that we're getting good distribution.

The patients six I don't have enough detail to tell you I know the patient had received from steroids and that may have been part of.

Stabilizing some expression and caused me to increase but I think if you look at all the patients the pattern as kind of different you see build a slow build a factor it over time and most of the patients right. It doesn't go spike in down it's it's slow build I.

I think that could bode well for gene therapy that actually would last more years now remember 88 was used in the original Packer nine program.

That was published in those patients have stable stable factor nine for 10 here.

So we think that the prevalence of distributor self produced factor eight are going to an important feature and getting stable long term expression.

I think so far the date are encouraging, but let's face it it's very early and many other programs as much more data and so we're going to wait and see how it comes out but we're encouraged that perhaps.

Our program with buyer will turn out to be an excellent factory gene therapy.

When might we expect to see updated data for that.

Well, we're not in control the development of that it's really under buyers control. So I'd have to really tougher to them on how its going.

I think there obviously very factory experience they haven't ask years around the world I think they're very encouraged and excited about the data, they're saying so I'd expect them to be doing the updates and we're at this point in the motor following along and supporting them, where we need to.

Great. Thank you very much.

Operator: Thank you.

Operator: Hi, this is Carly from Yigal. Thanks for taking our questions. Just on DTX 401 and 301, finalizing the endpoints for the planned Phase 3s will clearly be a key topic of the upcoming end of phase 2 meetings. So we just wanted to get your thoughts on what you would view as kind of the best case scenario in terms of the Phase 3 endpoints heading into those meetings for each program.

This concludes our question answer session, although a lot to turn the call over about 2% eager for closing or farther from it.

Emil D. Kakkis: Well, yes, no, I get you. One of the reasons we like these two disease areas, frankly, is because they are biochemical genetic disorders. Therefore, the biochemical endpoints are

Emil D. Kakkis: ..

Emil D. Kakkis: Measuring the Disease. OTC is a disease of ureagenesis. Ammonia is obviously the thing that accumulates if you don't have it. It's well described in literature.

Emil D. Kakkis: So we'd expect ammonia to be part of it, and we will look to try to supplement the biochemical primary endpoints with secondary endpoints that would give some measure of clinical efficacy. But we'd expect to have a biomarker primary endpoint of ammonia in some form. Now, for GST-1A... Glucose is just a well-accepted biomarker from FDA. Its implications at its level are well-accepted and well-known.

Emil D. Kakkis: And cornstarch, in this case, is being used as a treatment, is essentially oral glucose replacement therapy. So if you don't give cornstarch, your glucose levels go low. And what we're seeing very clearly here is that the amount of cornstarch required is highly dependent on how much the gene therapy is releasing glucose on its own, sort of obviating the need for oral glucose replacement. So we think that anything that manages glucose, removal of the treatment like cornstarch reduction or monitoring glucose in some form, time to have glycemia or... Maintenance of glucose within the normal control region, for example, using continuous glucose monitoring, would all be wins for us because all of those are easily determined biomarker-based endpoints, and I think those would be ones that would be well-powered in the trial. We will, of course, look at cognitive and other types of outcomes, but we would look at those as secondary and tertiary outcomes, and we would not expect them to be part of the primary.

Emil D. Kakkis: Okay, great. That's helpful. Thank you. And then, just a quick follow-up. Could you talk a little bit more specifically about CGM and how that could be utilized as a potential primary or secondary endpoint for 401?

Emil D. Kakkis: Sure. The challenge with glucose monitoring is it's very good for diabetes, but until the Dexcom 6, they weren't the best for GST one specifically because of a particular challenge with measuring lactate. Lactate is very high in glucose and GSD-1A. And so if that interferes, it would create problems. The Dexcom 6 now gives you very accurate glucose levels even in the presence of lactate. And therefore, that's why it's a step forward in GSD-1A is that new probe. When you have continuous monitoring, it allows you to monitor in real world settings what patients are doing at home. And what we're learning from that, and what we've shown in patients that are further down, more than 24, is that you can watch them all through the night, many nights in a row, with that, and see that their glucoses are not going low, that they're managing without starch in the middle of the night. Very interesting.

Emil D. Kakkis: So it allows us to capture so much more data in the real world environment that it's far, I think, more powerful than an in-hospital assessment, drawing blood from a patient into a very artificial setting. So I think it gives us massive data. It gives us highs and lows. It manages us in a repeated fashion that will allow us to both demonstrate the improved efficacy and safety and better control of glucose, both high and low, as important measures of glucose control. So we think it is a powerful part of the story and something that will really help us demonstrate the improved efficacy of using gene therapy versus oral corn syrup.

Emil D. Kakkis: Great, that's helpful. Thanks for all the detail. The next question is from Jeff Hung of Morgan Stanley. Your line is open.

Operator: Thanks for taking the questions. For CRUZVIDA and TIO, you indicated there are 500 to 1,000 Americans. Can you remind us how many patients in the U.S. have already been identified and what kinds of efforts you're planning to identify additional patients? And then I have a follow-up.

Emil D. Kakkis: Yeah, we haven't really put out for any of our programs identified patient numbers, so we're not disclosing that we're We're continuing to get up by patients, but TIO patients are definitely... can be more challenging to find because they're often, because they're a new onset problem and they can take several, many years in fact, to diagnose. We need to work on helping people diagnose it quicker, but we're not gonna be disclosing patient numbers at this point. We haven't tried it for other programs either.

Operator: Do we have follow-up questions? Yeah, and then for Toby, you mentioned that there are some naive patients with star forms. Can you comment on the proportion of star forms from naive patients?

Operator: are forms from naive patients compared to your expectations.

Thank you. This concludes today's call or additional questions. Please contact us by phone or an IR at Ultragenyx dot com. Thanks for joining.

Ladies and gentlemen, this does conclude today's teleconference. You may now disconnect.

Thank you for your participation.

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Operator: Well, I don't think that that proportion so early in the launch is going to be all that lightning. Obviously, the doctors in our trials are [inaudible] Diagnosed newborn. Tazeen Ahmad, Yigal Nochomovitz, Christopher Raymond, Gena Wang, Anupam Rama, Kristen Kluska, Maury Raycroft, Joseph Schwartz, Emil Kakkis, Yaron Werber, Jeff Hung, Camille Bedrosian, Laura Chico, Jack Allen, Aaron Wolfenstein

Operator: Thank you.

Operator: The next question is from Salveen Richter of Goldman Sachs. Thanks for taking our questions. This is Andrew.

Operator: Transcription by Transcription Outsourcing, LLC.

Emil D. Kakkis: I see, well... The gene therapy program involves, essentially, multiple programs, three programs can be in the clinic, plus the fourth part, which is FIRES, plus early stage. So the gene therapy franchise and the team it will burn are clearly a substantial part of our R&D investment. And we've added a number of people and built out the platform there. And so it's a really substantial investment there.

Emil D. Kakkis: Our ASO deals with genetics, so that is the one we're working on. It uses standard ASO technology, and it's contract manufactured. And so it's a relatively focused choice. And in that situation, for Angelman, the ASO strategy, eliminating the regulatory RNA, we think is the best strategy for treating Angelman. And that's why we opted to go in that direction, because our goal as a company is to focus on the right drug for the right disease and not get hung up on it. Our mechanism, we happen to have inside the house. So right now, gene therapy is a big investment area. ASO is a very targeted investment.

Emil D. Kakkis: And then maybe just another strategy question. We recently saw that agreement with Daiichi. Is this something that we should expect you to pursue more collaborations like this in the future?

Emil D. Kakkis: Yes, we expect to do another such collaboration in the future. We think that the HeLaCell platform, the current version and the new version which was presented at ASGCT, is going to substantially improve the productivity and cost of goods for gene therapy programs and scale, and we think that that's going to be an increasingly important point of focus, more important than the choice of catheters and other things. So we do think that the Daiichi deal will be something that we expect to do other deals on. They may not be quite the same, but I think people will want to have access to a large-scale mammalian AV production system and the HeLa platform, which we think is the best one out there. Great, thanks so much.

Operator: And the last question is from Vincent Chen of Bernstein. Your line is open.

Operator: Thank you very much for taking the question. Just one quick question on the DTX-201 data at ISTH. I recognize it's still early days, but the longer-term data from the earlier cohorts shows very sustained factory expression for up to nearly a year and a half in one patient without any

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Operator: Unknown Attendee, Huidong Wang, Dae Ha, Joori Park, Howard Horns, Ultragenyx Pharmaceutical Inc. Unknown Attendee, Huidong Wang, Dae Ha, Joori Park, Howard Horns, Ultragenyx Pharmaceutical Inc.

Emil D. Kakkis: Sure, we'll talk about the stable question issue. But I think one of the things that's important in Factor VIII that's not fully appreciated is that Factor VIII as a protein is very hard to synthesize. In manufacturing factory companies, they make milligrams per liter type of quantities because cells just can't make it. It's a very hard to fold protein.

Emil D. Kakkis: What's important then is when you're doing in vivo gene therapy, you're really doing factory replacement therapy with cells expressing it. They're manufacturing it inside the body. The key thing there to understand is if you make a cell express too much individually, you'll end up putting heat shock stress on the cells, and they may not necessarily last long term. Optimal factory therapy, in our minds, would be achieved by having a larger number of cells producing a smaller amount of factory and that you would end up with a more stable producing cell rather than an overexpressed cell that can't actually continue doing that. With And by having more expression across many cells, we think that that could potentially give you a more stable type of phenotype. But we didn't do the hottest expressing promoters and things because, in fact, I think that is what creates more stress.

Emil D. Kakkis: And I think the team made good choices in finding a good expression clone, but it's reassuring that we're getting good distribution. Patient 6, I don't have enough detail to tell you. I know the patient had received some steroids, and that may have been part of stabilizing some expression and causing it to increase. But I think if you look at all the patients, the pattern is kind of different. You see a slow build of Factor VIII over time in most of the patients, right? It doesn't go spike and down; it's a slow build.

Emil D. Kakkis: And I think that could bode well for a gene therapy that actually would last longer. Now, remember that 88 was used in the original Factor IX program that was published. And those patients have had stable Factor IX for 10 years. So we think that the problems of distributed cells that produce factor VIII are going to be an important feature in getting stable long-term expression, and I think so far the data are encouraging, but let's face it, it's very early, and many other programs have much more data, and so we're going to wait and see how it comes out, but we're encouraged that perhaps Our program with Bayer will turn out to be an excellent factory gene therapy.

Emil D. Kakkis: When might we expect to see updated data on that?

Emil D. Kakkis: Well, we're not in control of the development of that. It's really under the buyer's control.

Emil D. Kakkis: So I'd have to really defer to them on how it's going. I think they are obviously very factory experienced. They have investigators around the world. I think they are very encouraged and excited about the data they're seeing. So I'd expect them to be doing the updates. And we're at this point in the mode of following along and supporting them where we need to.

Operator: Great, thank you very much.

Joshua Higa: This concludes our question and answer session. I would now like to turn the call over back to Mr. Higa for closing or further comments.

Operator: Thank you. This concludes today's call. If there are additional questions, please contact us by phone or at ir at ultragenyx.com. Thank you for joining us.

Operator: Ladies and gentlemen, this does conclude today's teleconference. You may now disconnect. Thank you for your participation.

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