Q3 2020 Ultragenyx Pharmaceutical Inc Earnings Call

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Ladies and gentlemen, thank you for standing by and welcome to the Ultragenyx third quarter 2020 financial results and corporate update at this time all participants are in a listen only mode. After the speaker presentation. There will be a question and answer session to ask a question. During the session you will need to press star one on your telephone. Please me.

Operator: Ladies and gentlemen, thank you for standing by, and welcome to the Ultragenyx Third Quarter 2020 Financial Results and Corporate Update. At this time, all participants are in a listen-only mode.

Operator: 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. Please be advised that today's conference may be recorded. If you require any further assistance, please press star 0.

Advises that todays conference maybe recorded if you require any further assistance. Please press star zero I would now like to hand, the conference over to your host Josh what he got Sir. Please go ahead.

Good afternoon, and welcome to the Ultragenyx financial results and corporate conference call for the third quarter 2020, we.

Joshua Higa: Good afternoon, and welcome to the Ultragenyx financial results and corporate conference call for the third quarter of 2020. We have issued a press release detailing our financial results, which you can find on our website at ultragenyx.com. I'm Joshua Higa, Director of Investor Relations.

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

I'm, Josh when he got director of Investor Relations joining me on this call or email Cacace, Chief Executive Officer, and President Camille Bedrosian, Chief Medical Officer hair care, Chief Commercial officer, and Mardi Dier, Chief Financial Officer, who joined the company a couple of weeks ago.

Joshua Higa: Joining me on this call are Emil Kakkis, Chief Executive Officer and President, Camille Bedrosian, Chief Medical Officer, Erik Harris, Chief Commercial Officer, and Marty Deer, our Chief Financial Officer, who joined the company a couple of weeks ago. Shalini Sharp, Executive Vice President for Finance, is also on and will be available if needed for Q&A at the end of the scripted portion of this call. I would 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 that was filed on February 14, 2020, our quarterly report on Form 10-Q that we filed today, and our subsequent periodic reports filed with the SEC. These forward-looking statements represent our views only Please note that actual results could differ materially from those projected in any forward-looking statement. 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, please see our periodic reports filed with the SEC.

Any Sharpe executive Vice President for Finance is also on and will be available if needed for Q and a at the end, but the scripted portion of this call.

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

In 2020.

Our quarterly report on form 10-Q that we filed today and our subsequent periodic reports filed with the FCC.

Which will all be available on our website in the 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 that the actual results could differ materially from those projected in any forward looking statement.

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. Please see our periodic reports filed with the SEC I'll now turn the call over to him.

Emil D. Kakkis: I'll now turn the call over to Mike. Good afternoon, and thank you everyone for joining us on today's call. It's been a busy week, quarter, and year for Ultragenyx. This match is a fundamental part of my philosophy for the company, which is a relentless focus on execution.

Good afternoon, and thank you everyone for joining us on todays call.

It's been a busy week quarter end year for Ultragenyx.

Mismatch of the fundamental part of my philosophy for the company, which is a relentless focus on execution.

I'm proud of how productive the company has been throughout the year across all facets of our diverse business.

Emil D. Kakkis: I'm proud of how productive the company has been throughout the year across all facets of our diverse business. Regular team and development teams have gotten two new approvals in two weeks in June. The commercial team and all the people supporting the products have rapidly and successfully launched those products to patients in need while still growing ChrisFeed in exhalation, improving our annual guidance despite the global impact of COVID. The clinical team, internally and jointly working with our partner, Genetics, has delivered a series of positive updates on our gene therapy programs, and now the Angel Womb Program, and the business development team brought in a new gene therapy program for Duchenne Announced with Daiichi Sankyo in March.

Regular team and development teams have got two new approvals in two weeks in June.

Commercial team and all the people supporting the products have rapidly and successfully launched those products to patients in need while still growing crow's feet in exelate and improving our annual guidance. Despite the global impact of coated.

The clinical team internally and jointly working with our partner genetics has delivered a series of positive updates on our gene therapy programs and now the engine program.

That had been development team brought into new gene therapy program for Duchenne on top of the gene therapy technology partnership.

Announced with Daiichi Sankyo in March Weve been firing on all cylinders and we'll provide updates on all this progress on the call today.

Emil D. Kakkis: We've been firing on all cylinders, and we'll provide updates on all of this progress on the call today. Starting with our commercial programs, which provide a stable source of growth that underpins the rest of our development, CRISFIDA continues to perform strongly and is now bolstered by the additional tumor-reduced osteomalacia indication. In the first quarter of launch, they're always off to a strong start in its first quarter, which is encouraging.

Starting with our commercial programs, which provide a stable source of growth underpins the rest of our development. The city graffiti continues to perform strongly enough now bolstered by the additional tumor induced osteomalacia indication.

In the first quarter launch.

As always off to a strong start in its first quarter, which is encouraging.

We would see start from sort of large number for subscribers for patients that are trials, but also those naive to Dolby speaks to the unmet need for those living with a healthy at the end of the strong relationships that we have with physicians and the major treatment centers.

Emil D. Kakkis: We've received starter forms from a large number of prescribers for patients in our trials but also those nave to Bill Shulby. Speaks to the unmet need for those living with L-C-F-A-O-D and to the strong relationships that we have with physicians and major treatment centers. Moving on to our strategic collaboration with Solid Biosciences. Last week, we announced that we'd be developing a new gene therapy for the treatment of Duchenne muscular dystrophy, or DMD. While there are other Duchenne programs that are far more advanced, this was a unique opportunity to combine SOLIDS technology with our technology and two like-minded companies to create a next-generation gene therapy for this disease. We will combine SOLID's best-in-class microstrophin, with its potential ability to enhance blood flow to working muscles, with our novel cathid, which has an excellent immune profile and is produced by a high-quality 2,000 liter HeLa cell line manufacturing process. We believe this could be a differentiated therapy for Duchenne that we will seek to achieve global accessibility. We look forward to collaborating with you all to bring a new treatment forward rapidly, and we'll continue to update you on the progress coming out of the collaboration in the coming quarters. Moving to Angelman.

Moving to our strategic collaboration with solid bio Sciences.

Last week, we announced that we've been developing a new gene therapy for the treatment of Duchenne muscular dystrophy or DMD.

Well there are other duchenne programs that are far more advance this wasn't a unique opportunity to combine solid technology with our technology and to like minded companies to create a next generation gene therapy for this disease.

We will combine solid best in class microstructure with its potential ability to enhance blood flow to working muscles, where.

With our novel Capsid, which has an excellent immune profile as produced by our high quality 2000 liter Hewlett sell.

Producers selling manufacturing process.

We believe this could be a differentiated therapy for duchenne that we will seek to achieve global accessibility.

We look forward to clarify the cells are bringing new treatment for rapidly will continue to update you on the progress coming other collaboration in the coming quarters.

Moving to Angel and yesterday, we announced positive interim data from the ongoing phase one two study of the investigational product.

Emil D. Kakkis: Yesterday, we announced positive interim data from the ongoing Phase 1-2 study of the investigational product, GX102, and Angeman Syndrome, which is a part of a collaboration with Genetics Biotherapeutics. GTX-102 is the first antisense alginuclide program for Angelman to reach the clinic, and it is based on the extraordinary science from Dr. Scott Dindo, supported by Genetics. In our update, all five patients in the first patient's treason study have shown substantial improvements in the clinical global impression scale, or CGI, tailored for some of the key domains of Angeman with a mean change score of 2.4. The positive clinical effects are supported by other endpoints and remarkable reports of changes provided by the caregivers of patients treated with GTX-102. These include two patients going from being nonverbal their entire lives, with difficulty communicating, to now using multiple words, while others are beginning to use signs, gestures, and augmentative communication devices for the first time.

If one or two in Asia than syndrome, which is.

Part of the collaboration with genetics Biotherapeutics.

Gtx, one or two of the first and just since all unit type program for management to reach the clinic.

And is based on the extraordinary signs from Dr., Scott didn't do supported by genetics.

In our update all five patients.

Of the first patient treated the study have shown substantial improvement from the clinical global impression scale or seizure tailored for some of the key domains of agent with a mean change score of 2.4.

The positive clinical Texas supported by other endpoints and remarkable reports of changes provide by the characters of patients treated with Gtx, one or two.

These include two patients going from being nonverbal their entire lives with because of the difficulty communicating to now using multiple words well others are beginning you signed the gesture augmented of communication devices for the first time.

Some patients adopt independent capabilities, such as using a fork to feed themselves for the first time.

Emil D. Kakkis: Some patients acquire an independent capability, such as using a fork to feed themselves for the first time. Others are learning to swim on their own. And other reports include the ability to follow commands, focus on tasks, respond by name, and sleep through the night. Not only were these changes profound, but they began rapidly, often after just a few weeks to a few months of treatment, and in some patients after the lowest dose. In part, due to these reportedly unprecedented changes, all families have indicated a desire to continue in the study. Turning to safety, all five patients at the highest doses had a serious adverse event or SAE of lower extremity weakness with an elevation of protein in the CSF, which has now completely resolved. We believe the SE is related to local inflammation in the region of the intrathecal administration of GTX-102. This lower extremity weakness was not observed at the lower doses in the study, where we also saw a clinically meaningful response.

Others are learning to swim on their own.

And the other reports include the ability to follow Cummins spokesman tasks respond by name and sleep through the night.

Not only were these chains profound but they begin rapidly often after just a few weeks to a few months of treatment and in some patients after the lowest dose.

In part is due to these reportedly unprecedented changes all families of Didnt indicate a desire to continue in the study.

Turning to safety all five patients at the highest doses had a serious adverse event or if you have lower extremity weakness.

An elevation of protein in the CSF and now which have now completely resolved.

We believe this is related to local inflammation in the region of the Intrathecal administration of Gtx, one or two.

This lower extremity weakness was not observed at the lower doses in the study where we also saw a clinically meaningful responses.

We believe the impact of Gtx two is manageable with changes in dose administration strategy.

Emil D. Kakkis: We believe the impact of GTX-2 is manageable with changes in dose and administration strategy, and so we expect to resume enrollment and dosing once we get an amendment filed and agree with the FDA. We are very excited about what we're seeing, as are the patients' families who heard about these results for the first time yesterday. We plan to provide additional data on these patients at the FAST Summit in December and additional safety and efficacy data on the program in 2021. Looking at these two recent developments, both Shen and Angeman, are very significant to these both in terms of unmet need and prevalence. They're aligned with our company's strategy of developing therapies for rare diseases where there is the greatest need and will leverage our various modalities and platforms to create the best treatment options for patients.

And so we expect to resume enrollment and dosing once we get an amendment filed an agreed to with the FDA.

We are very excited about what we're seeing is are the patient families. We're hearing about these results for the first time yesterday.

We plan to provide additional data on these patients at the fast summit in December and additional safety efficacy data on the program and 2021.

Looking at these two recent developments both to Shen enhancement are very significant disease, both in terms of unmet need and prevalence.

They are aligned with our company strategy of developing therapies for rare disease, where there is a great greatest need and will leverage our various modalities and platforms to create the best treatment options for patients.

Now before I turn call over to Marty I'd like to stop start first by thinking Shalini sharp for joining us on one last conference call all the way from New Zealand.

Emil D. Kakkis: Now, before I turn the call over to Marty, I'd like to... Start first by thanking Shalini Sharpe for joining us on one last conference call all the way from New Zealand. Charlie Sharp has been with me from the early days of the company and has been a greatly valued friend, colleague, and superb CFO. She has been instrumental in building RARE to where it is today, and we could not be here without her contributions throughout that time, the ups and downs, and all the financing, and all the work with many of you on the phone call. We certainly wish her the best going forward, but I just want her to know that her legacy and contribution to the company will remain with us at Rare forever. And with that, I hand the call over to Sean.

John Sharp has been with me from the early days of the company.

And has been greatly valued friend colleague in a superb CFO.

She has been instrumental in building rare to where it is today and we could not be here without her contributions throughout that time, the ups and downs and all the financings and all the work with many of you on the phone call.

We certainly wish him the best going forward, but I just want her to know the her legacy and contribution to the company will remain with us at rare forever.

And with that I hand, the call over to show any.

Well. Thank you so much ammo and good afternoon to everybody.

Shalini Sharp: Well, thank you so much, Emil, and good afternoon to everybody. I am delighted to join you all for our last quarterly conference call. I'd like to take this opportunity to thank Emil, the executive team, the finance team, the IT team, and the rest of the Ultragenyx team for the extraordinary experience that I have had working here. I could not be more proud of this company, its mission to serve patients above all, and its ability to effectively execute on this mission every day. I'd also like to thank you all, our analysts and our investors, for your support of Ultragenyx over these past years. And with that, I'm very pleased to introduce you to our new CFO, Marty Deer. You will be in excellent hands with Marty, and I'll now turn the call over to her to walk you through the financials for the quarter.

I am delighted to join you off for our last quarterly conference call I'd like to take this opportunity to thank him on the executive team the finance team by team and the rest of the Ultragenyx team for the extraordinary experience that I have had working here.

I could not be more proud of this company its mission to serve patients above all and.

And its ability to effectively execute on this mission every day.

I'd also like to thank you all our analysts and our investors for your support of Ultragenyx over these past cares.

And with that I'm very pleased to introduce you to our new CFO Marty there will be an excellent hands with Marty and I'll now turn the call over tougher to walk you through the financials for the quarter were well.

Well, thank you Shalini and I am very excited to be joining orogenic. During its next stage of growth in helping patients with rare diseases.

Maurice Thomas Raycroft: Well, thank you, Shalini, and I am very excited to be joining Ultragenyx during its next phase of growth in helping patients with rare diseases. Shalini has been a critical part of building a fantastic team that I know already will make this a very smooth transition. So, thank you, Sean. So today we issued a press release that included a financial update, which I will briefly summarize. Total company revenue for the first nine months of 2020 totaled $179.5 million, representing 163% growth over the same period in 2019. This includes revenue from CRISPIDA in ultragenic territories of $98.5 million, a 91% growth over 2019, and combined revenue from Metsevi and Djovi totaling $18.3 million, or a 78% increase compared to 2019. Total revenue for the three-month ending September 30, 2020, was $81.5 million.

Shalini has been a critical part of building a fantastic team one that I know already will make this a very made a transition. Thank you shalini.

Today, we issued a press release that included a financial update which I will briefly summarize.

Total company revenue for the first nine months of 2020 totaled 179.5 million, representing a 163% growth over the same period. In 2019. This includes revenue from Christina and Ultragenyx territories at $98.5 million and 91% growth over 2018.

And combined revenue from savvy, and agility totaling $18.3 million or 78% increase compared to 2019.

Total revenue for the three months ending September Thirtyth 2020 was 81.5 million for the quarter ended September Thirtyth 2020, Kristina revenue any allergenic territory with 37.3 million. This included 34.1 million in collaboration revenue and the North America profit share territory and the net.

Maurice Thomas Raycroft: For the quarter-ended September 30, 2020, CRISPI's revenue in the ultragenic territory was $37.3 million. This included $34.1 million in collaboration revenue in the North America profit share territory and net product sales in other regions of $3.3 million. Total royalty revenue related to the sales of CRISPRIDA in the European territory was $3.3 million.

Net product sales in other regions at 3.3 million homes.

Total royalty revenue related to the sale of Christina in the European territory with $3.3 million.

Net Debbie product revenue for the third quarter of 2020 with 4.1 million.

We expect these revenues may modestly increase over time that we did not expect it to be significant ground.

And the initial quarter after receiving you at the FDA approval worldwide revenue from that Jody what $3.9 million.

Maurice Thomas Raycroft: Nesteve product revenue for the third quarter of 2020 was $4.1 million. We expect these revenues may modestly increase over time, but we do not expect there to be significant. In the initial quarter after receiving U.S. FDA approval, worldwide revenue from DeJolvi was $3.99. This includes named patient sales and U.S. products. We also recognize $32.9 million of revenue related to the collaboration and license agreement with Daiichi Sankyo that was executed in March 2020. The majority of revenue from this agreement will be recognized as work is performed on the technology transfer. It will be recognized based on progress towards completion, not straight lines, and we expect the majority of this work to be completed by the end of 2021. Our total operating expenses were $131.8 million for the third quarter of 2020, which includes research and development expenses of $87.3 million and SG&A expenses of $42.1 million.

This included named patient sales and you asked products down.

We also recognized 32.9 million of revenue related to the collaboration and license agreement with Daiichi Sankyo. There was actually executed in March 2020 the.

The majority of revenue from this agreement will be recognize at work is performed on the technology transfer to Daiichi It will be recognized based on progress towards completion not straight line and we expect the majority of this work to be completed by the end of 2021.

Our total operating expenses were $131.8 million for the third quarter 2020, which includes research and development expenses of 87.3 million and SGN expense at $42.1 million.

We expect our R&D cost to continue increasing over time as we advance additional product candidates from preclinical development into early and pivotal clinical study we.

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 to Toby for F LP Epay or D. and proceed expert CIO.

Expect that split of R&D versus SGN accent to remain fairly consistent.

In the third quarter of 2020, we reported a net loss of 68 million $68.8 million or $1.13 per share basic and diluted.

Maurice Thomas Raycroft: 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 trials. We also expect SG&A to modestly increase over the coming quarters as we support the expanse of our existing commercial programs and the launch of Djolby for LCFAOD and Crispida for TIO. We expect the split of R&D versus SG&A expense to remain fairly consistent. In the third quarter of 2020, we reported a net loss of $68.8 million, or $1.13 per share of basic endowments. This compares to a net loss of $113 million, or $1.96 per share, basic and diluted, for the third quarter of 2019.

This compares to a net loss of $113 million or $1.90, 6%, our basic and diluted for the third quarter of 2018.

The net loss for the third quarter of 2020 includes 11.5 million unrealized loss from the fair value adjustment on the investment in the Arcturus equity.

Also include 8.6 million and noncash interest expense on the liability related to the sale of future royalties.

For the first nine months of 2020 net cash used in operations were $69.8 million compared to 273.3 million for the same period in 2019.

We ended the third quarter 2020, with $765.5 million in cash cash equivalent and available for sale investments.

Maurice Thomas Raycroft: The net loss for the third quarter of 2020 includes an $11.5 million unrealized loss from the Fair Value Adjustment on the investment in the Arcturus equity. This also includes $8.6 million in non-cash interest expense on the liability related to the sale of future royalties. For the first nine months of 2020, net cash used in operations was $69.8 million, compared to $273.3 million for the same period in 2019. We ended the third quarter of 2020 with $765.5 million in cash, cash equivalents, and available for sale investments. I would now like to turn the call over to Eric, who will provide an update on our commercial performance for the quarter and an update on our guidance range for CRISPR-Eta. Thank you, Marty. In the third quarter, Clifida continued to deliver meaningful revenue growth. The company also launched Adobe for patients with long-chain fatty acid oxidation disorders. Chris Vita for Tumor-Induced Osteomalazia.

I would now like to turn the call to Eric who will provide an update on our commercial performance for the quarter and an update on our guidance range for Christina.

Thank you Marty in the third quarter, Chris for you to continue to deliver meaningful revenue growth.

The team also launched Adobe for patients with long chain fatty acid oxidation disorders, and Chris feeder for tumor induced osteomalacia.

Our third product MEP savvy continues to provide a meaningful therapy to patients with MPS seven and ultra rare disease.

I would like to begin by providing an update on budget that the Gobi launch, which is going very well. The joby was approved in June by the U.S. FDIC and was launched on July 22nd for the treatment of all forms of LC FHLB or commit that clearly confirmed diagnosis across the 2500 to three.

Thousand pediatric and adult patients in the U.S.

As of the end of the third quarter. We have received approximately 120 start forms from approximately 60 unique prescribers.

All 80 of the clinical trial and compassionate use patients have been converted to commercial therapy with many successfully navigating reimbursement.

Erik Harris: Our third product, Mevsevi, continues to provide meaningful therapy for patients with MPS-7 and Ultra-Rarities. I would like to begin by providing an update on the Jovi launch, which is going very well.

And approximately 30% of all star wars or for patients who are naive to prior as Yogi bear.

The team has made significant progress on the reimbursement front in the first few months after being approved.

Erik Harris: Jovi was approved in June by the U.S. FDA and was launched on July 22nd for the Treatment of All Forms of LC-FALD, with a molecularly confirmed diagnosis across the 2,005, 3,000 pediatric and adult patients in the U.S. As of the end of the third quarter, we have received approximately 120 starter forms from approximately 60 unique prescribers. All 80 of the Clinical Trial and Compassionate Youth patients have been converted to commercial therapy, with many successfully navigating reimbursement. And approximately 30% of all star forms are for patients who are naive to prior visual therapy. The team has made significant progress on reimbursement in the first few months after being approved, which has led to more than 60 patients on reimbursed commercial therapy. The payer mix is approximately 70% commercial and 30% government. Some pairs have formal policy in place, but most are approving VJOBI on an exception basis during their new-to-market coverage guidelines.

There's less or more than 60 patients on reimbursed commercial therapy.

The payer mix is approximately 70% commercial and 30% government.

Compares with formal policies in place, but most are proving to zero on an exception basis during a new to market coverage guidelines.

We continue to work closely with commercial and government payers to ensure that the joby is accessible to all LCR failed the patients as indicated by the broad FDA label.

Joe we as a pharmacy benefit and it is important.

Person or process does take time as various payers establish their coverage policies.

Looking forward, we will continue leveraging our established commercial infrastructure, along with a fewer than 10 incremental hires we added to support the Dolby launch.

Over time, we expect revenue from digital will be in the U.S. to gradually build as the launch gain even more traction.

Outside of the United States Dolby has been submitted for approval with Anvisa in Brazil and has been submitted to health, Canada after being granted priority review.

The discussions with the regulators are ongoing.

Erik Harris: We continue to work closely with commercial and government payers to ensure that Dajobe is accessible to all LC-FLD patients as indicated by the broad FDA label. Jovi has a pharmacy benefit, and it is important.

And with the U.S. approval patients in other European and Latin American countries are now able to access to jolie through named patient programs. These.

These programs have been meaningful.

There have been a meaningful way for patients in France, and Italy to gain access to this important therapy I would like to reiterate our commitment to broad access very.

Erik Harris: The reimbursement process does take time as various payers establish their coverage policies. Looking forward, we will continue leveraging our established commercial infrastructure, along with the fewer than 10 incremental hires we added to support the DOB line. Over time, we expect revenue from Djovi and the U.S. to gradually build as the launch gains even more traction. Outside of the United States, the Joby has been submitted for approval with a visa in Brazil and has been submitted to Health Canada after being granted priority review. The discussions with EU regulators are ongoing.

These regulatory discussions and review phases request for named patient access will continue to be supported in all relevant countries. We continue to expect named patient sales to make up the bulk of the yodlee sales in Twentytwenty.

Moving next to Chris feeder, which was approved last quarter by the FDA for a second indication the treatment of FGF 23 related hyperphosphatemia in tumor induced osteomalacia or Ti Vo, yes.

We estimate there are to be between 501000 T O patients in the us with 50%, having unresectable tumors launch for this indication has gone well as we have been able to successfully leverage our existing infrastructure and relationships with physicians to ensure the small patient populations able to receive.

Erik Harris: And with U.S. approval, patients in other European and Latin American countries are now able to access Joby through named patient programs. These programs have been a meaningful way for patients in France and Italy to gain access to this important therapy. I would like to reiterate our commitment to broad access. During these regulatory discussions and review phases, requests for named patient access will continue to be supported in all relevant countries.

This important therapy.

Now turning more broadly to closely to proactively.

We have been able to maintain continuity of care for just about all patients on treatment.

Continue to adapt to the covert situation by shifting more resources to digital initiatives, along with virtual virtual personal promotions and limited in person meetings more recently.

Erik Harris: We continue to expect named patient sales to make up the bulk of Joby sales in 2020. Moving next to Crisvita, which was approved last quarter by the FDA for a second indication, treatment of SDF23-related hypophosphatemia in tumor-induced osteomalacia, or TIO.

We are also starting to see increasing success, finding more patients leading to growth in new start forms and reimburse patients.

In Latin America, a strong patient community and Kale support continuing to drive a lot of awareness and demand for Chris BITA and.

Brazil region's largest market we are seeing a steadily growing number of injunctions that are being granted and funded by both the state and federal governments.

Erik Harris: We estimate there to be between 500 and 1,000 TIO patients in the U.S., with 50% having unresectable tumors. The launch for this indication has gone well, as we have been able to successfully leverage our existing infrastructure and relationships with physicians to ensure this small patient population is able to receive this important therapy. Now, turning more broadly to Chris Wheeler for XLA.

Similarly in Colombia, and Argentina, the number of patients on reimbursed named patient treatment have increased.

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

[noise] recall at the beginning of the year pre Kogut, we established a range of 125 million to $140 million for Chris media revenues and Ultragenyx there towards.

Erik Harris: We have been able to maintain continuity of care for just about all patients on treatment. We continue to adapt to the COVID situation by shifting more resources to digital initiatives along with virtual personal promotion. Unlimited in-person meetings more recently. We are also starting to see increasing success with finding more patients. Leading to Growth in New Start Forms and Reimbursed Patients. In Latin America, a strong patient community and K.O. Support continues to drive a lot of awareness and demand for Crisvita. In Brazil, the region's largest market, we are seeing a steadily growing number of injunctions that are being granted and funded by both the state and federal government.

On our second quarter call. We maintain this range as we continue to evaluate the impact of the pandemic and our team's ability to execute.

Based on recent trends, we are raising the lower end of our guidance to 130 million, bringing the revised range to 130 million to 140 mode.

There is still some uncertainty related to co grid as we enter the winter season, and its long term impact on Chris three to revenue we are confident this.

Strategies and tactics, we have put in place will allow us to close out the year within this range.

As Pete we continue to believe Chris FIDA has the potential to be a blockbuster as it will be a significant rare disease treatment for patients with silage and T O around the world.

Erik Harris: Similarly, in Colombia and Argentina, the number of patients on reimbursed named patient treatment has increased. Over time, we expect Latin America to provide a more meaningful contribution. revenue as the launch of this region progresses. Recall that at the beginning of the year, pre-COVID, we established a range of $125 million to $140 million for CRISPR revenues in Ultragenyx territory. On our second quarter call, we maintained this range as we continue to evaluate the impact of the pandemic and our team's ability to execute. Based on recent trends, we are raising the lower end of our guidance to $130 million, bringing the revised range to $130 million to $140 million. While there is still some uncertainty related to COVID as we enter the winter season and its long-term impact on Chris Reeder's revenue, we are confident.

With that I'll turn the call over to Camille.

We'll provide an update from the gene therapy clinical programs.

Thank you Eric and good afternoon, everyone ammo provided the encouraging uptake on our Angelman syndrome program and I will review progress with our other clinical stage programs.

Starting with Dts fail, one our gene therapy program for the treatment of aren't Athene, transcribe emulates deficiency or Otcs Oh.

LTC is the most common of urea cycle disorders caused by the inability to detoxify ammonia into urea.

And patients with LTC can experience metabolic crises that could result in neurological complications hospitalizations and coma.

And also sometimes result in death.

Camille L. Bedrosian: [inaudible] At peak, we continue to believe Presvita has the potential to be a blockbuster, and it will be a significant rare disease treatment for patients with XLH and TIO around the world. With that, I'll turn the call over to Camille, who will provide an update on the Gene Therapy Clinical Program. Thank you, Erik, and good afternoon, everyone. Emil provided an encouraging update on our Angelman Syndrome program, and I will review progress with our other clinical stage programs. Starting with DTX301, our gene therapy program for the treatment of Ornithine Transcarbamylase Deficiency, or OTC. OTC is the most common of urea cycle disorders caused by an inability to detoxify ammonia into urea, and patients with OTC can experience metabolic crises that could result in neurological complications, hospitalizations, and coma. It also sometimes results in death.

Data from our ongoing phase one two study demonstrate durable and clinically meaningful responses to exzeo one.

Importantly, these improvements have continued after patients discontinued their previous alternative pathway medications and liberalized their diet.

For DTN X C. I won a fourth cohort of three patients at the one times 10 to the 13th genome copies per kilogram dose is ongoing using prophylactic steroids.

We expect data by the end of 2020.

We are also continuing facing planning and discussions with the FDA and plan to start the phase three study in 2021.

Moving to Dts floral one for glycogen storage disease type one day.

CSD Renee is a life threatening disease that requires patients to take cornstarch every three to four hours to avoid severe hypoglycemia long term complications and potentially death.

Results from the phase one two study so far so that detects far one is changing the lives of these patients who are showing improved glucose metabolism. This significant reduction in and less reliance on corn starch.

Camille L. Bedrosian: Data from our ongoing Phase 1-2 study demonstrate durable and clinically meaningful responses to DTX301. Importantly, these improvements have continued after patients discontinued their previous alternative pathway, medications, and liberalized their diet. For DTX-301, a fourth cohort of three patients at the 1 times 10 to the 13th genome copies per kilogram dose is ongoing using prophylactic steroids. We expect data by the end of 2020. We are also continuing Phase 3 planning and discussions with the FDA and plan to start the Phase 3 study in 2021. Moving to DTX-401 for glycogen storage disease type 1a. GSD1A is a life-threatening disease that requires patients to take corn starch every three to four hours to avoid severe hypoglycemia, long-term complications, and potentially death.

Prior to gene therapy. These levels of corn starch reduction would have put these patients at risk for DAF.

Safety has been acceptable today with any transaminase elevation managed by reactive steroids.

In addition to following the first three cohorts for longer term data.

Also our enrolling a fourth cohort of three patients using a prophylactic steroid regimen at the same six times.

10 to 12 feet I'm copies per kilogram dose level.

This decision is based on the value of preventing.

[noise] standardize use of steroids, rather than reactive monitoring and treatment present in the commercial setting.

The timing of this cohort will not impact the initiation of the phase three study.

We are moving forward with planning our phase three study for DTN X for one.

Following meetings with the FDA and Finalization of the study design, we plan to initiate the study in the first half of 2021.

Camille L. Bedrosian: Results from the Phase I-II study so far show that DTX-401 is changing the lives of these patients, who are showing improved glucose metabolism with a significant reduction in and less reliance on cornstarch. Prior to gene therapy, these levels of cornstarch reduction would have put these patients at risk for death. Safety has been acceptable to date with any transaminase elevations managed by reactive steroids. In addition to following the first three cohorts for longer-term data, we are also enrolling a fourth cohort of three patients using a prophylactic steroid regimen at the same six times, 10 to the 12th genome copies per kilogram dose level. This decision is based on the value of prevention. Standardized use of steroids rather than reactive monitoring and treatment presents in the commercial setting.

With these updates I will now turn the call back to April Thank you very much.

Thank you Camille.

Adding to Eric summary on our commercial programs have been very strong through 2020, and we are unique position with this robust commercial business that has three products simultaneously in the growth phase of launch.

On top of that we have a gene therapy platform has delivered positive clinical results in 2020 across three diseases, but also continues to be a source of new pipeline opportunities and new partnerships.

Next up we'll be Wilson disease gene therapy was alert was it which is a larger rare disease will be the first program internally to leverage the scalability of our HILA manufacturing platform that is vital for larger patient populations.

And behind that we have other large indications moving ahead. This includes the newly announced addition program which is a competitive space one that we believe.

We are uniquely able to bring forward.

And beyond the gene therapy space, we have the exciting engeman data from yesterday that supports that we have a potent molecule in that disease and we have a plan in place to work through the safety issues advances path forward for this large and severe disease.

Camille L. Bedrosian: The timing of this cohort will not impact the initiation of the Phase 3 study. We are moving forward with planning our Phase 3 study for DTX-401. Following meetings with the FDA and finalization of the study design, we plan to initiate the study in the first half of 2021. With these updates, I will now turn the call back to Emil. Thank you very much. Thank you, Camille.

Over the last couple of years has gone from a clinical stage biotech to a diversified commercial rare disease leader.

So there are number of large opportunities ahead of us we will continue executing across all facets of our business.

Emil D. Kakkis: Adding to Eric's summary of our commercial programs, we are in a unique position with this robust commercial business that has three products simultaneously in the growth phase of launch. On top of that, we have a gene therapy platform that delivered positive clinical results in 2020 across three diseases but also continues to be a source of new pipeline opportunities and new partnerships. Next up will be Wilson Disease Gene Therapy, which is a larger rare disease and will be the first program internally to leverage the scalability of our HeLa manufacturing platform that is vital for larger patient populations. Behind that, we have other large indications moving ahead. This includes the newly announced Duchenne program, which is a competitive space but one that we believe we are uniquely able to bring forward.

Well, they're dedicated employees across the globe and a strong balance sheet and growing revenue.

Let's move on to your questions. Operator, please provide instructions for the Q and a portion of the call.

Yes, Sir as a reminder to ask a question you will need to press star one on your telephone again, a star wanting your touchtone telephone to ask a question.

Withdraw your question press the pound key we ask that you. Please restrict yourself to one question and one follow up please stand by while we compile procure on a roster.

Our first question comes from the line of yarn Werber of Cowen Your line is open.

Hi, guys. This is brendan on for your own thanks, very much for taking the question and congrats again on the progress just a couple of quick ones from us.

I guess first first on DMD as you mentioned there are obviously a few players already in motion here I'm going to and I totally understand it very early in the process, but can you just give us maybe a little bit of a sense of how you kind of plan to be differentiated in your approach, maybe mechanistically or two it's really a matter of your caps diversity other ones out.

Emil D. Kakkis: And beyond the gene therapy space, we have the exciting engagement data from yesterday that supports that we have a potent molecule in that disease, and we have a plan in place to work through the safety issues to advance this product forward for this large and severe disease. Over the last couple of years, he's gone from a clinical stage biotech to a diversified commercial rare disease leader.

There.

And then just really quickly on the data from the gene therapy prophylactic steroid cohorts.

I know you mentioned, we could potentially get data from the LTC by year end I'm, just kind of wondering about timing for the GST when a patient thanks very much.

Emil D. Kakkis: With a number of large opportunities ahead of us, we will continue executing across all facets of our business, with our dedicated employees across the globe and a strong balance sheet and growing revenue. Now, let's move on to your questions. Operator, please provide the instructions for the Q&A portion of the call. Yes, sir. As a reminder, to ask a question, you will need to press star 1 on your telephone. Again, that's star 1 on your touch-tone telephone to ask a question. To withdraw your question, press the pound key.

Very good well when I look at the Duchenne program. There are several aspects of this differentiation one is the non binding micro dystrophin from solid the second is the the cap that we view, which has very an excellent mean profile and third is the ability to produce these avi in a moment.

In large scale system, which weve been used now for two programs very successfully and produce a high quality. The high quality. Many features which are achievable with the producers selling approach is more difficult to do with transfer.

Operator: We ask that you please restrict yourself to one question and one follow-up. Please stand by while we compile the Q&A roster. Our first question comes from the line of Yaron Werber of Cohen. Your line is open.

Transaction approach, we think with those three areas, we are differentiated and combine that with the skills. Both companies have in the space I think we have an opportunity to something special edition patients and to bring a program forward that can become successful.

Brendan Mychal Smith: Hi guys, this is Brendan on for your own. Thanks very much for taking the question. And congratulations again on the progress. Just a couple quick ones from us.

Globally, not just in the U.S.

Brendan Mychal Smith: I guess first, first on DMD. As you mentioned, there are obviously a few players already in motion here, and I totally understand it's very early in the process. But can you just give us maybe a little bit of a sense of how you kind of plan to be differentiated in your approach, maybe mechanistically, or if it's really a matter of your capsid versus the other ones out there? And then just really quickly on the data from the gene therapy and prophylactic steroid cohorts? I know you mentioned we could potentially get data from the OTC by year-end. I'm just kind of wondering about timing for GSD-1A patients. Thanks very much.

So that's a I think how I would answer that question.

The privilege story timing, we are dosing patients in both groups. We will have some data on them this year and but neither program does the steri core hard.

Interfere with initiation of phase three.

Gross profit was well planned to have the prophylactic steroids approach built into the program, but it is helpful to us before we start phase three to have done some patients and shown how it looks good.

So the phase three planning continues for both them pull back story did it will provide some data this year on those patients.

All right great. Thanks very much.

Thank you. Our next question comes from Chris Raymond of Piper Sandler Your question. Please.

Thanks.

Also on the DMD program, you know anymore. It there's a hypothesis surrounding gene therapy, and DMD were muscles are able to be transduce, maybe as efficiently as they would normally because of the damage caused by actual disease.

Emil D. Kakkis: Very good. Well, when I look at the Duchenne program, there are several aspects of differentiation. One is the NOS binding microdystrophin from SOLID. The second is the capsid we've used, which has an excellent immune profile. The third is the ability to produce these AAVs in a mammalian large-scale system, which we've been using now for two programs very successfully, and produce a high-quality AAV, high-quality many features, which are achievable with a producer-selling approach. It's more difficult to do with a transaction approach. We think with those three areas, we are differentiated. Combine that with...

I guess you I'm sure you've looked at this closely.

Is there a way to address that clinically or do you have any thoughts on that.

And then also maybe sort of a question just execution.

On the program and you have specifically can you remind us how long it takes to establish a hero producer cell line.

Thanks, Sean.

Sure.

So on Duchenne and really were filled with water and muscle diseases muscle even without injury by the way is very difficult to deliver particulates or large molecules in general they have.

Emil D. Kakkis: With the skills both companies have in the space, I think we have an opportunity to do something special for Duchenne patients and to bring a program forward that can become accessible globally, not just in the U.S. So that's, I think, how I would answer that question. On the prophylaxis steroid timing, we are dosing patients in both groups.

Very tight demonstrated capillaries a difficult just delivery of of of products is designed that way. So you don't create big small and muscles. When you exercise designed to control fluid flow.

So that creates challenges have been delivering we're highly aware of the issue and we have ways that we're approaching on how to improve it.

The issue being damaged or not I think that the there's certainly another part of the story, but.

Emil D. Kakkis: We will have some data on them this year, but neither program does the steroid cohort interfere with the initiation of phase three. Both programs will plan to have the prophylactic steroid approach built into the program, but it's just helpful to us before we start phase three to have done some patients and shown how it looks good. So the phase three planning continues for both, and Prozac steroid data will provide some data this year on those phases. All right, great, thanks very much.

We are looking at ways to help improve that.

Okay anymore, but at this point in time, but we are aware of the challenge and the challenging muscle in general.

With regard to produce and sell on using the automated approaches we have created at the company and processes that Weve test tablets generally we can identify a high quality stable clone within are usually about six months.

Of time that would be a clone that we that can.

Brendan Mychal Smith: Thank you. Our next question comes from Chris Raymond of Piper Sandler. Your question, please.

Revive growth to 2000 liters maintained stable incorporation and can produce high titers of eighties. After the process. So the modification allows us to actually screen, a large number of clones and help densify, a stable and low and the high producing phone the combination of those approaches us gives us the power them to create a I'm going.

Christopher Joseph Raymond: Also on the DMD program, you know, Emil, there's a hypothesis surrounding gene therapy and DMD where muscles aren't able to be transduced maybe as efficiently as they would normally because of the damage that's caused by actual disease. Yeah, I guess, um, yeah, you I'm sure you've, you've looked at this closely, you know, is there a way to address that clinically? Or do you have any thoughts on that? And then also, maybe sort of a question on just execution, on the program that you have specifically.

The faction platform as hyper reproducibility high quality.

And to do it in a way that.

And from a long term commercial standpoint, reproducible at the 2000 liter scale.

Thank you.

Thank you. Our next question comes from the line of Maury Raycroft of Jefferies. Your line is open.

Hi, Thanks for taking my questions.

Christopher Joseph Raymond: Can you remind us how long it takes to establish a HeLa producer cell line? Thanks. Sure. So on Duchenne, and really, we're familiar with a lot of different muscle diseases; muscle, even without injury, by the way, is very difficult to deliver particulates or large molecules in general. They have very tight fenestrated capillaries and difficult disc delivery of products. It's designed that way so you don't create big swollen muscles when you exercise.

Forward to Jovi, just wondering for the 30% naive patients. If you can talk more about those patients and their demographics, including age and can you comment if the naive patients represent a bolus or more of a natural uptake of getting patients on treatment.

Well.

We have really described in detail with the exact ages of the patients I think that they are across the spectrum and there have been newborns of course identified and put on drug as well.

Emil D. Kakkis: They're designed to control fluid flow, and that creates challenges by the delivery system. We're highly aware of the issue, and we have ways that we're approaching it on how to improve it. The issue of being damaged or not, I think that there's certainly another part of the story, but we are looking at ways to help improve that. And I won't say any more of it at this point in time, but we're aware of the challenge and the challenge in muscle in general. With regard to producer cell lines, using the automated approaches we have created at the company and processes that we've established, generally, we can identify a high-quality stable clone within or usually about six months. Time.

But in general, it's a spectrum of patients and.

You know obviously, it's early launch and I don't think we can say, if it's a bolus or steady yet because we're just talking about a quarter of work.

But we believe from the response, we're getting from best for them.

Physicians out there.

And the number of prescribers, which is now already 60 is clearly broad interest in the product and we'd expect this to continue continue.

Continue.

King start form generated exactly.

It's both but I think that we're going have to watch and wait how it moves forward.

Got it Okay and then.

Emil D. Kakkis: That would be a clone that we can use. The process allows us to screen a large number of clones and help identify a stable and high-producing clone. The combination of those approaches gives us the power to create a manufacturing platform that has high reproducibility, high quality, and to do it in a way that's, and from a long-term commercial standpoint, reproducible at the 2,000-liter scale. Okay, thank you. Thank you. Our next question comes from the line of Maury Raycroft of Jeffreys. Your line is open.

For Angel been I guess, besides the natural history data out there is there good existing efficacy data to contextualize, what you're seeing in April and then based on the time points in the age range and along these lines is it possible to reconcile or convert data on the C.G.I. I guess versus the more.

General C.G.I. scale.

Well certainly I can try to buy some help for you when you look at natural history data in instrumentation.

Generally gain some ground until I think around two or three years age and from there on the relatively flat and you don't really change much over time, the pretty flat so.

Maury Raycroft: Hi, thanks for taking my questions. For Joel Beatty, just wondering about the 30% naive patients, if you can talk more about those patients and their demographics, including age. And can you comment if the naive patients represent Ebola or more of a natural uptake of getting patients on treatment? Well, we haven't really described in detail the exact ages of the patients. I think they're across the spectrum.

The changes we are seeing are not something it seen people. These are non verbal and by the way all deletion patients are non verbal.

He never become verbal and so to have patients becoming wearable in the using words is highly unusual and regardless of what Fiji I or any other score you can make up the fact that patients are talking learning their names responding instructions and using other forms of communication or is something unique and different and value.

Bulk in of itself because communication problems are the number one family reported need.

Emil D. Kakkis: And there have been newborns, of course, identified and put on the drug as well. But in general, it's a spectrum of patients. And, you know, obviously, it's early in the launch.

That affects them in their life with the patient.

With regard to the C.G.I.E. The global score is involved looking at all the domains that just creating a summation of the physician view, but then each domain has particular areas that they look at in making the score free C.G.I., it's not really that different from any other C.G.I.. It's just it is based on particular problems of patients with age.

Emil D. Kakkis: And I don't think we can say if it's a bolus or steady yet because we're just talking about a quarter of work, but we believe from the response we're getting from positions out there. And the number of prescribers, which is now already 60, is clearly a broad interest in the product, and we'd expect this to. Continue, continue, continue, start form, generated exactly as I think it's bolus, but I think that we're going to have to watch and wait how it moves forward.

I don't have an inside each domain.

I would say to you in general people do not see changes in management on any score, including C.G.I. and there is some data on what the placebo effect might be and C.G.I., but I think the kind of magnitude were seeing which was a mean change score of 2.4.

Which means basically half would be much improved very much improved as a very strong for the past anything possible with natural history by far and for families with the disease absolutely unique.

Emil D. Kakkis: Got it. Okay. And then for Angelman, I guess, besides the natural history data out there, is there good existing efficacy data to contextualize what you're seeing in Angelman, based on the time points in the age range? And along these lines, is it possible to reconcile or convert data on the CGI IAS versus the more general CGI scale? Well, certainly, I can try to provide some help for you. When you look at the natural history data in Angelman patients, they generally gain some ground until, I think, around two or three years of age. And from there on, they're relatively flat, and they don't really change much over time. They're pretty flat,

And compelling so we're comfortable with the potency and we'll put out more data at the December fast meeting in on the details of information that support the CGM data.

Got it that's really helpful. Thanks for taking my questions.

Thank you. Our next question comes from Gena Wang of Barclays. Your question. Please.

Thank you for taking my questions first I wanted to see to Shalini.

Great working with you for the past five six years.

Best wishes to your next June.

Emil D. Kakkis: So... The changes we're seeing are not something that's seen before. People, patients are nonverbal. And by the way, all deletion patients are nonverbal. They never become verbal. And so to have patients becoming verbal and using words is highly unusual. And regardless of what CGI or any other story you could make up.

Yeah, I'm looking forward to working on so I have a two sets of questions. First one is that you will be so is it fair to assume majority of the patients right now on drug is two and a down from 7% to 80% our team.

And also how many oculus patients rollout.

Yeah named patient program and my second question is regarding the BMPG therapy.

Emil D. Kakkis: The fact that patients are talking, learning their names, responding to instructions, and using other forms of communication is unique and different and valuable in and of itself because communication problems are the number one family afforded need that affects them in their life as a patient. With regard to the CGI, the global score involves looking at all the domains and just creating a summation of the physician view, but then each domain has particular areas that they look at in making the score for each CGI. It's not really that different from any other CGI; it's just that it is based on particular problems that patients with Angelman have in each domain. I would say to you, in general, people do not see change in management on any score, including CGI.

You mentioned that you could file on due within one year, So what additional corporation Q.

Continued with additional color on all that crap, reaching the need to do for the R&D, including.

Picture this theme potency assay and also do you need you need.

Section.

Nothing to stop.

[noise] well think thinks you know that's quite a few questions I don't know if you want to say anything showing me.

Okay. So just thinking about Gina to you and your team and.

Really enjoyed working with you all as well.

Pretty good so with those shobi.

The thing to understand about dosing is that.

The patients you know in the first four or five years life have increasing amount of drug usage, but once you get to about 5678 years old them. It's a very flat curve and so patients from school age two adults are getting very similar amounts of drug which we estimate it is.

Emil D. Kakkis: And there is some data on what the placebo effect might be in CGI. But I think the kind of magnitude we're seeing, which was a mean change of 2.4, which means basically halfway between much improved and very much improved, is a very strong score that's past anything possible with natural history by far. And for families with the disease, absolutely unique and compelling. So we're comfortable with the potency, and we'll put out more data at the December FAST meeting and on the details of information that support the CGI data. I got it.

After adjusting for the gross to net and compliance around 103000, a year or so.

What might matters, how many very young patients we have a we have we're probably not going to be putting out that much delineation at this point in time I don't know if you want anything else Eric on this issue of patients under Shobi.

No no nothing out there today.

All right I think the other question you asked was how many patients were on named patient X.U.S.

Maury Raycroft: That's really helpful. Thanks for taking the time to answer my question. Thank you. The next question comes from Gena Wang of Barclays. Your question, please. Thank you for taking my questions. First, I wanted to say to Shalini, it has been great working with you for the past five, six years, and my best wishes for your next journey. And Marty, we are looking forward to working with you. So I have two sets of questions. The first one is a de juvie.

Yes on in the yeah. The French HQ program is a little less than 50 patients I think are on a on the affinity in France.

In Italy, it's a it's a handful of patients, but because of the approval in the U.S., we're able to respond to name patient requests in more countries now so we expect that to.

When she too.

Although not dramatically the U.S. revenue is certainly going to grow we think significantly as we move forward and the launch.

Gena Wang: So is it fair to assume the majority of the patients right now on the drug are teen and adult? Let's say 70 to 80% are teen and adult. And also how many ex-US patients are... write out the main patient access program. And my second question is regarding BMD gene therapy. Emil, you mentioned that you could file R&D within one year. So what additional preparation, can you give additional color on all the preparation you need to do for the R&D, including such as a CMC, potency assay, and also do you need FDA inspection in order for you to start? Well, thank you. Thanks, Gina. That's quite a few questions. I don't know if you want to say anything, Shalini.

Last question was on high end diesel Wilson.

So so far the program is gone.

Dear for DMD did you say I'm, sorry, yes, again for both wells and it would be.

Okay.

Well for Wilson I'll start with Wilson now I guess you added that.

For Wilson, we have completed the making the drug substance at scale and it runs well on the heel platform. We made a lot of product where the test released phase of that program.

And that requires a lot of analytical methods and so forth. That's ongoing there are some nonclinical work going in and those pieces are coming together and we should be on track to hit two filed in the year the I. Andy.

Emil D. Kakkis: Okay. Oh, just thank you, Gena, to you and your team. I really enjoyed working with you all as well. Okay, good. The thing to understand about dosing is that patients, you know, in the first four or five years of life, have an increasing amount of drug usage, but once you get to about five, six, seven, eight years old, then it's a very flat curve.

And our expectation is that as long as there's no more covert related shutdowns of labs or other things going on than we should have there are some problems with that then we could find ourselves somewhat delayed but overall the process has gone well and we have been working and have a clinical development plan.

Put together for the program.

So on Duchenne.

Emil D. Kakkis: And so patients from school age to adults are getting very similar amounts of the drug, which we estimated is, after adjustment from growth to net and compliance around $130,000 a year. So what might matter is how many very young patients we have, but we're probably not going to be putting out that much delineation at this point in time. I don't know if you want anything else, Erik, on this issue of patient-funded Jolvi. I have nothing else to add to that.

Well the other program it's at a beginning stage we are in the process of making the production system.

Which is the feel of producers selling system. We're also going to be testing a number of other factors in the design that will take some months to get through that process. Then we have to use a scale up and so forth, which will take some time, we haven't set a port.

Timeframe, but I wanted to be clear, it's certainly well more than a year for us to be able to get the manufacturing and non clinical work put together so it's not an immediate.

Erik Harris: Alright, I think the other question you asked was how many patients were on named patient XUS? Yes, in the French HEU program, it's a little less than 50 patients, I think, are on the FEOD in France. Um, in Italy, it's a handful of patients, but because of the approval in the U.S., we are able to respond to named patient requests in more countries now, so we expect that potentially to grow, although not dramatically. The U.S. revenue is certainly going to grow, we think, significantly as we move forward in the long term.

It started to media event, we want to get it right if were coming in at this point after other parties already in the clinic, we want to come in and nail it with a very high quality system and quality production as well as a good strategy administration that will optimize the treatment effect.

Okay.

Thank you. Our next question comes from the line of two theme Ahmad of Bank of America. Your line is open.

Hi, good afternoon. Thanks for taking my questions Hmm I just wanted to get your thoughts on where you are in reaching commercial supply scale for both TTX for our one and 301 program.

Emil D. Kakkis: Last question was on IND for Wilson. So, so far, the program has gone. DMV, did you say?

Gena Wang: Oh, I'm sorry. Yeah, for both Wilson and DMV. Okay. Well, for Wilson, let's start with Wilson, and I guess you added that.

And more specifically have you completed any necessary potency assays for the FDA and then I have a follow up.

Emil D. Kakkis: For Wilson, we have completed the making of the drug substance at scale, and it runs well on the HeLa platform. We made a lot of product. We're in the test release phase of that program, and, you know, that requires a lot of analytical methods and so forth. That's ongoing. There is some non-clinical work going on, and those pieces are coming together. And we should be on track to file the IND at the end of the year. And our expectation is that as long as there's no more COVID-related shutdowns of labs or other things going on, then we should. If there are some problems with that, then we could find ourselves somewhat delayed. But overall, the process has gone well, and we've been working, and we have a clinical development plan. Put together for the program.

Yes, well, we've been deal as opposed to say across the program across all the programs and I have an understanding of how we're managing that for all the programs. They have been talking to us about this for a while so it's not a new thing and I think it's pretty clear to them that in entering phase three.

They want to see opposed yes as part of.

Each manufacturing process and on lot release in their point is they want to make absolutely sure that we're getting.

Mm vector we have a number of the guidance allows for a matrix of multiple assets, where multiple but they definitely want one that looks at the active protein story and we will have those in place for that for those programs.

Okay, and then can you just give us a little bit more background on what led to the decision to add a prophylactic steroids cohort to the vcs for one summer.

Emil D. Kakkis: So on Duchenne, with the other program, it's at the beginning stage. We are in the process of making the production system, which is the HeLa producer cell line system. We're also gonna be testing a number of other factors in the design, so it'll take some months to get through that process. Then we have to do the scale up and so forth, which will take some time. We haven't set a fourth timeframe, but I wanted to be clear: it's certainly well more than a year for us to be able to get the manufacturing and non-clinical work put together. So it's not an immediate event. We wanna get it right.

Well it was actually strategics World. One plan was sort of there we just haven't talked about it as much we.

We are in Coordthree, we use steroids a little earlier, we've set the trigger for initiation varies a little bit earlier. It looked like we got a better effective controlling the into any inflammatory response or liver in the sense was it.

The safety apparent doing that we decided.

We would look at moving the stewards of even a little bit earlier on in the process and we think that we're just right.

Actually speaking become a lot easier in the commercial setting.

Gena Wang: If we're coming in at this point, after other parties are already in the clinic, we wanna come in and nail it with a very high-quality system and quality production, as well as a good strategy for administration that will optimize the treatment effect. Thank you. Thank you. Our next question comes from the line of Tazeen Ahmad of Bank of America. Your line is open.

And would help us get ahead of any.

Inflammation that might get going so it's basically.

Learnings from co or three but it was actually in the plan and with the data the way it looks from from our third quarter. It seemed prudent to do that as well it doesn't affect us we have slot product available and we could treat another three I will tell you. The other benefit of course, we're having 12 patients here in 12 patients in the other program is it.

Tazeen Ahmad: Hi, good afternoon. Thanks for taking my questions. Emil, I just wanted to get your thoughts on where you are in reaching commercial sales of Biscayle for both DTX 401 and 301 programs. And more specifically, have you completed any necessary potency assays for the FDA? And then I have a follow-up.

While the number of patients that we treat that are successfully treated it certainly can help us with the long term durability argument because they will be on treatment far ahead of the phase three program in that as you know is going to become an important piece.

Emil D. Kakkis: Yes, well, we've been dealing with the potency assay across the program, across all the programs, and we have an understanding of the agency, how we're managing that for all the programs. They've been talking to us about this for a while, so it's not a new thing. And I think it's pretty clear to them that in entering phase three, they want to see a potency assay as part of each manufacturing process and on lot release. And their point is they want to make absolutely sure that we're getting Potent Vector. The guidance allows for a matrix of multiple assays, but they definitely want one that looks at the active protein story, and we'll have those in place for those programs. Okay, and then can you just give us a little bit more background on what led to the decision to add a prophylactic steroid cohort to the DTX-401 program? Well, it was actually the DTX 401 plan that was sort of there.

Matt.

As getting.

Moving forward in a filing approval process is to show that we have enough durability and so having a few extra probably helpful. In that so we'll be floorings. The that we are already enrolling patients in it and I think it just adds to the story.

For how to treat in an efficient way when you're in the commercial setting.

Okay. Thank you.

Thank you. Our next question comes from the line of Yigal Matrimony.

Some of it of Citi. Your line is open.

This is Samantha on for you at all thanks very much for taking our question.

Just first on the Cetone guidance revision is that incremental 5 million on the lower end related to the expectations for the CIO launch or is that related to the increase.

And the identification of new accolades patients that you mentioned in your prepared remarks.

Emil D. Kakkis: We just hadn't talked about it as much. We, in cohort three, used steroids a little earlier. We set the trigger for the initiation of steroids a little bit earlier, and it looked like we got a better effect at controlling the inflammatory response from the liver. And the sense was that, with the safety of parents doing that, we decided we would look at moving the steroids up even a little bit earlier in the process. And we think that would just, practically speaking, become a lot easier in the commercial setting and would help us get ahead of any inflammation that might get going. So it's basically, learnings from Cohort 3, but it was actually in the plan. And with the data, the way it looks from our third cohort, it seemed prudent to do that as well. It doesn't affect us.

Well is the guidance, we put out in the beginning year did assume that you would get approved launch that was the guidance. We put out was for all krissy to sales for the year and so we moved up the lower end of the guidance because our revenue is actually guiding into the higher part of the guidance.

So that was a.

Simply of.

Tightening up the predictions for the street.

You know Eric if he had the other thoughts them on the guidance that you want to provide.

Yeah, I would just say just to build on my remarks earlier, so far or less than 1% of existing patients have been impacted as a result of the cobot pandemic and while we are seeing growth rates that are trending back toward pre kogut levels, they're not there yet but are too.

Tazeen Ahmad: We have the product available, and we could treat another three. I will tell you the other benefit, of course, for having 12 patients here and 12 patients in the other program is that, well, the number of patients that we treat that are successfully treated certainly can help us with the long-term durability argument because they will be on treatment far ahead of the phase three program. And that, as you know, is gonna become an important piece in getting moving forward in the filing approval process to ensure that we have enough durability, and so having a few extra is probably helpful in that. So we'll be exploring that. We are already enrolling patients in it, and I think it just adds to the story of how to treat cancer in an efficient way when you're in the commercial setting. Okay, thank you. Thank you. Our next question comes from the line of Yigal Nochomovitz. Nochomovitz of Citi, your line is open. This is Samantha on Yigal.

Pointing in the right direction.

I think that's as a result of the team is continuing to find innovative ways to educate providers and patients to virtual meetings and in lot of meetings were allowed according to safety protocols.

And.

More offices are opening up and seeing more patients in clinic, so where.

We are encouraged by.

The rebound that we're seeing.

Great. Thanks, Eric so.

I don't I mean, the bottom line not to you know really the the maintenance of the base off of Cove is kept us in game in the.

Launches continued and we're able to tighten up our focus and remove the bottom end of the guy the guidance range I think thats. Good news for the Ppas feed a franchise.

Okay, great. Thank you and then just a follow up from DMD question. You know once you get this construct into the clinic. How quickly do you think you can advance into pivotal trials do you think you'll be able to use the safety data that you've generated for us for a one real one to sort of.

Samantha: Thanks very much for taking our questions. Just first, on the CRISVITA guidance revision, is that incremental 5 million on the lower end related to the expectations for the TIO launch, or is that related to the increase in the identification of new XLA? that you mentioned in your prepared remarks. Well, the guidance we put out at the beginning of the year did assume that TIAA would be approved and launched. So the guidance we put out was for all CRIS-FITA sales for the year.

Advanced that's a little bit faster maybe than some of your other can therapy program.

Well I think we would be able to understand from those programs the safety profile, but more importantly, the dosing range of you know have.

Emil D. Kakkis: And so we've moved up the lower end of the guidance because our revenue is actually guiding into the higher part of the guidance. So that was simply a matter of tightening up the predictions for the street. I don't know, Erik, if you have any other thoughts on the guidance that you want to provide. Yeah, I would just say, just to build on my remarks earlier, so far, less than 1% of existing patients have been impacted as a result of the COVID pandemic. And while we're seeing growth rates that are trending back toward pre-COVID levels, they're not there yet, but they are trending in the right direction.

So, but I think the truth is in Duchenne the dosing is quite different the safety will be quite different so there's a little bit less than we can leverage upon I think the manufacturing might be helpful. Particularly that he may program, which has healer produced would give us some more.

Provide us some advantage.

So you know I don't think I would say is that fair those programs alone I think the biggest advantage would come through and understand the likely dose range, we need to achieve and being able to design and the biomarker endpoints involved as.

Erik Harris: I think that's because the team is continuing to find innovative ways to educate providers and patients through virtual meetings, in live meetings where allowed according to safety protocols, and more offices are opening up and seeing more patients in clinics. So we're encouraged by the rebound that we're seeing. Great, thanks, Eric. I don't, I mean the bottom line is not TAO, it's really the maintenance of the base off of COVID has kept us in the game. The launch has continued, and we were able to tighten our focus and remove the bottom end of the guidance range. I think that's good news for the Crispita franchise.

As well as clinical endpoints and being able to design, a seamless design trial, which would take us through the dosing phase with wells the randomized phase.

More rapidly which is the approach we're going to take with Wilson I think that type of design, which has been promoted by CBER and.

Peter marks.

I think isn't it possible when you know enough about the disease to know the endpoints and the measures you want to make then you can kind of predict the plan and just settle the dosing and move right into phase three without having a gap that would be one of the ways. We can shorten the timeline after we get to the clinic.

Emil D. Kakkis: Okay, great. Thank you. And then just to follow up on the EMD question, you know, once you get this construct into the clinic, how quickly do you think you can advance into a pivotal trial? Do you think you'll be able to use the safety data that you've generated for 401 and 301 to sort of, Transcribed by https://otter.ai, Well, I think we would be able to understand from those programs the safety profile, but more So there's a little bit less than we can leverage. I think the manufacturing might be helpful, particularly the HEMA program, which is HeLa produced, would give us some would give us some advantage.

Okay, great. Thanks for taking my question.

Thank you. Our next question comes from the line of Cory Kasimov of JP Morgan. Your question. Please thank.

Hey, good afternoon first of all it's great to hear from Shalini. So hope you're enjoying your time in New Zealand I have two questions for me as well first on a new x. seven or one in Wilsons can you just give some insight into how you're thinking about initial clinical studies and what the duration of follow up might look like there and then myself.

Second question is just a follow up on a on Dts for one for GST, one and with your comment that the new prophylactic steroid cohort that you're evaluating now won't impact the timing of phase three does that mean, you would start phase three and amend the protocol if necessary just taken early work and build a build a prophylactic steroids.

Emil D. Kakkis: So, you know, I don't think I would say it's necessarily those programs alone. I think the biggest advantage would come from understanding the likely dose range we'd need to achieve in being able to design the biomarker endpoints involved, as well as clinical endpoints, and being able to design a seamless design trial, which would take us through the dosing phase, as well as the randomized phase, more rapidly, which is the approach we're gonna take with Wilson. I think that type of design, which has been promoted by Sieber and Peter Mark.

Kinda regimen into that.

Okay.

So first question is around you have seven to one which the gene therapy for Wilson disease. The clinical studies are planned in the clinical studies is to is to do a significantly larger say that what we did in the others, but it will be there will be three cohort groups that we will be exploring dose and then with that dose information will essentially go straight into.

The phase three design in one seamless design and so we're getting really seeking is approval on doing a single seamless design, where you go through dosing and go right to.

Samantha: I think it's possible when you know enough about the disease to know the endpoints and the measures you want to make, then you can kind of predict a plan and just settle the doses and move right into phase three without having a gap. That would be one of the ways we can shorten the timeline after we get to the clinic. Great, thanks for taking our questions. Thank you. Our next question comes from the line of Corey Kazimoff of J.P. Morgan. Your question, please. Hey, good afternoon. First of all, it's great to hear from Shalini, so I hope you're enjoying your time in New Zealand.

The pivotal designed the reason that's possible is that the agreement on primary endpoint is is on a biomarker based primary endpoint is doable because of the history of treat approvals in Duchenne and therefore, we think we can set up an operator program straight through in one shot so that will help but the study length.

Look I think the FDA is very clear that they want to make sure there's sufficient durability in the program the patients from the early dose cohorts would probably end up having.

Corey Kazimoff: Two questions for me as well. First, on UX701 in Wilson's, can you just give some insight into how you're thinking about initial clinical studies and what the duration of follow-up might look like there? And then my second question is just a follow-up to DTX401 for GSD1A. And with your comment that the new prophylactic steroid cohort that you're evaluating now won't impact the timing of Phase 3, does that mean you would start Phase 3 and amend the protocol? If necessary, just take an early look and build a prophylactic steroid regimen into that? Okay.

Close to a year or more time on drug than the fee component patients.

But we haven't fully Adnan.

Nailed down what exactly the Mount length of time is but our expectation based on design.

And to have a 48 week blinded study.

How much extension day, we'll need will need to discuss with the agency at some point in time, but.

Our plan with them 40, we plan to study where the core efficacy.

Safety determination.

So with the four one prophylactic steroid question.

We're primarily looking to see that we can keep the inflammation down in the first few weeks and that that that effect is sufficient to allow us to get the good corn search reductions, we only need a few weeks of data in order to know how the stories are working for us. So that's where we are looking forward with last time in the third cohort.

Emil D. Kakkis: So the first question is around UX701, which is the gene therapy for Wilson disease. The clinical studies, our plan for the clinical studies is to do a significantly larger study than what we did in the others, but it will be, there will be three cohort groups that will be exploring dose, and then with that dose information, we'll essentially go straight into the phase three design and one seamless design. And so we're getting, we're gonna be seeking his approval on doing a single seamless design where you go through dosing and go right to Pivotal Design. The reason that's possible is that the agreement on the primary endpoint is on a biomarker-based primary endpoint is doable because of the history of treatment approvals in Duchenne, and therefore, we think we can set up and operate a program straight through in one shot, so that will help it.

What we did with steroids that were as soon as they change from baseline, which really meant it was only like a couple of weeks in from the treatment.

And so now we're just starting a little bit earlier, so it's really not that fundamentally different from where we are it's just a little bit earlier, and we'll look to see that it's safe. It doesn't have any issues with the GST one patients and as long as that happens first weeks, we'll know our plan, though is to submit the protocol with the new proposed traditions that way if.

If we had an issue in the third quarter, we ask you to bend amend the protocol and back away from that but I doubt that we will and I think that's the probably the best way forward.

Emil D. Kakkis: The study length Look I think the FDA is very clear that they want to make sure there's sufficient durability in the program. The patients from the early dose cohorts would probably end up having, you know, close to a year more time on the drugs than the phase 3 component patients. But we haven't fully knit in... nailed down what exactly the amount of time is, but our expectation based on design, Did they have a 48-week blinded study? How much extension data we'll need, we'll need to discuss with the agency at some point in time, but our plan is to have a 48-week plan to study for the core efficacy and safety determination.

Okay. Thanks Emma.

Thank you. Our next question comes from the line of Salveen Richter of Goldman Sachs. Your question. Please.

Good afternoon, and Sean it's been great working with you and enjoy the break and Mighty congratulations on joining ultragenyx.

Im also wondering if you could update us where you stand with regard to optimizing the software platform to create that cracker generation process and how you intend to layer.

So I mean, you factoring into your pipeline, particularly with our Wilson.

Emil D. Kakkis: So with the 401 prophylactic steroid question, we're primarily looking to see that we can keep the inflammation down in the first few weeks and that that effect is sufficient to allow us to get the good corn starch reduction. So we only need a few weeks of data in order to know how the steroids are working for us. So that's what we're looking for.

Right. So the Wilson program is is produced with the healer. We called 2.0 version of the process. However, we've already created healer 3.0 versions from that version and we don't have at this point.

Time or need to crossover to it but we could at some point in time, but right now were head to the clinic with the 2.0 version, which is already very productive and certainly providing more than enough product. He was 3.0 level of productivity improvements, which are some patent additional changes, we're making which were presented at the.

Emil D. Kakkis: Last time in the third cohort, what we did was steroids that changed from baseline, which really meant it was only like a couple weeks into the treatment, and so now we're just starting a little bit earlier, so it's really not that fundamentally different from where we are; it's just a little bit earlier, and we'll just see that it's safe, it doesn't have any issues with the GST-1 patients, and as long as Our plan, though, is to submit the protocol with the new proposed steroid regimens. That way, if we had an issue in Theracore, yes, we could then amend the protocol and back away from that. But I doubt that we will.

TCT.

Those change I think we will particularly be valuable for the Duchenne program, because where you really need that much higher productivity. Therefore, as a real big win for that with those changes we can get the productivity up several fold, even higher and reach levels that will really enable the ability at 2000 liter scale to produce.

Enough product to treat many patients for every run so.

Emil D. Kakkis: And I think it's probably the best way forward. Okay, thanks. Thank you. Our next question comes from the line of Salveen Richter of Goldman Sachs. Your question, please. Good afternoon, Shani. It's been great working with you, and enjoy the break.

We're looking at deals recon is really coming into play there.

That process, so making a 3.0 version can be done with any existing heel of cruiser cell line, we can actually take existing line and turn it into the 3.0 version. So we could certainly go back we havent done it for Wilson with your three other programs and do that as well.

Salveen Jaswal Richter: And Marty, congratulations on joining Ultragenyx. Emil, I was just wondering if you could update us on where you stand with regard to optimizing the HeLa platform to create this third generation process and how you intend to layer this HeLa manufacturing into your pipeline, particularly with Wilson. Right, so the Wilson program is produced with the HeLa we call 2.0 version of the process. However, we've already created HeLa 3.0 versions from that version.

Going forward, we would look to see the heel of 3.0 version is being the right version, but were still finishing the development of that acquisition will give us a chance to optimize it for.

For human use.

Great. Thank you.

Thank you. Our next question comes from Laura Chico of Wedbush Securities. Please go ahead.

Hi, this is concealed on for Laura Chico. Thanks for taking my question. So one for Marty what green tea opportunity and how should we think about capital allocation and finance and try again.

Genex's benefited from recent transaction so what should we anticipate if we look at.

Emil D. Kakkis: And we don't have at this point, which are some patented additional changes we're making which were presented at the ASGCT. Those changes, I think, will particularly be valuable for the Duchenne program because where you really need that much higher productivity, it is a real big win for that. And with those changes, we can get the productivity up several fold even higher and reach levels that will really enable the ability at the 2000 liter scale to produce enough product to treat many patients for every run. So we're looking at Heal3Point is really coming into play there. The process of making the 3.0 version can be done with any existing HeLa producer cell line. We can actually take an existing line and turn it into the 3.0 version. So we could certainly go back. We haven't done it for Wilson.

Yeah, great great. Thanks for the question and I'm pretty easy decision to join Ultragenyx. Then I think you heard a lot about it on the call I think.

The team has guided the company in such a great way ticket that point, but they certainly plan for their next phase of growth and I'm pretty honored to be part of the team now and to help them achieve that.

No in terms of capital allocation I think the company's 10 events have big job frankly, you know to be here. If you look at our cash balance at the end of last year and the cash balance today, it's pretty darn close to the same number and.

Particularly the last two deals that brought in capital non equity dilutive in nature, where their royalty pharma royalty deal last December and then of course, the Daiichi deal, which we've talked about today.

Salveen Jaswal Richter: We could go through the other programs and do that as well. Going forward, we'd look to see the HeLa 3.0 version as being the right version, but we're still finishing the development of that. And GCHEN will give us a chance to optimize it for human use. Great, thank you. Thank you. Our next question comes from Laura Chico of Web Bush Security. Please go ahead. Hi, this is Ken Shields on behalf of Laura Chico.

Together, bringing and you know well over 500 million into the company. So that's fantastic.

So the company is in a really strong cash position you know we did announce a course see solid deal recently.

Maurice Thomas Raycroft: Thanks for taking my question. So one for Marty, what drew you to the opportunity? And how should we think about capital allocation and financing strategy? And Ultragenyx has benefited from recent transactions. So what should we anticipate as we look ahead? Yeah, great.

But with that deal and sort of our base business going forward, we have cash that takes us into 2023, but I want to highlight that were on a growth path that we liked deal that looked like solid and you know I want to highlight the genetics purchase option as well for for the entitlement program, which you know we have.

Maurice Thomas Raycroft: Great. Thanks for the question. And a pretty easy decision to join Ultragenyx.

The option to purchase that company for 125 million. After some period of time after phase two data. So we're in great position that we are very active as well and we look forward to the next steps.

Maurice Thomas Raycroft: And I think you heard a lot about it on the call. The team has guided the company in such a great way to get to this point, but they've certainly planned for their next phase of growth, and I'm pretty honored to be part of the team now and to help them achieve that. You know, in terms of capital allocation...,,,,,,,,,,,,,,,,,, Thank you. And maybe just one more.

Thank you and maybe just one more so on Angelman syndrome.

You think about the competitive landscape and the potential for a CRISPR based therapy versus an ACO strategy.

There was a recent publication that came out.

Maurice Thomas Raycroft: So on Angelin Syndrome, how do you think about the competitive landscape and the potential for a CRISPR-based therapy versus an ASO strategy? I think there was a recent publication that came out. And in light of your interim data, I was just wondering if you could comment on the potential for gene editing in this disease. Thank you. Well, for Angelman disease, fortunately for Angelman patients, there are a lot of people working on strategies right now, and there are a lot of very interesting strategies out there, so they certainly all have potential. We picked ASO, by the way, particularly because we felt it was more likely to be superior to gene therapy or even a CRISPR-type approach. The ASO can, in particular, their ASO distributes well to the whole brain, and induces expression in a wide variety of neurons across the brain, which we think is really important in this disease state, whereas gene therapy now, even in the primate or in humans, is still getting a small fraction of the total neurons, and while that can work in something like SMA, it may not work in a disease that has very complex neuronal communication,

And in light of your internal data just wondering if you could define omni clinical forcing anything.

Thank you the well for the engine disease, Fortunately for range limitations as a lot of people working on strategies right now there's a lot of very interesting strategies out there. So it's certainly all of potential we ticked is so by the way, particularly because we felt it was more likely be superior than gene therapy.

Or even a crisper type approach is so can just in the particularly the area. So distributors well do the whole brain induces the expression in a wide variety of neurons across the brain, which we think is really important in this disease state, whereas gene therapy now even in the human primate or you in humans is still getting a slow.

Now for action until neurons, while that can work in something like since the may It may not work in disease and has very complex terminal a communications.

I think.

Gene editing is going to be extremely challenging the brain getting an adequate and an effective Ics.

Expression in enough neurons to actually have the impact you desire and keep in mind. It's only the neurons that are important to the other cells are not imprinted. So if you Jean correct non neuronal sells here there that's actually may not be what you want to do so well just complicated I would say having looked at all our view.

Emil D. Kakkis: Gene editing is going to be extremely challenging for the brain getting an adequate and effective, Transcribed by https://otter.ai. Our view is ASL is the best strategy. It turns on the paternal chromosome, which was there. It allows that expression to occur in a regulated fashion, and it does it in a wide variety of neurons. I think that's still going to be hard to beat.

As if those who is the best strategy. It turned on the maternal chromosome which was there that allows that expression occur in a regulated fashion and it does in a wide variety of neurons I think thats still going to be hard to beat.

Even so they're more if those out theres enough. So the Roche Biogen eye on us.

Emil D. Kakkis: Even so, there are more ASOs out there than us, so there's Roche and Biogen Ionis, both very capable firms with a lot of expertise. We picked the genetics program to get involved because we felt they had a superior understanding of RNA regulation and that the science, which was, we think, superior and it was, basically, more evolved in understanding regarding how to knock down the RNA in their oligo, I think, is substantially more potent than others that were tried in the laboratory. So we're excited about that oligo, and I actually think it's still going to be the best strategy, and it will be hard to match, I think, with others.

Both very capable firms with a lot of expertise.

We picked the genetics program to get involved because we felt they had a superior understanding of the Ernie regulation and that the science, which was we think superior and it's basically more evolved in understanding regarding how to knock down the.

Arnie and they're all go I think it's substantially more potent than.

Others that were tried.

The laboratory so.

We're excited about that all go and I actually think it's still going to be the best strategy and we will be hard to match I think with other changes.

Okay. Thank you very much.

Maurice Thomas Raycroft: Okay, thank you very much. Thank you. Our next question comes from Jeff Hung of Morgan Stanley. Please go ahead.

Thank you. Our next question comes from Jeff Hung of Morgan Stanley. Please go ahead.

Jeff Hung: Thanks for taking the question and best wishes to Shalini. Just to clarify on the guidance, if I understand this right, the midpoint of the range implies approximately flat sequential growth for fourth quarter Crisvita sales in Ultragenyx territories. You mentioned outstanding uncertainty due to COVID, so is that the main driver, or is it conservatism, or are there any other potential factors that we should be thinking about for the fourth quarter?

Thanks for taking the question and best wishes to Shalini I'm.

Just to clarify on the guidance if I'm looking at this right the midpoint of the range implies approximately flat sequential growth for fourth quarter Christmas sales and Ultragenyx territories, you mentioned outstanding uncertainty due to Covance. So is that the main driver or is it conservatism or are there any other potential factors that we should be thinking about for the fourth quarter. Thanks.

Well I think they are probably a lot of factors like how about the widely discussed could surge ongoing out there.

Emil D. Kakkis: Thanks. Well, I think there are probably a lot of factors, like how about the widely discussed COVID surge ongoing out there? Eric, do you want to touch on the question which is really how the guidance relates to what's happening, what are the risks of the guidance maybe going forward, and what the changes were, is that about right, Jeff? Yeah, we're encouraged by the rebound that we're seeing, but there's still a great deal of uncertainty as to when the market will fully open, to pre-COVID levels, so. It creates some challenges with forecasting, as you think about, you know, as we move in close out the year and move into 2021. Right now, yep, thank you.

Eric do you want to touch on the question, which is really.

How the guidance relates to what's happening what are the risks to the guidance, maybe going forward and what the changes where is that about right Jeff.

Yes, yes data we're encouraged we're encouraged by the Ameriana. The rebound there were saying, but there is still a great deal of uncertainty as to when the market will fully open.

Two pre corporate levels so.

It creates some some challenges with we're forecasting.

As you as you think about that.

As we moving close out the year and move into 2021.

Yes, that's right now yes. Thank you.

Jeff Hung: Thank you. Our next question comes from Joon Lee of Truist Securities. Your line is open.

Thank you. Our next question comes from Julie Truest Securities. Your line is open.

Joon So Lee: Hi, congratulations on the strong quarter and thanks for taking my questions as well. On GTX 102 for Angelman's, you used IVIG to treat some of the patients, which implies an IGT response, yet you said on the call yesterday, I believe, that IGT, the alpha-immune ratio, was not altered. Can you just tell us a little bit more about what the nature of the immune response was? And then the second question is, based on the MRI, the reaction, as you described, appeared to be very localized, but my question is, what was the greatest extent of the spread of the inflammation in the patient, in any patient, actually? Just try to assess the potential for it to spread to other spinal cord levels, maybe more vital functions. Thank you.

Hi, Congrats on the strong quarter and thanks for taking my questions as well, our GTS, one or two for enjoyment use ideology treat that some of the patients which implies I'd team response, yet you said on the call yesterday I believe that ICICI to often ratio were not altered. So can you just help a little bit more about what nature of the.

In response was and then the second question is.

Based on the M. ROI and reaction as you described appear to be very localized such that my question is what was the greatest extent of the spread of inflammation and the patient any page actually just trying to assess the potential to spread to other favorite spinal cord and levels, maybe the more but battle.

Thank you.

Sure. So the use by the age year, stairways, where we've done or reactively as the patient symptoms. There was not actually based on and a known immunological situation that were thought Ibiza would work. It was just looking parallel to some other conditions not because there's any rational basis.

Emil D. Kakkis: Sure, so the use of IVIG or steroids was done more reactively according to the patient's symptoms. It was not actually based on a known immunological situation that we thought IVG would work. It was just looking parallel to some other conditions, not because there was any rational basis it should be used.

Was it with you it's not clear the Ivy Jane series are actually having impact effect, we were just using including them.

Emil D. Kakkis: It's not clear if the IVG and steroids are actually having an effect, we were just including them for completeness, but it does not indicate that there's an immunoglobulin based cause, and we have no evidence for that at this point. With regard to localized, we said lumbosacral, but actually lumbosacral was the largest extent, and that was in the smallest patients. That's where it extended to the lumboral region. But in bigger patients, it was really almost in the sacral region only, so it was actually smaller.

For completeness, but it does not indicate that there's anything loveland based and we have no evidence for that at this point.

Regard to localize, we said Loveless April but actually lemon chicken was the largest extent and that was in the smallest patients that's where it extended to the lumbar region, but in the bigger patients is really almost as a sequel region. The only.

So it was actually smaller the biggest region was up to the lumbar and not did not include the rustic levels or higher levels. So we don't think it would spread we think its peers through the region, where the drug sits immediately after administration without trend ellenberger small patient they would it would fill up a little more than a big station, where it only fill up the bottom part.

Emil D. Kakkis: The biggest region was up to the lumbar, and it did not include thoracic levels or higher levels, so we don't think it would spread. We think it appears to be the region where the drug sits immediately after administration. Without Trendelenburg, it's a small patient. It would fill up a little more than a big patient where it only filled up the bottom part.

Art.

So we think that the Delaware, which hopefully tip the cup over and have all the stuff part of this top is what were we think will change things and.

We're adding a flush additionally, our efficiencies at the after the dosing to help wash out the drugs from was the lumbar almost sequel region, which we think would both producers local effect and help promote the movement. The thing once the drug loose nordson slows it will mix now with yourself up in the spot.

Emil D. Kakkis: So we think that the Drendelenburg, which hopefully will tip the cup over and have all the stuff pour out the top, is what we think will change things. And we're adding a flush of additional artificial CSF after the dosing to help wash out the drug from the lumbosacral region, which we think would both reduce the local effect and help promote the movement. The thing is, once the drug moves north and flows, it will mix now with CSF up in the spinal cord, mix, and dilute. And when it reaches the sternum magna, there's almost a pumping-mixing action that goes on.

Or mix and dilute and when it reaches a string of Magna there was almost a pumping mixing actually goes on with those so if you sit there long enough the drug should move farther up and mix more efficiently and not sit in any one place. So with why we believe we can also the distribution it's not a new thing turned ellenberg and this these actions are commonly is.

Emil D. Kakkis: So if you sit there long enough, the drug should move farther and mix more efficiently and not sit in any one place. So that's why we believe we can alter the distribution. It's not a new thing.

In other words with equal drugs and I've been personally reached Intrathecal therapy for 20, or so is there im quite familiar with them. It's a very simple you things you can do to alter and that's why we're pretty confident we can manage this and it will not become an issue.

Emil D. Kakkis: Drendelenburg and these actions are commonly used in other intrathecal drugs. And I've been personally doing research into intrathecal therapy for 20 years, so it's an area I'm quite familiar with. And these are very simple things you can do to alter, and that's why we're pretty confident we can manage this and it will not become an issue.

And just a follow up question, but there are other assets therapies that led to some localized inflammation or reactions that would resolve returned on her.

Well there are other areas. So therapies that clearly cause me Angela irritation in an elevated shifts of protein cement multiple ones of the clinic have shown that so that's definitely true.

Joon So Lee: And just a follow-up question, were there other ASL therapies that led to some localized inflammation or reactions that were resolved with Trendelenburg? Well, there are other ASL therapies that clearly cause meningeal irritation and elevate the CSF protein, so multiple ones in the clinic have shown that, so that's definitely true. So Trindallenberg can be used in any situation.

So magellan Bergen to use in any situation I don't know, but I can't speak to the clinical judgment other people, what they do or don't do but current ellenberger is widely used in intrathecal therapies as a way to take the heavier drugs solution to move it towards the brain, where it needs to work.

Thank you.

Thank you. Our next question comes from Arlinda Lee of Canaccord. Your question. Please.

Unknown Attendee: I don't know, but I can't speak to the clinical judgment of other people and what they do or don't do, but Trindallenberg is widely used in intrathecal therapy as a way to take the heavier drug solution and move it toward the brain where it needs to work. Great, thank you. Thank you. The next question comes from Arlinda Lee of Canaccord. Your question, please. Thank you for taking my questions. Maybe a quick one on the Jolvi, can you provide an update on... And then maybe something more involved on the HeLa efficiencies you've mentioned that here now. 3.0.

Hi, Thank you for taking my question maybe.

Brian on the Jody can you provide an update on.

The discussions with regulatory agencies, and then maybe more involved on the Sheila efficiencies you've mentioned that.

We're now in.

And three point Alan I'm wondering if you're looking to further enhance.

There and can you talk about how you think about it.

The healer pushing that program and your appetite for additional collaboration.

Additional indications it's interesting too thank you.

Thank you.

So on digital all the regulatory agencies Weve Joe.

Just to update we have filed in Canada under priority review, we filed in Brazil. In addition, and so those are the two that are in play in Europe, we're having discussions because we need to get a pediatric investigational plan and we're having ongoing discussion so no filing plan yet for Europe. So that's where we are in the Greg agencies look to U.S. approval, though.

Emil D. Kakkis: I'm wondering if you're looking to go further, can you talk about how you think about Thank you. So on Dujovi Regulatory Agency, we've, Just to update, we have filed in Canada under priority review. We filed in Brazil in addition, and so those are the two that are in play. In Europe, we're having discussions because we need to get a pediatric investigational plan, and we're having ongoing discussions. So, no filing plan yet for Europe.

We can do named patient sales in many places where the requests come to us and we can fulfill those requests.

With regard to heal a 3.0.

The new version is some alterations, which helped generate more productivity in our early substantial and very important and so the team led by Sam was worth as of course, he tuning looking on what's next in our continuing adding to the platform and building its value and I I think these changes are the kind of thing that happened in the early.

Emil D. Kakkis: So that's where we are in the regulatory agencies. With U.S. approval, though, we can do name patient sales in many places where the requests come to us, and we can fulfill those requests. It is regarded as HeLa 3.0. The new version is some alterations which help generate more productivity and are really substantial and very important. And so the team, led by Sam Wadsworth, is, of course, continuing to look at what's next and are continuing to add to the platform and building its value.

It is a monoclonal antibodies that the wherever controlled the creation of large scale cost efficient system for monoclonal antibodies started kind of owning the field and ending up partnering into and gaining a lot of ground now.

Now we believe there are additional collaborations are possible whether for indication, we would develop or ones for which we would provide the technology in an agreement as we did with Daiichi Sankyo, we're looking at those kind of arrangements we would.

Emil D. Kakkis: And I think these changes are the kind of thing that happened in the early days of monoclonal antibodies, that whoever controlled the creation of large-scale cost-efficient systems for monoclonal antibodies, [inaudible] The deal with HEC will also involve a lot of tech transfer, a lot of effort, but on the spectrum, we could do another deal as extensive as that or other deals in which the technology is licensed for particular indications, and And if we've created the largest mammalian system and a high-quality system for any manufacturer, it's incumbent on us to make it available and work with companies to put more products in play, for which Solid, as a partner, was available to help bring their Duchenne particular knowledge to the fore, especially their microdystrophic We certainly would look at other deals of a similar type where we would supply our technology and pick up So we are looking at them, and Sam will continually ask for investment in further versions of the platform. I guarantee it.

The deal with as you think it will also involve a lot of tech transfer a lot of effort, but on the spectrum, we could do another deal as extensive as that or other deals and what's the technologies license for particular indication and we're open to a variety of avenues and we've created the largest mailing system and high quality system Brady manufacturer.

Coming to us to make it available and worked with companies and putting more products in play.

Shen story, just became one that we could take advantage ourselves as an area of muscle that were pretty knowledgeable about and.

For which a solid as a partner was available to help bring their duchenne particular knowledge to the four especially their micro dystrophin.

We certainly would look at other deals with similar type, where we would supplier technology and pick up another product, where the unique scalable and large scale production and high tide tighter productivity of the helix platform could be a distinct advantage, so, particularly then and high dose indications.

So we are looking at those and and Sam will continually ask for investment in further versions of the platform I guarantee it.

Unknown Attendee: Thank you. Our next question comes from Vincent Chen of Bernstein. Your question, please. Thank you so much for fitting me in.

Great. Thank you very much.

Thank you. Our next question comes from Vincent Sen of Bernstein. Your question. Please.

Thank you social thing he and I have a couple of a science questions on engines and DMD, starting with Angela and I was hoping you could provide some more color on what you think the mechanism is for the potential inflammation CNN or findings or observations support deferred losses is this something that you think is likely to be aspects come into simply alternate dosage typically both.

Vincent Chen: I have a couple of science questions on Angelman's and DMD. Starting with Angelman's, I was wondering if you could provide some more color on what you think the mechanism is for the potential inflammation scene and what findings or observations support this hypothesis. Is this something that you think is likely to be in effect common to simply RNA dose intrathecally above a certain dose? Or is this something that may be related to certain RNA molecules or certain RNA modifications? And then for DMD and the SOLID collaboration, I'd be curious what your thinking around what causes the complement-related side effects that SOLID has seen previously. Are these likely to be related to the use of a longer half-life vector like AV9? And do you think a program using your capsid would be potentially less susceptible? Sure, so in the ancient story...

Windows or is this something or maybe related to certain arent a molecules or certain R&D modifications.

And then for DMD in the solar collaboration I'd be curious what is your thinking around what causes the complement related side effects that sort of thing previously or is likely to be related to the use of a longer half life vector like gave you know do you think the program using your hubs that would be potentially less susceptible.

Sure so in the ancient history.

Emil D. Kakkis: The mechanism of the inflammation, we think, is probably very distinctive from the mechanism of the action of the drug. All ASOs can have toxicity when applied to cells and culture, and Ionis has published some very elegant papers showing that, showing how ASOs of various kinds combine with certain proteins and lead to toxicity. And so the idea of ASL as positive toxicity as a class is pretty well established in many different oligos, so it's not something very new. The issue of meningeal inflammation protein in CSF is also widely observed.

[noise] they mechanisms inflammation, we think it's probably very distinct from the mechanism of the action of the drugs.

All his those can have toxicity applied to cells in culture and.

Stand for from.

Own is published and very elegant papers, showing that showing how episodes of various kinds.

Combine certain proteins to lead to touch the city. So that idea is less positive to see as a class is pretty well established in many different oligos. So its not something very new the issue of millennial inflammation protein or proteins yourself is also widely observed.

Emil D. Kakkis: We don't think the mechanism has anything to do with the mechanism of the oligo in RNA. It has really to do with local cell toxicity relating to too much oligo present and being taken up. That's why we believe it's primarily an issue of getting the concentration and the contact time down locally. What we know, and the data supports this, is that we have looked in our non-human primates, and we know that in those non-primates, not without trendental organs, done the same way as we're doing in humans, we do see very high concentrations in the local tissues. They haven't been associated with a problem in a non-human primate, and the concentrations in the brain are lower than what you see with locally applied drugs. But now, in humans, that isn't a problem, and so, therefore, we're having to take action. But it hadn't caused this problem in non-human primates. So we know the concentration is higher there.

I don't think the mountains ending do with the medicines all gone already it has really to do with a a local cell toxicity relating to too much oligo present and being taken up slightly.

That's why we believe is primarily an issue of getting the concentration in the contact time down locally, but we know in the data supports this is that we have looked in our non human primates, and we know that in those non prime is not without trend downward and done the same ways were doing in humans, we do see very high concentrations in local tissues that hasn't been associated with the problem.

In the non human primate concentration the brain are lower than what you see locally applied drug.

But now in humans that isn't problem and so therefore, we are having to take action, but hadn't profit caused this problem in nonprime. It. So we know the concentration is higher there we know from in vitro work been number laboratories that all goes in high concentration can cost its local toxicity. So we think the simple manner, just lowering the exposure level.

Emil D. Kakkis: We know from in vitro work by a number of laboratories that oligos at high concentrations can cause, you know, localized toxicity. So we think it's a simple matter of just lowering the exposure level in the local area and trying to reduce that inflammation. I think it's something that's completely manageable and not a fundamental type of toxicity that's related to the actual drug action that's related to a local toxicity of just too much drug in the locally applied space.

On the local and trying to reduce that inflammation I think it's something it's completely manageable and not a fundamental type toxicity that's related to the actual drug action is related to a local toxicity of just too much drugs in the local applied space.

So we feel that's something very differentiated from what the drug does and therefore very manageable and I feel confident we will get it managed.

Emil D. Kakkis: So we feel that's something very differentiated from what the drug does and therefore very manageable, and I feel confident we'll get it managed. Now, with regard to Duchenne, both Pfizer and the Pfizer program and the SOLIDS program have had complement activation, which appears to be antibody-related complement activation. This could be due to longer exposure time with AV9, which lasts longer. The SIRREPTOR program, to the extent they've disclosed about this, appears to not have this particular problem. We know that 88 related vectors clear a little bit quicker, and that may be a factor.

Guard to Duchenne above.

Both Pfizer and the Pfizer program and follows program have had common activation appears see antibody related common activation. This could be due to longer exposure time Navy nine which last longer.

Keep the Sarepta program to extent they've disclosed on this appears to have not have this particular problem, we know that aviate related vectors clear a little bit quicker and that may be a factor.

We haven't aviate variant that is has a very good ammonium profile and which we did.

I think has a good potential of being a an optimum product we know it delivers to muscle and therefore, we feel confident it's a good choice from its immune profile standpoint, it faster clearance from the circulation to be a good option to combine with the really best in class, Mike dystrophin that that that saw.

Emil D. Kakkis: We have an AVA variant that has a very good ammonium profile which, I think, has good potential to be an optimum product. We know it delivers to muscle, and therefore, we feel confident it's a good choice from its immune profile standpoint, its faster clearance from circulation, to be a good option to combine with the really best-in-class microstrophin that SOLID has. And for SOLID, this gives them another way to win. They've got their current product, it could do well, and they could be fine to figure out the issues they've had. This also gives them another way to work with us and another upside potential for Duchenne patients. I like deals that get two winners to put together something that will create. Duchenne is a very big indication.

It has it.

For solid just gives them another way to when they've got their current product it could do well and they could be fine and figure out there. The issues. They've had this also gives them another way to work with us and another upside potential for duchenne patients I like deals that get two winters put together something that will create.

Common goal and combine the best technology, there is out there and they've done that type of deal in the past and I think it was kind of deal that can work Duchenne is a very big indication. There is a lot of room here and I think a lot of room for doing better and we think the platform. We have in the dystrophin combined with some learnings and.

Vincent Chen: There's a lot of room here, and I think there's a lot of room for doing better. And we think the platform we have and the distro, combined with some learnings and an intelligent approach, could provide a very good option for treating Duchenne. We're behind everyone else, but I think we can be.

Teligent approach could provide a a very good option for treating duchenne.

We're behind everyone else, but I think we can be.

We can be better.

Great. Thanks for taking the question congrats on the progress.

Joshua Higa: We can be better. Great, thanks for taking the questions. Congratulations on all the progress. Thank you. Thank you. At this time, I'd like to turn the call back over to Joshua Higa for closing remarks, sir. Thank you. This concludes today's call. If there are any additional questions, please contact us by phone or at IR@Ultragenyx.com. Thank you for joining us. Ladies and gentlemen, thank you for participating. You may now disconnect.

Thank you [laughter].

Thank you at this time I'd like to turn the call back over to Josh We Hager for closing remarks, Sir.

Thank you. This concludes today's call scare any additional questions. Please contact us by phone current IR at Ultragenyx Dot com, thanks for joining us.

Ladies and gentlemen, thank you for participating you may now disconnect.

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