Q4 2019 Earnings Call

Ladies and gentlemen, thank you for standing by welcome to Ultragenyx fourth quarter and full year 2019 financial results Conference call. At this time all participant lines are in listen only mode.

Operator: Thank you for standing by. Welcome to the Ultragenyx fourth quarter and full year 2019 financial results conference call. At this time, all participant lines are in 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 need to press star one on your telephone. If you require any further assistance, please press star zero. I would now like to hand the conference to your speaker today, Danielle Keeley. Please go ahead. Good afternoon and welcome.

After the speaker presentation, there will be a question and answer sessions to actually question. During the session. You went to press star one on your telephone.

If you require any further since please press star zero.

I'd now like to have the conference to speaker today, Daniel Keatley. Please go ahead.

Thank you good afternoon welcome.

Danielle Keeley: Financial Results & Corporate Update Conference Call for the 4th Quarter, We've issued a press release detailing our financial results, which you can find on our website at ultragenyx.com. I'm Danielle Keatley, Senior Director of Investor Relations, and with me today are Emil Kakkis, Chief Executive Officer and President, and Shalini Sharp, Chief Financial, I'd like to remind investors that this call will include forward-looking statements within the meaning of the Safe Harbor provisions of the Private Security Litigation Reform Act of 1995, including but not limited to the types of statements identified as forward-looking in our quarterly report on Form 10-Q that was filed on November 6, 2019, our annual report on Form 10-K that will be filed soon, and our subsequent periodic reports filed with the SEC, which will all be available on our website in the Investor section.

Pharmaceutical financial results in corporate update conference call for the fourth quarter and full year 2019, we've issued a press release detailing our financial results, which you can find on our website <unk> Dot com and Daniel Keatley Senior director of Investor Relations and with me today, ARYMO Caucus, Chief Executive Officer, and President and Shalini Sharp chief.

Angelakis or.

I'd like to remind investors that this call will include forward looking statements within the meaning of the safe Harbor provisions of the private Securities Litigation Reform Act of 1995, including but not limited to the types of statements identified as we're looking in our quarterly report on form 10-Q that was filed on November six 2019, our annual report on.

On form 10-K that will be filed soon and our subsequent periodic reports filed with the FCC, which will all be available on our website in the Investor section.

Danielle Keeley: 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 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 relating to our business, see our periodic reports filed with the SEC. I'll now turn the call over to Emil. Thank you, Danielle.

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

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 could differ materially from those expressed in the forward looking statements.

As well as risks relating to our business see our periodic reports filed with the FCC I'll now turn the call over to ammo.

Thank you Daniel I'll start with our commercial performance in the fourth quarter of 2019.

Emil D. Kakkis: I'll start with our commercial performance in the fourth quarter of 2019. Shalini will then summarize our financial results for the quarter and the year. I'll come back at the end to discuss the progress across our clinical and preclinical programs and our outlook for the rest of the year. Starting with Kris Vita, which has been the main focus of our commercial efforts and the primary driver of revenue in 2019. Performance in the fourth quarter built on the momentum in the first five quarters of launch, as reflected by continued increases in completed start forms and the number of patients on reimbursed therapy. In the U.S., we ended the year with approximately 1,590 complete START forms, 160 more than in the third quarter.

Tony will then summarize our financial results for the quarter end the year.

Oh come back at the end to discuss the progress across or clinical and preclinical program and our outlook for the rest of year.

Starting with Privy to which has been the main focus of our commercial effort from the primary driver of revenue in 2019.

For the fourth quarter built on the momentum in the first five quarters watch. This was reflected by continued increases in completed start form.

And the number of patients on reimbursed therapy.

In the U.S., we ended the year with approximately 1500 90 completed start 460 more than third quarter. We also ended the year with approximately 1300 30 patients unreimbursed therapy. He 200 patient increased versus the end of the third quarter.

Emil D. Kakkis: We also ended the year with approximately 1,330 patients on reimbursed therapy, a 200 patient increase versus the end of the third quarter. As the commercial team continues to work to penetrate the adult market, we believe CRISPR-V will continue to be one of the most successful rare disease programs launched. Our 2020 CRISPR-Vita revenue guidance of $125 million to $140 million further reflects the confidence we have in CRISPR-Vita and our commercial teams' ability to execute. Now that the early launch period is over, going forward, we do not plan on providing specific launch metrics, but we'll focus on revenue for Christmas.

As a commercial team continues to work to penetrate the adult market. We believe krispies will continue to be one of the most successful where disease program launched.

Our 2020 crispy to revenue guidance of 125 million to 140 million further reflects the comps we haven't crispy the inner commercial teams ability to execute.

Now with the early launch period is over going forward, we do not plan and providing specific want to watch metric, but we'll focus on revenue for Chris either.

Emil D. Kakkis: To put our launch progress in perspective, we mapped out the top rare disease launches through their first six quarters over the last 15 years. We found that CRISPR is one of the top rare disease launches based on top-line total product sales. We've also generated substantial revenue while setting a price that is substantially lower than any of the other top rare disease drugs.

To put our launch progress in perspective, we mapped off the top rare disease launches through their first six quarters over the last 15 years. We found the crispy is one of the top rare disease launch is based on top line total product sales.

We've also generated the substantial revenue offsetting a price at a substantially lower than any of the other top rare disease drugs. As a result with successful ensure that paired with you our pricing as responsible allowing us to reach more patients, especially adult and achieve a positive financial outcome for the company. This approach is core to our philosophy.

Emil D. Kakkis: As a result, we have successfully ensured that payers view our pricing as responsible, allowing us to reach more patients, especially adults, and achieve a positive financial outcome for the company. This is an approach to the Corridor philosophy about improving access and total revenue by moderating rare disease pricing. Turning to Canada, we are seeing continued prescribing interest from physicians, and the number of reimbursed patients with private insurance has exceeded our expectations. More than half of Canadians have supplemental private insurance today, and the number of pediatric and adult patients who are receiving Chrispedia through their private insurance drug plans continues to grow.

About proving access and total revenue by moderating rare disease pricing.

Turning to Canada, we're seeing continued prescribing interest for physicians and the number of reimbursed patients with private insurance has exceeded our expectation.

More than half Canadians have supplement our private insurance today, and the number of pediatric and adult patients word field proceeded through their private insurance drug plans continues to grow.

Emil D. Kakkis: We also continue to pursue public reimbursement in Canada, which will take more time. Moving to Latin America, in Argentina and Colombia, the number of patients are reimbursed, name patient treatment continues to increase, and the feedback has been very positive. In Brazil, the demand has been strong, with a significant number of patients successfully navigating the comprehensive legal process and a few receiving reimbursed treatment to date. We're also seeking pricing and full reimbursement approved by the Ministry of Health to enable more rapid access for patients in Brazil. Ultimately, we believe there is significant potential for CRISPR-CoV-2 in Latin America, with growing demand in multiple countries for the product.

We also continue to pursue public reimbursement in Canada, which will take more time.

Moving to Latin America in Argentina, and Colombia. The number of patients are reimbursed named patient treatment continues to increase and the feedback has been very positive.

In Brazil, the demand has been strong with a significant number of patients successfully navigating the carbon some legal process and a few receiving reimbursed treatment today.

We're also seeking pricing at full reimbursement approval by the Ministry helped enable more rapid access for patients in Brazil.

Ultimately, we believe there is significant for Tesco crispy to in Latin America growing demand in multiple countries for the product.

Emil D. Kakkis: Briefly turning to MepSavvy, the therapy is approved in the United States, Europe, and Brazil, and demand continues to build gradually as typical for enzyme replacement therapy. We are also continuing reimbursement discussions with various government health authorities throughout the world. With that, I'll turn the call over to Shalini, who will provide a financial update. Thank you, Emil, and good afternoon, everyone.

Briefly turning to MEP savvy, the therapy approved in the United States, Europe, and Brazil, and demand continues to build gradual it's difficult for enzyme replacement therapies were also continuing reimbursement discussions various government health authorities throughout the world.

With that I'll turn the call over to show me, who will provide a financial update.

Thank you ammo and good afternoon, everyone earlier today, we issued a press release that included a financial update which I will briefly summarize.

Shalini Sharp: Earlier today, we issued a press release that included a financial update, which I will briefly summarize. Ultragenyx's total net revenue for the 12-month period ending December 31st, 2019, was $103.7 million, and for the fourth quarter of 2019, was $35.6 million. The following is a product by product breakdown of these figures.

Oh Genex's total net revenue for the 12 month period, ending December 31st 2019, with $103.7 million and for the fourth quarter play 19 were 35.6 million dollar.

The following is a product by product breakdown of these figures.

Shalini Sharp: For CRISPRIDA, during the year ended December 31, 2019, we recognized total revenue of $87.3 million. This includes $74.9 million in collaboration revenue in the U.S. Profit Share Territory and Canada, and $8.1 million in royalty revenue in the European Territory from our collaboration and license agreement with our partner, Kiowa Kirin, or KKC. Net product sales for KrisVita in other regions totaled $4.3 million. Total Chris Rita revenue recognized by Ultragenyx for the 3 months ended December 31, 2019 was $29.9 million.

Kristina during the year ended December 31st lien 19, we recognize total revenue of $87.3 million.

This includes $74.9 million and collaboration revenue in the U.S. profit share territory in Canada, and $8.1 million and royalty revenue in the European territories from our collaboration and license agreement with our partner Karen RK Casey.

Net product sales for Kristina in other regions totaled $4.3 million.

Total Chris me that revenue recognized Ultragenyx a three month ended December 31st 2019 was $29.9 million. This includes $26.1 million and collaboration revenue in the North American profit share territory $2.2 million in royalty revenue on Casey sales in the European territory, and $1.6 million and net product revenue in others.

Shalini Sharp: This includes $26.1 million in collaboration revenue in the North American Profit Share Territory, $2.2 million in royalty revenue on KKC sales in the European Territory, and $1.6 million in net product revenue in other regions. Recall that there was a significant order that was placed on the last day of the third quarter of 2019, which was recognized in the fourth quarter due to shipping terms. Depending on ordering patterns, we continue to expect fluctuations in our quarterly revenue recognition from time to time. In Latin America, full reimbursement takes place on a country-by-country basis and can take some time, which can be further complicated by economic and political instability. Total 2019 CRISPR data sales in North America, Europe, and Latin America, which are shared with KKC, were approximately $104 million for the fourth quarter and approximately $316 million for the full year of 2019. MEPCENTI product revenue for the fourth quarter of 2019 was $4.4 million, and it was $12.6 million for the year.

Region.

Recall, there was significant order that was placed on the last day of the third quarter 2019, which was recognized in the fourth quarter due to shipping term.

Depending on ordering patterns, we continue to expect fluctuations in our quarter to quarter revenue recognition from time to time.

In Latin America full reimbursement takes place on a country by country basis, and can take some time, which can be further complicated by economic and political instability.

Total 2019, Kristina sales in North America, Europe, and Latin America, which are shared with K Casey were approximately $104 million for the fourth quarter and approximately $316 million to the full year 2019.

Lets any product revenue for the fourth quarter play 19, with $4.4 million and was $12.6 million for the year.

Due to the rarity of MPS seven we expect revenues for this product to be somewhat irregular from quarter to quarter and to build very gradually as is typical for enzyme replacement therapy.

You also seven named patient revenue in the fourth quarter with $1.2 million and were $3.3 million for the year.

Shalini Sharp: Due to the rarity of MPS7, we expect revenues for this product to be somewhat irregular from quarter to quarter and to build very gradually, as is typical for enzyme replacement therapies. UXO-7 named patient revenue in the fourth quarter was $1.2 million, and was $3.3 million for the year. We also recognize $0.1 million in revenue this quarter and $0.5 million for the year from our research agreement with Bayer. As we have stated previously, we continue to expect revenue from this agreement to be minimal going forward. Our total operating expenses were $130 million for the fourth quarter of 2019.

We also recognized zero point $1 million in revenue this quarter and zero point $5 million for the year from our research agreement with bear.

As we've stated previously we continue to expect revenue from this agreement to be minimal going forward.

Our total operating expenses were $130 million for the fourth quarter of 29 team for the past several quarters after 20% of our operating expenses, excluding expenses related to business development transactions like genetics and Arcturus have consisted of noncash item.

Our research and development cost for 83.9 $83.1 million, we expect our R&D cost increased moderately overtime as we continue advancing product candidates from early critical preclinical development into early and pivotal clinical studies.

Shalini Sharp: For the past several quarters, up to 20% of our operating expenses, excluding expenses related to business development transactions like genetics and Arcturus, have consisted of non-cash items. Our research and development costs were $83.1 million. We expect our R&D costs to increase moderately over time as we continue advancing product candidates from early preclinical development into early and pivotal clinical studies. Our SG&A costs in Q4 were $41.9 million.

Our S DNA costs in Q4 were $41.9 million.

We expect us DNA to increased moderately overtime as we support our commercial program simultaneously launching across multiple geographies.

Our cost of sales were $5.1 million for the fourth quarter 2019.

This includes a 3.8 million dollar reserve unmet savvy inventory that did not meet our quality standards.

We call in the third quarter of 2019, there was a $1.9 million reserve for a similar issue.

We expect that a majority of these reserves will be recovered from our supplier and we do not currently anticipate any supply interruptions or future reserves related to this issue.

Shalini Sharp: We expect SG&A to increase moderately over time as we support our commercial program simultaneously launching across multiple geographies. Our cost of sales was $5.1 million for the fourth quarter of 2019. This includes a $3.8 million reserve on Metsevi inventory that did not meet our quality standards. Recall that in the third quarter of 2019, there was a $1.9 million reserve for a similar issue. We expect that a majority of these reserves will be recovered from our supplier, and we do not currently anticipate any supply interruptions or future reserves related to this. The net loss for the fourth quarter of 2019 was $93.8 million, or $1.62 per share, basic and diluted, compared with a net loss of $87.8 million, or $1.73 per share, basic and diluted, for the fourth quarter of 2018. For the year ended December 31, 2019, its net loss was $402.7 million, or $7.12 per share, basic and diluted, compared with a net loss for the same period in 2018 of $197.6 million, or $3.97 per share, basic and diluted.

Net loss for the fourth quarter of 29 team was $93.8 million or $1.62 cents per share basic and diluted compared with a net loss of $87.8 million or $1.73 cents per share basic and diluted for the fourth quarter of 2018.

For the year ended December 31, 2019, net loss was $402.7 million.

$7.12 per share basic and diluted compared with a net loss for the same period in 2018 of $197.6 million or three dollarsninety seven cents per share basic and diluted.

The net loss for the fourth quarter of 2019 and for the year ended December 31st 2019 includes unrealized gains of $1.4 million and $13.4 million, respectively from their fair value adjustment on the investment in Arteris equity Securities.

Net loss for the full year ended 2018 was reduced by $170.3 million due to sales and priority review doctors.

For the year ended December 31st plane 19 cash used in operations were $345.4 million. This includes $20 million for this next upfront payment in the third quarter of 2019 $15.6 million for the amended Arcturus license rights in the second quarter play 19, as well as adjustments for significant non cash charges.

Including stock based compensation expense of $82 million.

Shalini Sharp: The net loss for the fourth quarter of 2019 and for the year ended December 31, 2019, includes unrealized gains of $1.4 million and $13.4 million, respectively, from the fair value adjustment on the investment in Arcturus Equity Security. The net loss for the full year end of 2018 was reduced by $170.3 million due to sales of priority review vouchers. For the year ended December 31st, 2019, cash used in operations was $345.4 million.

We ended the fourth quarter, 2019, with $760.4 million and cash cash equivalents and available for sale investments.

This includes proceeds at $320 million, we received from the sale of the company's royalty interest in Kristina in the European territory.

Moving to our guidance for 2020, we continue to expect to Chris meta revenue to Ultragenyx in our territories to be between $125 million and $140 million.

Those territories, including North America, Latin America in Turkey, and exclude the EU royalty at this was monetized in the transaction that was completed with royalty pharma that was announced in December 2019.

Shalini Sharp: This includes $20 million for the Genetics Upfront Payment in the third quarter of 2019, $15.6 million for the amended Arcturus license rights in the second quarter of 2019, as well as adjustments for significant non-cash charges, including stock-based compensation expense of $82 million. We ended the fourth quarter of 2019 with $760.4 million in cash, cash equivalents, and available for sale investments. This includes proceeds of $320 million we received from the sale of the company's royalty interest in Krasita in the European territory.

We expect the pace of our revenue growth to significantly exceed the pace of expense growth and therefore, we are projecting a greater than 20% decrease in net cash burn which includes net cash used in operations as well as capital expenditures.

Thank you Shirley I'll spend a few minutes on our clinical and preclinical programs before turning to the upcoming catalysts.

I'll start with crispy deferred tumor induced osteomalacia, a rare disease for which approximately half the patients have tumors that cannot be surgically removed and lean limit with no other current treatment options.

Shalini Sharp: Moving to our guidance for 2020, we continue to expect the CRISP VITA revenue for Ultragenyx in our territories to be between $125 million and $140 million. Those territories include North America, Latin America, and Turkey and exclude the EU royalty, as this was monetized in the transaction that was completed with Royalty Pharma that was announced in December 2019. We expect the pace of our revenue growth to significantly exceed the pace of expense growth, and therefore, we are projecting a greater than 20% decrease in net cash burn, which includes net cash use in operations as well as capital expenditure. Thank you, Shalini.

The summer of last year, we submitted a supplemental biologic license application ahead of our anticipated timing, we expect to hear back from the FDA submission acceptance and review designation later this month.

Turning to you X or seven four LC Apio D. A devastating sub diseases with a high mortality rate despite newborn screening and current use of MCT oil.

Yes. She is currently reviewing the new drug application to set up due to date for July 31st 2020.

As we've discussed before the update does not currently planned hold Advisory Committee meeting discuss the application.

The review process continues on track and we expect to review decision by the PDUFA date.

Emil D. Kakkis: I'll spend a few minutes on our clinical and preclinical programs before turning to the upcoming catalyst. I'll start with CRISPR for tumor-induced osteomalacia, a rare disease for which approximately half of patients have tumors that cannot be surgically removed, leaving them with no other current treatment options. In December of last year, we submitted a supplemental biologic license application ahead of our anticipated timing. We expect to hear back from FDA on submission acceptance and review designation later this month. Turning to UX007 for LC-FAOD, a devastating set of diseases with a high mortality rate despite numerous screenings and current use of MCT oil, the FDA is currently reviewing the new drug application and has set up a due date for July 31, 2020. As we've discussed before, the FDA does not currently plan to hold an advisory committee meeting to discuss the application.

In addition to the progress in U.S.. We've also submitted a marketing authorization application to regulatory authorities in Brazil, and we continue to schedule other regulatory authorities in the you in Canada.

Based on our experiences we know that there are a lot of patients LCASD, who are not doing well on current treatment of MCT oil that are seeking new treatment options in France alone. For example, there were originally only a few doctors requesting yield of seven via the ATM named patient program now there are approximately 20 physicians treating through.

For patients with LCFS Cody, who are using you echo seven through that named patient program.

We expect there to be significant interest the project if approved but as with many inborn error products. We believe we will build steadily and will take time.

In the developed World. There are approximately 8000 to 14000 patients with LC facility and we own the worldwide rights to the product.

Moving to Dcxthree, a one our gene therapy program for Argentine Transco families deficiency or Otcs deficiency.

Emil D. Kakkis: The review process continues on track, and we expect a review decision by the PDUFA date. In addition to the progress in the U.S., we've also submitted a marketing authorization application to regulatory authorities in Brazil, and we continue discussions with other regulatory authorities in the EU and Canada. Based on our experiences, we know that there are a lot of patients with LC-FEOD who are not doing well on the current treatment of MCT oil and are seeking new treatment options.

I would you see deficiency is an X linked to recycle the sort of that limits the body's ability tough by ammonia into urea. These patients can quickly deteriorate into full metabolic crisis, causing neurologic deficit hospitalization coma in some cases depth.

Generally reported positive data from dose cohort three and longer term data from the first two cohort of our Otcs study.

The core three we're seeing responses from all three patients to the patients are confirm responders in the third patient appears to be responded as well, though we will wait until we have longer term to confirm this.

Emil D. Kakkis: In France alone, for example, there were originally only a few doctors requesting UX-07 via the ATU named patient program. Now there are approximately 20 physicians treating 34 patients with LC-FOD who are using UX-07 through that named patient program. We expect there to be significant interest in the product if approved, but as with many inborn error products, we believe it will build steadily and will take time. In the developed world, there are approximately 8,000 to 14,000 patients with LC FEOD, and we own the worldwide rights to the product. Moving to DTX-301, our gene therapy program for Ornithine Transcarfamilase Deficiency, or OTC deficiency. ODC deficiency is an X-linked urea cycle disorder that limits the body's ability to detoxify ammonia into urea.

In total up to six of the nine patients have responded importantly, three patients have come off their ammonia scavenger medications and liberalize their diet. We consider these patients complete responders in these patients appear to be metabolic lead cured.

Based on these days in the favorable safety profile, we believe the cohort three one E 13, GC per kilogram dose is the appropriate dose level, we're seeing a more consistent response across patients and we believe this higher doses achieved the adequate level therapeutic effect.

From here, we will enroll a fourth cohort at the same doses coordthree. This time using prophylactic steroids rather than reactive series.

We believe this low hands the level of expression often provide more consistent expression.

Emil D. Kakkis: These patients can quickly deteriorate into full metabolic crisis, causing neurologic deficits, hospitalization, and, in some cases, death. In January, we reported positive data from Dose Cohort 3 and longer-term data from the first two cohorts of our OTC study. In cohort 3, we are seeing responses from all three patients. Two of the patients are confirmed responders, and the third patient appears to be a responder as well, though we will wait until we have longer-term data to confirm this. In total, up to six of the nine patients have responded. Importantly, three patients have come off their ammonia scavenger medications and liberalized their diets.

We expect days in the second half of 2020 from this cohort.

The positive will proceed to dose three more patients the cycle to discuss advised of the phase three study endpoints with regulators.

Based on our ongoing conversation with FDA expected ammonia will be a primary endpoint.

Update considers ammonia validated clinical endpoint and they've approved other products based on ammonia.

Switching to detect for one or gene therapy program and Glaxo in store disease type one a disease that leads to severe and sometimes life threatening hypoglycemia.

Page with GFT, one day today have to take cornstarch every three to four hours, which can keep glucose levels up but it does not address the disease and as long term consequences.

Well for course, our therapy has save lives and improved health is not a normalized by any measure of patients or their parents live in fear of death, the mid single dose of corn starch.

Emil D. Kakkis: We consider these patients complete responders, and these patients appear to be metabolically cured. Based on these data and the favorable safety profile, we believe the cohort 3, 1E13Gc per kilogram dose is the appropriate dose level. We're seeing a more consistent response across patients, and we believe this higher dose has achieved the adequate level of therapeutic effect. From here, we will enroll a fourth cohort at the same dose as cohort 3, this time using prophylactic steroids rather than reactive steroids. We believe this will enhance the level of expression and also provide more consistent expression.

Today, we show data from the first two cohorts of all six patients demonstrating a meaningful clinical response to the therapy of the two each 12 and 60 12 dose levels.

This includes improvement in glucose control show by time to hypoglycemia reductions in corn starch requirements for all patients.

The second dose cohort all patient showed a meaningful reduction in collection storage and improvements in metabolism. These days data indicate the court two doses showing greater trends gene expression in our view that these patients have greatly improves glucose control the are winding down their storage requirements and we think we have treatment that could change the future GST one a pay.

Emil D. Kakkis: We expect data in the second half of 2020 from this cohort, and Deposit will proceed to dose three more patients and simultaneously discuss the design of the Phase 3 study and endpoints with regulators. Based on our ongoing conversation with the FDA, we expect that ammonia will be a primary endpoint. The FDA considers ammonia a validated clinical endpoint, and they've approved other products based on ammonia. Switching to DTX-401, our gene therapy program in glycogen storage disease type 1A, a disease that leads to severe and sometimes life-threatening hypoglycemia. Patients with GST1A today have to take cornstarch every three to four hours, which can keep glucose levels up, but it does not address the disease and its long-term consequences. While cornstarch therapy has saved lives and improved health, it is not a normal life by any measure, and patients or their parents live in fear of death if they miss a single dose of cornstarch.

Patients.

We've now moved to a confirmatory cohort of three patients at the same dose and our simultaneously having discussion with FDA above the phase three study.

We expect to have data from the confirmatory cohort in the first half of 2020, and we could be in position then to begin phase three in the second half 2020.

I will also touch on our agreement with the gene genetics bio therapeutics to advance Gtx, one owed to an end to since all the nucleotide for the treatment of Andrew with syndrome.

Andrew when the devastating neurologic disease that affects approximately 60000 patients worldwide and there are no approved treatment options today.

Diseases Nondairy regenerative. So there is potential diverse some disease symptoms, which include speech cognitive impairment seizures, a taxi and sleep dysfunction.

As a result, we think engagement is one of the disease in neurology that could benefit most from a treatment.

The disease mechanism is well understood and those are well valid class of can target the disease directly.

Emil D. Kakkis: Today, we've shown data from the first two cohorts with all six patients demonstrating a meaningful clinical response to the therapy at the 2E12 and 6E12 dose levels. This includes improvement in glucose control shown by time to hypoglycemia reductions in corn starch requirements for all patients. In the second dose cohort, all patients showed a meaningful reduction in glycogen storage and improvements in metabolism. These data indicate that the CoRT2 dose is showing greater transgene expression, and our view is that these patients have greatly improved glucose control. They are weaning down their starch requirements, and we think we have a treatment that could change the future for a GSD1A patient. We've now moved to a confirmatory cohort of three patients at the same dose and are simultaneously having a discussion with the FDA about the phase 3 study.

We believe the team of generics have developed very potent this specific differentiated antisense oligonucleotides, we're excited to partner with this group.

I'd for this product has no active index has received RFP or institutional review board approval for the first study site.

We expect enrollment in the phase one to say to begin the coming months.

Following the acceptance in the we paid the 25 million dollar welcome to obtain the option to maintain the option to acquire the company until the earlier 30 months. After the first patients dose or 90 days. After the results are available from the phase one two study.

The last profile discusses Dts tool one for hemophilia a program has partnered with fire the news and material from our proprietary Hewlett manufacturing platform.

The European Association them Hemophilia Allied disorders meeting last week bare presented data on first to low dose cohorts of the phase one two study.

All four patients showed a response with three of the four patients showing clinically meaningful increases in factor eight levels.

Emil D. Kakkis: We expect to have data from the confirmatory cohort in the first half of 2020, and we could be in position then to begin phase three in the second half of 2020. I will also touch on our agreement with Genetics Biotherapeutics to advance GTX-102, an antisense organucleotide for the treatment of Angelman Syndrome. Angeman is a devastating neurological disease that affects approximately 60,000 patients worldwide, and there are no approved treatment options today. Angeman is non-neurodegenerative, so there is potential to reverse some disease symptoms, which include speech, condom impairment, seizures, ataxia, and sleep dysfunction. As a result, we think Angeman is one of the diseases in neurology that could benefit most from a treatment.

One patient Cort, one achieved clinically meaningful factory levels and has experienced only four believe posttreatment compared to 99 leads the prior year.

Both patients and dose cohort to achieve clinically meaningful factory levels out to 24 and 30 weeks.

Patient for core to has been bleed free and treatment free for up to seven months of of the data cut off.

The same patient had a mild is LTSS elevation. There were managed with a short tapering course of steroids and the other patients have not required steroids at all.

A third high dose cohort hasn't dosing, we expect to see additional updates this year well buyer is responsible for the clinical execution of the program. We're pleased to see that our HILA manufacturing platform validated and look forward to continue progress with the program. As a reminder, we are eligible to receive milestones the royalty payments for buyer for this program.

Emil D. Kakkis: The disease mechanism is well understood, and ASOs are a well-valued class that can target the disease directly. We believe that the team at Genetics has developed a very potent and specific differentiated antisense oligonucleotide, and we are excited to partner with this group. The IND for this program is now active, and GenX has received IRB or Institutional Review Board approval for the first study site. We expect enrollment in the Phase 1-2 study to begin in the coming months. Following the acceptance of the IND, we paid a $25 million milestone to maintain the option to acquire the company until the earlier of 30 months after the first patient's dose or 90 days after the results are available from the Phase I-II study.

I'll spend a few months now discussing a number of important milestones the coming month, there will continue to drive our progress and then we can move to Q a day.

For crispy to.

In 2020 was sick revenue between 125 to 140 million across North America, Latin America, and Turkey, representing a 58% to 77% increase versus 2019 same territories.

This will be driven by continued strong performance in us and expansion of our region Latin America through named patient sales and pending regulatory decisions as well as growth in Canada.

With our readiness mish were to see to for the treatment of Tio. We are looking expanding procedures. This additional patient population, while there are fewer pace with tio, there's often a very urgent need for treatment. If approved this indication. We believe proceeded therapy will be adopted over phosphate therapy.

For us so seven we will continue to work with the FDA. The route view, our NDA working towards the PDUFA date of July 31st 2020. The review is progressing well and we look forward to being able to provide the stream to many more patients with LCFS Cody.

Emil D. Kakkis: The last program I'll discuss is DTX-201 for hemophilia A, a program that's partnered with BioArk and uses material from our proprietary HeLa manufacturing platform. At the European Association of Hemophilia and Allied Disorders meeting last week, Bayer presented data on the first two low-dose cohorts of the Phase I-II study. All four patients showed a response, with three of the four patients showing clinically meaningful increases in factor VIII levels. One patient in court, one achieved clinically meaningful fat grade levels and experienced only four bleeds post-treatment compared to 99 bleeds the prior year. Both patients in Dose Cohort 2 achieved clinically meaningful factor VIII levels out to 24 and 30 weeks. A patient for a court who has been bleed free and treatment free for up to seven months of the data cut off. The same patient had a mild ALT-ESD elevation that was managed with a short tapering course of steroids, and the other patients have not required steroids at all.

For the gene therapy program, we have shown strong data for our two programs and GST, one day and ODC and at both ends we believe we found the appropriate dose.

GFT one a program will have a data readout from the diversity cohort in the first half and the OTA fee program will read out in the second half.

We are simultaneously, having discussion with FDA about the phase three studies for both programs.

The buyer hemophilia approaches bridal us with the first clinical data using material from our proprietary HILA platform. Our Wilson disease program will use this HILA manufacturing system, what enters the clinic and we are targeting and I'd for this program by the end of 2020.

We will also provide more updates on the gtx, one or two azo program for Angelman as a program begins to enroll patients.

To summarize briefly our commercial team continues to execute an extremely high level vacant Chris either one of the top rare disease launches.

We continue efforts with TV to end Meps heavy as well have to more potential launches fear set us up to grow substantially grow our commercial business.

In 2019, we had annual revenue exceeding $100 million for the first time with substantial growth expected in 2020.

Emil D. Kakkis: A third high-dose cohort has been dosed, and we expect to see additional updates this year. While Bayer is responsible for the clinical execution of this program, we are pleased to see that our HeLa manufacturing platform is validated and look forward to continued progress with the program. As a reminder, we are eligible to receive milestones and royalty payments from Bayer for this program. I'll spend a few minutes now discussing a number of important milestones in the coming months that will continue to drive our progress, and then we can move to Q&A with Chris Vita. In 2020, we expect revenue between $125 to $140 million across North America, Latin America, and Turkey, representing a 58% to 77% increase versus 2019 in the same territories.

We're now well capitalize was 750 million in cash equivalents when you combine that with the financial discipline, we are applying and expect to reduce net cash burn in 2020.

This puts us in good position to driver clinical programs forward.

Gene therapy programs are advancing through confirm to dose cohort through phase three studies and the age when a wilsons. These programs are both large indication opportunities that are nearing clinic with diverse set of early stage product candidates to follow.

We have become a diversified rare disease company and we'll continue to grow we're constantly innovating adapting rare disease drug development strategies trial designs endpoints working with regulators establish a more efficient model for rare to see drug development as well as evolving the way we commercialized product in the in these indications and the this efficiently managed the cost structure.

These are just some of things we do each day near the foundation, we built an exceptional rare disease company.

With that let's move your questions. Operator can you. Please provide instructions for the Q and a portion of call.

Emil D. Kakkis: This will be driven by continued strong performance in the U.S. and expansion of our reach in Latin America through named patient sales and pending regulatory decisions as well as growth in Canada. With our Radcliffe-Mishwak procedure for the treatment of TIO, we are looking to expand procedures in this additional patient population. While there are fewer patients with TIO, there's often a very urgent need for treatment.

Yes, Sir as a reminder to ask the question you when you press Star one on your telephone to withdraw your question Mr pounds.

And the interest with current please limit yourself to one question and one follow up.

Please stand by only component acumen a roster.

And our first question comes from line of Gena Wang from Barclays You may begin.

Thank you for taking my questions and I wanted to congratulate you on the recording.

Emil D. Kakkis: If approved in this indication, we believe CREFETA therapy will be adopted over phosphate therapy. For UX07, we will continue to work with the FDA to review our NDA, working towards the production date of July 31, 2020. The review is progressing well, and we look forward to being able to provide this treatment to many more patients with LC-FOD. For the gene therapy programs, we have shown strong data for our two programs in GST1A and OTC, and in both studies, we believe we have found the appropriate dose. The GSD-1A program will have data readout from the Diversity Cohort in the first half, and the OTT program will read out in the second half. We are simultaneously having discussions with FDA about the Phase III studies for both programs. The Bayer Hemophilia A Program has provided us with the first clinical data using material from our proprietary HeLa platform.

Two questions. The first one is regarding the Christie 2020 revenue guidance.

Just wondering 50% to 77% growth is mainly driven by us gross or geographic expansion how much growth assumption was butane full in Latin America. My second question is regarding that and human single.

Could you walk through the phase one trial design.

In terms of initial dose and how would you dose escalate.

And what kind of data will lead your decision to acquire.

Yes.

Great. So on the crispy the launch growth as Sean do you want to answer that particular, one of the numbers sure Yeah no. Thanks for the question Gina and.

Emil D. Kakkis: Our Wilson Disease Program will use this HeLa manufacturing system when it enters the clinic, and we are targeting I&D for this program by the end of 2020. We'll also provide more updates on the GTX-102 ASO program for Angelman as the program begins to enroll patients. To summarize briefly, our commercial team continues to execute at an extremely high level, making CrisVita one of the top rare disease launches. Continued efforts with Kruzita and Metsevi, as well as two more potential launches this year, set us up to substantially grow our commercial business. In 2019, we had annual revenue exceeding $100 million for the first time, with substantial growth expected in 2020. We're now well capitalized with $760 million in cash and equivalents.

As has been the case, so far North America, the vast majority of our revenue expectations.

And that continues to be the case during 2020, although we expect the other territories to start to become more and more significant overtime.

Hey, good so on the Angel and program I don't think I can go through the entire clinical protocol on the call today, just would take too much time.

But what I can describe for you is that this design basically will take.

Children up to four to 17 and basically they are going to start at a low dose and then be able to tighter each patient up quickly to therapeutic dose levels.

Within just a few doses.

And as the first court gets through look safe than the next quarter will start at a higher dose in the next quarter to higher dose will be about 20 patients.

In these co dose cohorts, but all the patients will probably end up one of two.

Emil D. Kakkis: When you combine it with the financial discipline we're applying and expect to reduce net cash burn in 2020, this puts us in a good position to drive our clinical programs forward. Our gene therapy programs are advancing through confirmatory dose cohorts through phase 3 studies, and the Angeman and Wilson disease programs are both large indication opportunities that are nearing the clinic, with a diverse set of early stage product candidates to follow. We have become a diversified rare disease company and will continue to grow. We're constantly innovating, adapting rare disease drug development strategies, trial designs, and endpoints, working with regulators to establish a more efficient model for rare disease drug development, as well as evolving the way we commercialize products in these indications and efficiently manage the cost structure.

Therapeutic dose levels.

And we'll be able to evaluate than both therapy efficacy as well as safety at those two.

Therapeutic dose levels.

So it will be a very more rapid adaptive design, which is certainly our preference and frankly was supported requested to some grew by the FDA as well to genetics teams that an excellent job of putting that plan together and we're excited to see the site open things beginning.

Thank you.

Thank you and our next question comes from line.

Moreover from Cowen.

You may begin.

Hi, Thanks for taking the question I maybe of a couple Shelby may be just for you just so we know and we get the models right. So it looks like the European royalty will still be recorded but as a non revenue.

Im sorry, noncash revenue so that is it still contributing to earnings in a point and would use Vince showed a show us the GAAP to non-GAAP adjustments in that I've, a follow up as well.

Emil D. Kakkis: These are just some of the things we do each day, and they are the foundation of why we built an exceptional rare disease company. With that, let's move to your questions. Operator, can you please provide instructions for the Q&A portion of the call? Yes, sir. As a reminder, to ask a question, you need to press star 1 on your telephone. To withdraw your question, press the pound key.

Sure. So thats correct. It is considered a non cash revenue item going forward it well technically part of our net income net loss as all of those calculations, but in a noncash item our guidance for 2020 did not include the royalty because at the noncash item.

Operator: In the interest of time, please limit yourself to one question and one follow-up. Please sign by while we compile the Q&A roster. And our first question will come from the line of Gena Wang from Barclays. You may begin. I. The first one is regarding the CRISPIDA 2020 Revenue Guidelines. Just wondering, the 58 to 77% growth, is that mainly driven by U.S. growth or geographic expansion? How much growth assumption was building for Latin America?

We have around actually receiving cash based revenues for at are no longer providing that as part of the guidance going forward.

Okay. So hopefully thats helpful. In terms of our plans in terms of how to make this more clear going forward. We are planning to segregate the noncash interest in noncash revenue on the income statements and I'd be very obvious to you where those items are coming from and as we go forward throughout the year, we will evaluate whether it makes sense.

To provide more different kinds of key performance metrics that might be helpful. Since street.

Gena Wang: My second question is regarding Andrew Mann syndrome. Could you walk through the phase one trial design in terms of initial dose and how would you escalate those? And what kind of data will lead your decision to acquire GeneTX? Great. So on CRISPI to launch growth, Shelly, do you want to answer that particular one? What are the numbers?

Okay.

Got it and then enables for you I mean, the guidance Doesnt include CIO, and maybe give us a little bit of the sense how into tio patients are accrual new diagnosed and to use to be about an assessment of how big that lock it could be.

Well I'll tell you the exact number two is hard to say, but we've we've talked about it being a 1000 2000, perhaps half of them being excisable, but I would say to you those are soft numbers in the true exact number it's hard to know all I can say as we have and getting a lot of interest inquiries about ti vo and so.

Shalini Sharp: Sure. Yeah, no. Thanks for the question, Gina. And as has been the case so far, North America is the vast majority of our revenue expectations, and that will continue to be the case during 2020.

We think but I would just put it clears the size of market is clearly are relatively small fraction of what you see with Chris FIDA.

Shalini Sharp: Although we expect the other territories to start to become more and more significant over time, very good. So on the ANGEL1 program, I don't think I can go through the entire clinical protocol on the call today. It just would take too much time.

On the plus side the patients often are really sick and so the urgency to treat will be higher.

So hopefully that gives you a rough idea, but I would say our confidence around the exact number is you know is less.

But it's in that ballpark.

Emil D. Kakkis: But what I can describe for you is that this design basically will take children, you know, up to 4 to 17. And basically, they're going to start at a low dose and then be able to titrate each patient up quickly to therapeutic dose levels within just a few doses. And as the first cohort gets through and looks safe, and the next cohort starts at a higher dose, and the next cohort at a higher dose, there will be about 20 patients in these dose cohorts, but all the patients will probably end up on one of two therapeutic dose levels, and we'll be able to evaluate both therapy efficacy as well as safety at those two therapeutic dose levels. So it'll be a very more rapid, adaptive design, which The Genetics team has done an excellent job of putting that plan together, and we're excited to see the site open and things begin. Thank you. Thank you. And our next question comes from the line of Yaron Werber from Calen. You may begin. Hi, thanks for taking the question. I may have a couple.

Okay, and maybe just a final question on Angelman up now that.

Program is in the clinic in that business is really a super interesting program that preclinical data looks really good and so the question is in terms of the clinical assessment and this is obviously a phase one too, but what's the latest thinking about how to put together some kind of is there a composite or a.

Disease based metric or sort of a multi scale domain assessments for angelman.

Well I agree with you the instrument.

Is it an incredible opportunity and I think the science has been really solid and so when you look across what happens as usual and patients covered nearly five different domains of function and so the strategy is how would you figure out when you have a variable set of domains for this disease and we have certainly pioneered the use of multi.

The main responder the seasons, one way to do that that were involved looking at five different endpoints lets say sleep.

Speech cognition gate seizures.

As each individual domain the patients responded the domain the score when or if they did get worse in the score a decline you basically add up the wins across the patients. We've shown this strategy can allow you to look at heterogeneous diseases and gain substantially more power. So it may be approach, we would use we're still talking with our genetic colleagues.

Yaron Benjamin Werber: Shalini, maybe just for you, just so we know and we get the models right, so it looks like the European world will still be recorded but as a non-revenue, sorry, non-cash revenue, so is it still contributing to earnings at that point, and would you then sort of show us a gap to non-gap adjustment? And then I have a follow-up as well. Sure, so that's correct. However, it is considered a non-cash revenue item going forward. It will technically be part of our net income, net loss, EPS, and all of those calculations, but it is a non-cash item.

The exact strategy for a pivotal study I think the first thing we learn from phase. One two is is the drug safe does it help patients for the fundamental way.

As we learn from that we'll be able to go forward, but we think it's important to treat.

Shalini Sharp: Our guidance for 2020 did not include the EU royalty because it's a non-cash item. So, because we're not actually receiving cash-based revenues for it, we're no longer providing that as part of the guidance going forward. So hopefully that's helpful. In terms of our plans, in terms of how to make this more clear going forward, we are planning to segregate the non-cash interest and non-cash revenue on the income statement, so that would be very obvious to you where those items are coming from. And as we go forward throughout the year, we will evaluate whether it makes sense to provide more different kinds of key performance metrics that might be helpful to the street. Okay.

As many are all of the major manifestation.

And but at this point, we can't be sure what will happen until we get more data, but we're excited to see it happening and the prospect of change in future range. One syndrome being part of that is very exciting all of us here at Ultragenyx.

Thank you.

Thank you and our next question will come from the line of Joseph Schwartz from SVB Leerink you may begin.

Hi, I'm sure you parks dialing in for John Thank you for taking your question marks our first question has.

It is encouraging.

Our April.

You're expecting to reduce your operating expense this year as compared to last year I'm could you provide any color to help us understand how you'll be able to achieve this fall you expand your development and marketing initiatives in a variety of territories.

Emil D. Kakkis: And then Emil, for you, I mean, the guidance does include TIO. And maybe you could give us a little bit of a sense of how many TIO patients are currently diagnosed in the US? So we have an assessment of how big that market could be. Well, I'll tell you the exact number of TIOs is hard to say, but we've talked about it being 1,000, 2,000, and perhaps half of them being excisable. But I would say to you those are soft numbers, and the true exact number is hard to know.

Thank you it is amazing isn't it but let's be clear. We're we talked about was net cash for I'll, let Charlie speak to differ but I would put out you. There's some fundamental things we do that are unique to us. So I'll just touch on that for example that our whole post marketing programs are based on the single study called these marketing program. The reason I have some.

400, as both Chris speed and met savvy R&D costs are falling.

Precipitously following the approval the program because the cost of the DMP is more modest, but importantly in well spent but we've eliminated the need for multiple other programs because most companies have rising R&D expenses for our product after approval that ends up causing a problem and how you manage opex by that following it allows us to re.

Emil D. Kakkis: All I can say is we have been getting a lot of interest and inquiries about TIO. And so we think, but I would just put it clear that the size of the market is clearly a relatively small fraction of what you see with CRISPR-Vita. On the plus side, the patients are often really sick, and so the urgency to treat them will be higher. So hopefully, that gives you a rough idea, but I would say our confidence around the exact number is less, but it's in that ballpark.

Allocate resources and to manage our burn well I'll, let shortly that explain a little more of what we said about opex versus cash net usage.

Right. So so we have not said that operating expenses are expected to decrease in 2020, what we have said that they are expected to increase modestly in 2020, but that the pace of revenue growth for our exceed the pace of Opex growth and therefore, the net cash burn expected for 2020 to be more than 20% lower than in 29.

Emil D. Kakkis: Okay, and maybe just a final question on Angelman, now that that program is in the clinic, and this is really a super interesting program, that preclinical data looks really good, and so the question is, in terms of the clinical assessment, and this is obviously a Phase I-II, what's the latest thinking about how to put together some kind of either a composite or a disease-based metric or sort of a multi-scale Well, I agree with you that Angelman is an incredible opportunity, and I think the science has been really solid. And so when you look across what happens to individual patients, it covers really five different domains of function. And so the strategy is how would you figure it out when you have a variable set of domains for this disease?

Team and we have not had an opex will be decreasing the here and I think one ml described to you at on a per program basis for commercial programs, where we are able to reduce the operating expenses, particularly on the R&D side.

And as result of that we're able to absorb more new R&D programs without increasing operating expense in total but in total across all of our programs and across R&D and SDN and we do expect modest increases during 2020 and operating expense.

Okay, great. Thank you that's very helpful. And then my follow up question has to do with CTX for one.

Emil D. Kakkis: And we've certainly pioneered the use of multi-domain responder disease as one way to do that. That would involve looking at five different endpoints, let's say sleep. Speech, Cognition, Gait, and Seizures. In each individual domain, if patients respond in a domain, they score a win, or if they get worse, they score a decline, and you basically add up the wins across the patients. We've shown this strategy can allow you to look at heterogeneous diseases and gain substantially more power, so it may be an approach we would use. We're still talking with our genetics colleagues about the exact strategy for a PISL study, though. I think the first thing we need to learn from Phase I and II is whether the drug is safe and whether it helps patients in a fundamental way.

Is there a standardized protocol to decrease cornstarch in cohort three.

We ask because it seems like corn starch production is mainly up to the discretion of the trial sites physician and.

So we were just wondering if there will be more standardized protocols to decrease corn starts to have a more consistent.

Our results across all sites.

Thank you I think it's important to understand that the court starts reduction is a new thing and by the way when the trial will start as they weren't necessarily expecting that would decrease they thought they were just going to help patients have more steady glucose but.

Emil D. Kakkis: As we learn from that, we'll be able to go forward, but we think it's important to treat many or all of the major manifestations, but at this point, we can't be sure what will happen until we get some more data, but we're excited to see it happening, and the prospect of changing future Angelman Syndrome and being part of that is very exciting to all of us here at Ultragenyx. Thank you. Thank you. And our next question will come from Joseph Schwartz from SVB Lyric. You may begin. Hi, I'm Joori Park, dialing in for Joseph Schwartz.

It's pretty clear the can reduce their cards starch and so far there is not a defined protocol reviews. The let each we let each investigator tight trade each patient on a case by case basis than it's a little hard our protocol because these patient has a different amounts of starch, taking a different ways.

In.

And as various other assets to how they do it. So it actually is very would be challenged to have a single protocol, but your point as well taken I think as we look through our phase two data we will look at.

Joseph Patrick Schwartz: Thank you for taking our questions. Our first question has to do with your operating expenses. It's encouraging that you are able to, you know, you expect to reduce your operating expenses this year as compared to last year. Could you provide any color to help us understand how you will be able to achieve this while you expand your development and marketing initiatives in a variety of territories? Thank you. It is amazing, isn't it?

When to start tied trading starch and to try to create some parameters around that progression and particularly what target glucose is would you want to hit before Titrating I think thats. One thing we can kind of try to standardize so the progression tore reduction in starch is consistent across patients in groups, what I can say that were.

Emil D. Kakkis: But let's be clear. What we talked about was net cash flow. I'll let Shalini speak to that differently.

Shalini Sharp: But I will point out to you that there are some fundamental things we do that are unique to us. I'll just touch on that. For example, that our whole post-marketing programs are based on a single study called the Disease Monitoring Program. The reason that's important is that both CRISPR and MEPS-Sevi, R&D costs are falling. So, we have not said that operating expenses are expected to decrease in 2020. What we have said is that they're expected to increase modestly in 2020, but that the pace of revenue growth will far exceed the pace of OPEX growth. And therefore, the net cash burn expected for 2020 should be more than 20% lower than in 2019.

Please with is leased the earliest cohorts of tight traded down and we're pleased with the fact that we're able to greatly reduce cornstarch usage and still retain.

You guys seem yet for patients, but your is a good point, we're continuing to look at that but we don't we have now regimented currently in the phase two study.

Okay, great. Thank you very much.

And our next question comes from the line just seeing them on from Bank of America, you may begin.

Hi, good afternoon, thanks for taking my questions.

Just wanted to get a little bit more color you mentioned in your prepared remarks about pursuing Wilson's disease as part of your collaboration can you just give us a little bit more color on when that study will start and if we should expect to see any data on that in 2020, and then I have a follow up.

Shalini Sharp: So we have not said that OPEX will be decreasing this year. And I think what Emil described to you is that on a per program basis for commercial programs, we are able to reduce operating expenses, particularly on the R&D side. And as a result of that, we're able to absorb more new R&D programs without increasing operating expenses in total. But in total, across all of our programs and across R&D and SG&A, we do expect modest increases in operating expenses during 2020.

Yes. The Wilson program is not not a collaboration though it is our wholly owned program than the gene therapy program is currently in the manufacturing scale up stage in order to prepare the product using the HILA cell system, and we would expect to hit the Indian.

Emil D. Kakkis: Okay, great. Thank you. That's very helpful. And then my follow-up question has to do with CTX-401. Is there a standardized protocol to decrease cornstarch in Cohort 3? We ask because it seems like cornstarch reduction is mainly up to the discretion of the trial site physician, and so we were just wondering if there will be a more standardized protocol to decrease cornstarch to have a more consistent result across all sites.

Through the end of this year and.

Start to clinical program.

So thats kind of the general timeline and what were complete control of that program with our fully.

And at this point, we're looking to try to manage the development program will be meeting with the agency and we're trying to figure out the optimal combination of endpoints, but we will be looking for a streamlined development path and Thats something the agency has indicated they would support and that will something we'll have to talk through as we work through the year about works.

Emil D. Kakkis: Thank you. I think it's important to understand that the cornstarch reduction is a new thing. And by the way, when the trial was started, they weren't necessarily expecting that it would decrease. They thought they were just going to help the patients have more steady glucose. But it's pretty clear they can reduce their cornstarch.

About the potential to.

Treat Wilson disease, particularly because of such a large indication.

Okay I thought that was part of your license agreement with Gen X, maybe I was thinking about Oh, Oh is it was gen assuming the capsid.

Emil D. Kakkis: And so far, there's not been a defined protocol that we've used. We've let each investigator titrate each patient on a case-by-case basis. And it's a little hard to have a protocol because each patient has different amounts of starch taken in different ways and has various other aspects to how they do it. So it actually is very, would be challenging to have a single protocol. But your point is well taken. I think as we look through our phase two data, we will look at When to start titrating starch and to try to create some parameters around that progression, and particularly what target glucoses would you want to hit before titrating? I think that's one thing we can kind of try to standardize, so that the progression toward reduction in starch is consistent across patients and groups. What I can say that we're pleased with is that at least the earliest cohorts have titrated down, and we're pleased with the fact that we're able to greatly reduce cornstarch usage and still retain euglycemia for patients. But it's a good point.

Yes.

While there they license the caps into US, yes, but it's not really I thought you were talking about a partnership like the buyer with amazing.

I will return its license to the Capsids for all of rejects Cas is for.

For Wilson disease, So we have all of them.

Based on the original dimension license that we exercised.

Okay.

And then as it relates to the three on one program I know TC can you just talk about where you are with.

Treatment for that prophylactic steroid cohort.

What's the gaining factor and recruiting is patient.

Well, we from towards the end of last year were actually lining up patients for recruitment index cohort, but we do have to get through the DMC review and at the review and so those are some some regulatory steps that are ongoing but we have wind up patients and we believe the recruitment will go faster. This time, we had.

A slow period last year recruiting coordthree and we've ramped up the forces in our patient diagnosis program to tee up a lot more ODC patients.

Emil D. Kakkis: We're continuing to look at that, but we have not regimented it currently in the Phase II study. Okay, great. Thank you very much.

Earlier on so I feel we'll be able to handle that enrollment one well in the protocols approved and ready to run.

Tazeen Ahmad: And our next question comes from the line of Tazeen Ahmad from Bank of America. You may begin. Hi, good afternoon. Thanks for taking my questions. Emil, I just wanted to get a little bit more color.

Okay. Thanks, and then a quick last one if you if I may stay out the.

How should we be thinking about the size of the sales force and do you plan to expand beyond which you already have right now how many sales people do you currently have.

Emil D. Kakkis: You mentioned in your prepared remarks about pursuing Wilson disease as part of your collaboration. Can you just give us a little bit more color on when that study will start and if we should expect to see any data on that in 2020? And then I have a follow-up. Yeah, the Wilson program is not a collaboration, though. It is our fully owned program.

Well, our Chris feed a team will be staying dedicated to Chris FIDA. They won't be spending all time. This will be a separate team that will involve a small sales team and a likely a small coke coordinator team, which would be dietician typed group because the number of targets for efficacy or.

Emil D. Kakkis: And the program is currently in the manufacturing scale-up stage in order to prepare the product using the HeLa cell system. And we would expect to hit the IND through the end of this year and start the clinical program. So that's kind of the general timeline. But we're in complete control of that program. It's ours fully.

During the range of 160 metabolic centers versus more than 1000 for Chris fee that we think the scale of the field team could be UBS scaled. Similarly, so we expected to be a relatively small incremental step for us from a sales teams standpoint, and from an infrastructure standpoint look the ultra.

Emil D. Kakkis: And at this point, we're looking to try to manage the development program. We'll be meeting with the agency, and we're trying to figure out the optimal combination of endpoints. But we will be looking for a streamlined development path, and that's something the agency has indicated it would support. And that will be something we'll have to talk through as we work through the year. But we're excited about the potential to Treat Wealth and Disease, particularly because it's such a large indication. Okay, I thought that was part of your license agreement with Regenexx. But maybe I was mistaken about that. Oh. Oh, it was Genexx. You mean the CASTED.

Our team the handles reimbursement all that that will we'll be able to leverage our investment in the in that of the supply chain. Other things that we've already created so I think it will be a reasonably efficient addition to our portfolio and would not be an entirely.

New set of people for all aspects of commercialization.

And you've now said how big your current Salesforce is heavier.

Well the current field force is around 36, but there have been a few extras because we've added some special for more so it's probably closer to 40 now and that's the current USIO team, but there's also patient diagnosis team in the medical ferrous side, which is around.

Emil D. Kakkis: Yes. Yeah. Oh, well, they licensed the capsid to us, yes, but it's not really a... I thought you were talking about a partnership, like the buyer with EMA thing. Mm-hmm.

30 people.

And then we have myself as well, which we have really talk much about but do you feel.

Emil D. Kakkis: Right. We do have a Regenexx license to the capsids for all of Regenexx's capsids, for Wilson Disease. So we have all of them.

We would need with normally think was a field team is 36 for Chris FIDA.

Okay report on Paul Thank you.

And our next question on cost line on Maury Raycroft from Jefferies. Sir you may begin.

Emil D. Kakkis: Based on the original Dimension license that we exercised. Okay. And then as it relates to the 301 program and OTC, can you just talk about where you are with recruitment for the prophylactic steroid cohort? What's the gaining factor in recruiting? Well, we, from the, toward the end of last year, were actually lining up patients for recruitment in the next cohort, but we do have to get through the DMC review and FDA review, and so those are some regulatory steps that are ongoing, but we We had a slow period last year, recruiting cohort three, and we've ramped up the forces in our patient diagnosis program to tee up a lot more OTC patients earlier on, so I feel we'll be able to handle that enrollment when the protocol is approved and ready to run. Okay, thanks. And then a quick last one, if I may.

Hi, this is pricing falling filling in for Marty So for the Hemophilia program can you contextualize, how your program differentiates us from either he May program and how do you view this strategic opportunity.

Since like maybe and complete the first in class.

So the question is how does our he may program differentiated helping others, Yes, our program was better that's why.

The.

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I think the thing were this different about hours is.

The Avi that's being used.

Is the Navy eight clad E.

Variant and it has a relatively efficient capsid for delivery to the liver and we think we're seeing therapeutic levels achieved at 512, and 13 grade which is substantially lower than what you're seeing with the Biomarin 85, castings, which is no not to be as an affair.

Emil D. Kakkis: For SAOD, how should we be thinking about the size of the sales force, and do you plan to expand beyond what you already have right now? How many sales people do you currently have? Well, our CRISPR-Vita team will be staying dedicated to CRISPR-Vita. They won't be spending a lot of time.

And capsid the spark program was running at 212 wanting to a lower but it has had more inflammation. So the one differentiator I would see right now is that we're having at moderate titers clinically meaningful.

Emil D. Kakkis: This will be a separate team that will involve a small sales team and likely a small clinical coordinator team, which would be a dietician-type group. Because the number of targets for FEOD is more in the range of 160 metabolic centers versus more than 1,000 for CRISPR-Vita, we think the scale of the field team could be scaled similarly. So we expect it to be a relatively small incremental step for us from a sales team standpoint. And from an infrastructure standpoint, like the UltraCare team that handles reimbursement and all that, they will be able to leverage our investment in that and the supply chain and other things that we've already created. So I think it will be a reasonably efficient addition to our portfolio and would not be an entirely new set of people for all aspects of commercialization. And you've not said how big your current sales force is, have you? Well, the current field force is around 36, but there have been a few extras.

Backer eight produced with actually only one out of four patients being steroids, so without inflammation.

So we think there's some differentiation terms the combination of safety and dose that we're seeing and I think it puts it in position to be.

Credible opportunity that notwithstanding borrower in in their program with certainly well ahead of this program.

We think factory in hemophilia is a very large.

Opportunity. We also think that will take time that patients will not immediately jumped to do gene therapy.

And that there'll be plenty of time for an entrenched with an excellent safety and efficacy profile to be competitive in the space.

Thanks, that's helpful and prevented you executed at a seven has improved so lets you did the salesforce and commercialization efforts looked like it with a similar multi pronged approach at this FIDA.

Emil D. Kakkis: We've added some special four more, so it's probably closer to 40 now, and that's the current UCL team, but there's also a patient diagnosis team in the medical affairs side, which is around 30 people. And then we have MSLs as well, which we haven't really talked much about, but the UCL, who you would normally think of as a field team, is 36 people for Chris Fita. Okay, that Thank you. And our next question will come from the line of Maury Raycroft from Jefferies.

Well, yes. So there are some assets that will be the same for FCO D., we will have.

The patient diagnosis program will operate however, because it's a more narrow set of target sites that manage newborn screening of fees patients. The EMEA sales may take some of the load of patient diagnosis.

So the PD elds are out in the field could also find patients as they're out doing their work. So we will have a little bit of the PDL is helping the EMEA sales will be doing a lot of the patient during those work as well. So that part is somewhat similar because FIDA. The field team will be significantly smaller because it doesn't need to be as large scale more.

Maury Raycroft: You may begin. Hi, this is Farzaneh calling, filling in for- So for the Haemophilia A program, can you contextualize how your program differentiates from other Haemophilia A programs and how you view this strategy? For instance, like the bimedine could be the first in class.

Emil D. Kakkis: So the question is, how does our HeMay program differentiate itself from the others? Yes, our program is better. That's why.

Probably a number of targets.

But I think the overall structure of those teams of our our youth our ultra care guides, which are the people to handle reimbursement and do the.

Emil D. Kakkis: I think the thing that's different about ours is that the AV that's being used is an AV8-Clad E variant, and it has a relatively efficient capsid for delivery to the liver. And I think we're seeing therapeutic levels achieved at 5E12 and E13, right, which is substantially lower than what you're seeing with the Biomarin AV5 capsid, which is known not to be as efficient. The SPARC program is running at 2E12, 1E12 lower, but it's had more inflammation.

Personalized care for both patients and physicians that will be the same and the quality that team I think is extremely important at taking care of patients that are most fragile moment when they've got a bad diseases are trying to get treated.

Emil D. Kakkis: So the one differentiator I would see right now is that, at moderate titers, clinically meaningful factor VIII is produced with actually only one out of four patients needing steroids, so without inflammation. So we think there is some differentiation in terms of the combination of safety and dose that we're seeing, and I think it puts it in a position to be. Unknown Executive, Unknown Attendee, Unknown Attendee, Unknown Attendee, Thanks, that's helpful.

So we think a lot of it will leverage our expertise that we've put together and it's one of the great thing Chris feed a first that allowed us to build out a lot of these efforts and create.

Situation in which we can begin to leverage our experience and infrastructure for launching.

The product the other thing advantage was deputy Internet savvy are actually the same doctors as well and those are the same doctors as treat GST, one a as well as LTC. So with four programs now in the same dr. pool work in start gaining a lot of leverage in our patient diagnosis the MSL functions.

Emil D. Kakkis: And provided the UAX-007 is approved, what will the sales force and commercialization effort look like? Will it be a similar multi-pronged approach as Crescida? Well, yes, so there are some aspects that will be the same for FEOD. We will have The patient diagnosis program will operate. However, because it's a more narrow set of target sites that manage newborn screening and see these patients, the MSLs may take some of the load of patient diagnosis, and so the PDLs that are out in the field could also find patients as they're out doing their work, so we will have a little bit of The field team will be significantly smaller because it doesn't need to be as large, scaled more properly to the number of targets.

As well as the sales functions going forward and I think that will be a valuable part of creating an accretive business.

Prospect was the as each additional approval comes through.

Thank you very much.

And our next question on cost line on Adam Walsh from Stifel. You may begin.

Hi, This is Adam and John harmful item.

Look we see my question congrats on the successful 2019.

I have two questions on us all seven.

Emil D. Kakkis: But I think the overall structure of those teams, of our ultra-cared guides, which are the people that handle reimbursement and do the. The personalized care for both patients and physicians will be the same, and the quality of that team, I think, is extremely important in taking care of patients at their most fragile moments when they've got a bad disease and are trying to get treated. So we think a lot of it will leverage our expertise that we've put together, and it's one of the great things about having CRISPR-V as the first that allowed us to build out a lot of these efforts and create. A situation in which we can begin to leverage our experience and infrastructure for launching. The other advantage was that FEOD and NetSevi are actually the same doctors as well, and those are the same doctors that treat GSD-1A as well as OTC.

We know you have a PDUFA dates in July we thus be my first question is what is your plan for US all seven registration you I.

I know you have two cents from UK units file, but just wondering.

If you need to do on a decent those studies with suppose filing you then I'll have a follow up.

We were currently exploring with the EU authorities individual send countries as well as Emmy the EMEA itself regarding the strategy for filing.

So we've had discussions and a number of areas on that topic and we're trying to four way to do it. We also up to develop a pediatric investigational plan Thats accepted which would also be important allowing us to file in Europe that process is still ongoing.

Emil D. Kakkis: So with four programs now in the same doctor pool, we're going to start gaining a lot of leverage in our patient diagnosis, the MSL functions, as well as the sales functions going forward. And I think that will be a valuable part of creating a creative business prospect as each additional approval comes through. Thank you. And our next question comes from the line of Adam Walsh from Stifel. You may begin. Hi, this is Adam and John on behalf of Adam.

We expect we should be able to file however.

There is a process we have to go through and whether study would be required to something we'd have to look at overtime.

I'd also point out that if the US approval occurs with the US approval, we can take that as we have to Brazil, Canada and many other territories for.

For pressing head on the launch globally for the product. So Europe is an important territory, but as many other territories that leverage the us approval and drive forward.

Maurice Thomas Raycroft: Thanks for taking my questions. Congratulations on the successful year of 2019. I have two questions on UX007.

We believe the products is addressing a very profound need in the old FSD population and that delaying anything for another study was out it really appropriate the FDA agreed with us on that and we think we should be able to get the made under two appreciate that as well allow us to move forward, but we're still in talks on that topic.

Emil D. Kakkis: We know you have a production date in July with FDA. My first question is, what is your plan for UX007 registration in the EU? I know you have a patient from the UK in the trial, but just wondering if you need to do an additional study to support filing in the EU, then I have a follow-up. We're currently exploring, with the EU authorities, individual countries, as well as the EMA itself, a strategy for filing. We've had discussions in a number of areas on that topic, and we're trying to explore a way to do it.

Great. Thanks, a second question on you Act both some how you study on these discussions with payers on.

What is the initial feedback on for example pricing.

I believe you have down market research what is your expectation on the market uptick.

Emil D. Kakkis: We also have to develop a pediatric investigational plan that's accepted, which would also be important in allowing us to file in Europe. So that process is still ongoing. We expect we should be able to file soon.

Both seven after the produce oil U.S. approval. Thanks.

Well, we have done some initial work with payers.

Emil D. Kakkis: However... You know, there is a process we have to go through, and whether a study would be required is something we'd have to look at over time. I would also point out that if U.S. approval occurs, with U.S. approval, we can take that as we have to Brazil, Canada, and many other territories for pressing ahead on the launch globally for the product. So Europe is an important territory, but there are many other territories that will leverage U.S. approval and drive forward.

As well as physicians.

And I think what most where we've been hearing is that the reduction in major clinical events is considered a.

An important and meaning full benefit to patients who go on trap nine I think we've gotten universal agreement, that's important and a big effect in their mind. So we believe that theres good support from payers for covering the product we haven't put out what our pricing is this point I know the street.

In general is talking about a price point around $100000 per year per patient on average.

Emil D. Kakkis: We believe the product is addressing a very profound need in the FEOD population and that delaying anything for another study is not really appropriate. The FDA agreed with us on that, and we think we should be able to get the EMA to appreciate that as well and allow us to move forward, but we're still in talks on that. Great, thanks. A second question also from UX407. Have you started any discussions with your peers?

Weve guided.

People do not use the typical type of pricing for this product I think the key things understand about pricing and uptake is the fact that there is a relatively cheaper oil for MCT out there that has established usage, but certainly as a lot of shortcomings, we think.

But.

Prior to the often out of pocket for patients, whereas you Act. So seven would be a pharmacy benefit product not out of pocket.

Emil D. Kakkis: What is the initial feedback on, for example, pricing? I believe you have done market research. What is your expectation of the market uptake of UX407 after potential US approval? Thanks.

Purely out of pocket product. So we think those are some benefits and we'll continue to do our analysis of this but we caution on the whole inborn error thing is that all the enterprise air products, we've developed of usually had steady.

Emil D. Kakkis: Well, we have done some initial work with payers as well as physicians, and I think what we've been hearing is that the reduction in major clinical events is considered an important and meaningful benefit to patients. I think we've gotten universal agreement that it's important and has a big effect in their minds. So we believe that there is good support from payers for covering the product. We haven't put out what our pricing is at this point.

Slow steady kind of growth and adoption.

We don't expect to be precipitous large crossover to the drug immediately particularly in context of another existing established treatment, but we do believe the product will do well over time, but just it'll be a steady growth product for us.

Thank you.

Emil D. Kakkis: I know the street in general is talking about a price point of around $100,000 per year per patient on average. We don't expect to see a precipitous large crossover to the drug immediately, particularly in the context of another existing established treatment. But we do believe the product will do well over time. It'll be a steady growth product for us. Thank you. Thank you. And our next question comes from Laura Chico from Wedbush Securities. You may begin. Hi, this is Kenneth on behalf of Laura Chico.

Thank you and our next question comes on line of Laura Chico from Wedbush Securities You may begin.

Hi, this is kind of on for Laura Chico.

And we just had a question.

One of the objectives, you've talked about is remaining active on a business development front I guess I'd be curious explore if you see the potential in your pipeline given you're looking to advance mcbrien decent 2020.

Laura Kathryn Chico: I just had a question, one of the objectives you've talked about is remaining active. Tazeen Ahmad, Yigal Nochomovitz, Christopher Raymond, Gena Wang, Yeah, so we like to stay active in BD because, unfortunately, opportunities show up not when you're ready for them but when they're ready to show up. So, I think it's very important to open your eyes to what's there and do it. I would point out to you that you all like the Chris Vita product, but at that time, we had three to four products in play.

Theres a need to explore externally at this stage given the breadth of treatment modalities recruit thanks.

Yes, so we like to stay active mbd because.

Fortunately opportunities show up not when you're ready for them, but when they're ready when they're ready to show up so.

I think it's very important to open your eyes, what's there and do it I would point out to you that you all like the Chris FIDA product, but that time, we had four products are three to four products in play we were very busy but showed up and we could get the deal. We did the deal even though it seemed like an AD because it was a great opportunity for us and of course turned out to.

Emil D. Kakkis: We were very busy, but it showed up, and we could get the deal. We did the deal, even though it seemed like an ad, because it was a great opportunity for us. And, of course, it turned out to be quite important. We always keep our minds open to being ready for opportunities when they show up. Similar to the acquisition of Dimension, we weren't planning on an acquisition, but the moment arrived. I think it's extremely important for a company to be dynamic and nimble and take the shot. So we actively look at products. There are things out there.

We quite important we always keep our minds open to be ready for opportunities when they show up similar to the acquisition of dimension, we were planning and acquisitions at the moment arrived I think it's extremely important for comedy bead dynamic and nimble and take the shot. So we actively look at products. There are things out there they're also technology we.

Emil D. Kakkis: There is also technology we have that might be leveraged as well. So there are a lot of ways to do business development to help us, but we're gonna be cost conscious, and we're gonna try to make smart moves, and we're not a company that's gonna throw a lot of money into an auction that goes crazy and approach BD that way. It'll be judicious.

I have that might deleverage as well so there's a lot of ways to do business development to help us, but we're going to be cost conscious and we're going to make tried to make smart moves and we're not for the company that's going to go throwing a lot of money into an auction that goes crazy and the approach BD that will be it will be judicious.

Emil D. Kakkis: Prudent, smart, and I think we find undervalued things that we have a special skill at improving. So we are open to looking at things, but they have to be of high value. We're looking for things that are not gene therapy since we've got a lot of investment in gene therapy, and we don't wanna be all gene therapy. And so we'll keep our eyes open, and we'll make great deals. I think Angelman was one example of a deal we should do when it shows up.

Prudent smart and I think find undervalued things that we have a special skillet, making.

Improving.

So we're our open for looking at things with they have to be high value routing or things that are not gene therapy. Since we've got a lot of investment gene therapy, and we don't want to be all gene therapy.

And so we'll keep our eyes opened and we'll we'll do great deals I think Dangerman was one example, I think was a deal we should do when it shows up and we're excited about prospect of treating that disease, given the size that opportunity.

Salveen Jaswal Richter: And we're excited about the prospect of treating that disease, given the size of that opportunity. Thank you. And our next question will come from Salveen Richter from Goldman Sachs. You may begin. Thanks for taking our questions. This is Andrea on behalf of Salveen.

Thank you.

Thank you and our next question comes from client Salveen Richter from Goldman Sachs You may begin.

Thanks for taking your question just Sandra on for Celgene, maybe a question on your manufacturing for gene therapy on could you talk a little bit more about the processes in place to transition year GST, one a program to the HILA production and then.

Emil D. Kakkis: Maybe a question on your manufacturing for gene therapy. Could you talk a little bit more about the processes in place to transition your GSD1A program to HeLa production? And then, as a follow-up to that, what the transition process might look like as you move to your in-house manufacturing facility and what the associated timelines would be?

As a follow up to that with the transition process might look like as he moves at your in house manufacturing facility.

The associated timelines that be thank you.

Emil D. Kakkis: Thank you. Yes, so just to remind people, the OTC program and the GC1 are both using the Cripple Transfection 293 Strategy Using Suspension, a transfection type strategy. So those are both will be that when they get to commercial.

Yes, so just to remind people the otcs program and the GT, one or both using.

Triple transaction to nine three strategy using suspension.

Transfection type strategy. So those are both will be that when they get to commercial that is what we're planning with GST one a weve already created a he'll assist them for production of it.

Emil D. Kakkis: That is what we're planning. With GST-1A, we've already created a HeLa system for its production. I run it.

And Brian it.

Emil D. Kakkis: And so we know that it works and can be done. What we've decided to do is transition that to HELA after approval, in post-marketing because we didn't want to introduce another delay in the process of getting approved. So we'll go to Markit with the triple transfection program, assuming we do phase three and it's successful, and then we would transition to HeLa sometime after approval. Now the timeline for the plant that we are developing. There are two parts to the plant. One is the quality control analytical part, which we've already set up and built the lab and are operating our own analytical laboratory for the GMP test release of gene therapy products, which we think was a very important investment and that's already operating in the Woburn area. That will help shorten the time to drug product release and put those critical aspects of product quality in our own hands, with our excellent tech ops and quality teams. With regard to the plant itself, we are working on a site and putting it in play.

And so we know that it works and can be done what we've decided to do his transition that to HILA after approval.

In post marketing, because we didnt want to introduce another delay in the process of getting approved so we'll go to.

Market with the Triple transaction program, assuming we do the phase three is successful and then we would transition to heal.

Sometime after approval.

While the timeline for the plant that we are developing it there's two parts of the plant one is the quality control and a local part, which we've already set up and built the lab in our operating our own analytical laboratory for the GMP test release of gene therapy products, which we think it was a very important investment and that operating alright.

I'd in the Woburn area.

Part of it that will help shorten the time to drug product release inputs those critical aspects of product quality in our own hands in our excellent tech ops and quality teams.

With regard to the plant itself, we are working on citing and putting in play we'd expected to take a b as several year process to identify build at that point in time, we will shift our products.

Emil D. Kakkis: We'd expect it to take and be a several year process to identify and build. At that point in time, we'll shift our product, as necessary, into the plant, but I would also say it doesn't mean we wouldn't use contractors. I think we would be using contractors plus our own plant.

As necessary into the plant.

But I would also say it doesnt mean, we wouldn't use contractors I think we will be using contractors plus our plant with time, though the plant would take on a larger larger load of our commercial and well clinical development needs in the speed with which we can put a new clinical development program into the clinic should increase as we will have the flexible.

Emil D. Kakkis: With time, though, the plant will take on a larger and larger load of our commercial and clinical development needs, and the speed with which we can put a new clinical development program into the clinic should increase as we will have the flexibility then to put our programs into manufacturing. And our expectations are that the plant would run the HELA and potentially 293 triple transfection, though with time, we would try to get all of our programs to shift to the HELA platform, being that it's larger scale, better cost structure, no use of plasmids, and so far, at least with the HEMA that we have to date, looking very good from a safety and efficacy perspective. I got it. Thanks so much for the color.

Really the put our programs into manufacturing and our expectations that plant would run the HILA and potentially to nine three triple transfection, though with time, we would try to get all our programs the shifted the HILA platform being that it's larger scale that our cost structure no use of plasma and so far lease of the he may do we have today.

Great looking very good from a safety and efficacy perspective.

Got it thanks, so much for the color.

Emil D. Kakkis: Thank you. And our next question will be from the line of Yigal Nochomovitz from Citi. May we begin? This is Samantha on behalf of Yigal.

Right.

Thank you.

Our next question will be from the line, you're going to knock us from Citi maybe again.

Hi, This is math on for your call. Thanks, very much for taking my question.

Yigal Dov Nochomovitz: On DTX-301, for the ammonia being used as a phase 3 endpoint, I'm curious if you could elaborate on what assay you are planning to use to measure ammonia, and will it be the same assay and protocol used at all trial sites? I know that there's some variability with the motion measurements. I'm curious about what you've seen in terms of technical variability there. Well, ammonia is variable, but less about the assay than it is about the sample collection and transport. So the problem with ammonia is sample patient prep, sample collection, and sample transport care is where ammonia can go variable. And that's why it's important to what we are doing is a 24 hour area under the curve for ammonia. What that means is that the patients in the hospital are being treated.

On on Gtx Rio one.

For the ammonia being is facing Brian I'm curious if you could elaborate what assets are you planning to you measure ammonia and will it be the same asked Sam protocol that used to al trial sites.

I know that there is that there's some variability with emotion measurements I'm curious on what you see in on technical that ability there.

Well ammonia is variable, but less about the assay than it is about the sample collection and transport.

So the problem with money is the sample patient prep sample collection sample transport care is where ammonia can go variable and that's why it's important to what we are doing is the 24 hour area under the curve ammonia what that means as the patients in the hospital.

Yigal Dov Nochomovitz: Not as an outpatient, in the hospital, and they're there for 24 hours, and blood tests are taken every few hours, usually through a catheter rather than through a needle stick. The catheter allows you to then have free-flowing blood from the vein, allowing you to get more accurate venous blood ammonia levels, and those are then assayed in the traditional way, but the samples are able to be managed, set up, and sent to the proper lab.

Not as an outpatient in the hospital and there were 24 hours and blood tests are taking every few hours usually through a catheter rather than through a needle stick. The catheter allows you then to have free blowing flowing blood from the vein allow you to get more accurate Venus blood ammonia levels and those in our asset in the traditional way with the samples are able to.

To be managed set up and sent to the proper lab.

Emil D. Kakkis: In a prompt timeframe, by doing it that way, we've gotten relatively consistent ammonias on visits, and that's the approach we're taking for using it in the clinical program. Does that answer your question? Yes, it does. Thanks for that color.

In a prompt timeframe by doing it that way, we've gotten relatively consistent ammonia is on visits and.

Thats the that's the approach we're taking for using it in the clinical program does that answer your question.

Yes, it does thanks for that color.

Emil D. Kakkis: And just switching gears a bit, for TIO, I'm curious, would you leverage the similar regulatory path that you stated for FAOD in terms of utilizing a potential US approval for Canada and Brazil? And how are you thinking, would you bother with going into the EU given the royalties have been sold to Royalty Pharma? But we sold the royalty.

And just switching gears a bank Frick for T. <unk>, Oh, I'm curious would you.

Leverage this similar path regulatory path is data for FMC in terms of utilizing our potential U.S. approval for Canada, and Brazil, and how are you thinking would you bother with going into the email given the royalties have.

Ben Outlays are sold throughout the pharma.

Emil D. Kakkis: But remember, our partner still has the rights to Europe, so they're probably still going to want to sell it in Europe, I'm assuming. So the TIO will put that product into all of our territories for sure. We think we can leverage the data because it builds upon the XLH data in terms of phosphate control, bone fractures, and osteomalacia, which are verified at a pathologic level and using bone scans in the TIO population. It has already been approved in Japan, by the way; a partner has gotten it approved in Japan already.

Well, we sold the royalty, but remember our partner still has the right to Europe, so, they're probably still going to want to sell it in Europe I am assuming so let's see I will we'll put that product into our all of our territories for sure.

We think we can leverage the data because that is.

Builds upon the Ecollege data in terms of phosphate control bone fractures, and osteomalacia, which are verified it of pathlogic and using bone scans in the Tio population. It has already been approved in Japan by the way by our partner has gotten approved in Japan already so we think with the.

Emil D. Kakkis: So we think with the U.S. approval, we'll certainly be able to leverage that and file that elsewhere as well. And I expect there'll be patients globally that will benefit from the TIO, from treatment in TIO. Got it. And then, just on UXO7.

US approval, we'll certainly be able to leverage than file that elsewhere as well and I expect there would be patients globally that will benefit.

From the Tio from treatment in Tio.

Got it and then just on your XR seven how many formulations are you planning to bring to market I think I remember in the past you mentioned you may have had a powder formulation at one point.

Emil D. Kakkis: How many formulations are you planning to bring to market? I think I remember in the past you mentioned you may have had a powder formulation at one point. Yeah, so there are possible ways to make the oil into a powder. The current formulation will be in a bottle that patients can measure their quantity out. It's around, let's say, the total per day is around 70 cc, something like that. And they're usually doing it four times a day. There is the potential to make a powder, but the one we tried didn't work out.

Yes, so there are possible ways to make the oil into a powder or the current formulation will be a bottle that patients can measure their quantity out. It's a round, let's say total per day is around 70, Ccs something like that and they are you doing it in four times a day.

There is a potential to make a powder to the one power. We tried didnt work out we could look at other powders or sashays and other.

Emil D. Kakkis: We could look at other powders or sachets and other variations in the product presentation. And we want to do that actually to make it more convenient and easy for patients to take this with them to work or to school and other settings. So we're starting with the bottle, a 500 milliliter bottle that they measure and mix with their food or drink. And we'll probably work on having some other variations over time, but we don't currently have a powder ready to go. Okay. And just one quick one for Shalini.

Variations in the product presentation, and we want to do that actually to make it can be an easy for patients to take this with them to work or to school and other for setting. So we're starting with the bottle of 500 mill bottle that they measure and mixed with their food or drink and we'll probably work on having some other variations over.

Time, but we don't have a powder currently.

Ready to go.

Understood and just one quick one for shiny how quick do you expect opex to flatten it should we be using the moderate growth based on for Q numbers.

Emil D. Kakkis: How quick do you expect OPEX to flatten? Should we be using the moderate growth based on 4Q numbers? While it's not going to be sort of a precipitous drop from one quarter to the next, it's going to be gradually flowing down but still increasing. So the rate of increase will be slowing down over time. Thanks very much.

Well the.

It's not going to be sort of a precipitous drop from one quarter to the next it's going to be gradually slowing down, but still increasing the rate of increase will be slowing down overtime.

Thanks, very much that us thanks, very much for taking the questions.

Emil D. Kakkis: That is, thanks very much for taking the question. Thank you. And our next question comes from the line of Joon Lee from SunTrust. You may begin.

Thank you and our next question comes the line of Joon Lee from Suntrust You may begin.

Joon So Lee: Hi, thanks for taking my question. If I recall correctly, you mentioned before that you need an order of magnitude less vector to get the same effect in hemophilia as compared to Biomarin's hemophilia gene therapy product. So is the vector you generate using the new HeLa platform different in quality, or just different in terms of improved quantity of production? And if it's different in quality, what are your strategies to bridge from the old to the new, you know, GSD-1A?

Hi, Thanks for taking my question.

If I recall correctly, you mentioned before that you need an order of magnitude less sector to get the statement effect in hemophilia.

As compared to Biomarin seem Ofilia gene therapy product. So is the sector you generate using the new Sheila platform different in quality or just different in terms of improved quality quantity of production and if it's different in quality. What are your strategy to bridge from the old there's a new.

Yes.

Emil D. Kakkis: You know, vector, post-approval. Sure, thank you. There are several factors that make it different. One is that it is a 88 variant, and so AAV itself is a more efficient capsid than AAV5 in terms of delivery to the liver. So that is one feature of the improvement, but that's not related to the platform, but just the choice of capsid. The platform itself allows us to produce the AAV using normal biology and using adenovirus recovery. And that allows the biology means we get. It really acts as it normally would in nature, and the vector being made has a higher fill rate right off the column, right off the production line, and that allows us to create a better, consistent AAV that way.

Yes, Steve one a.

Vector post approval.

Yes.

Sure. Thank you the.

The several factors that make it different one is that it is avi.

The 88 variant.

And so aviate itself is a more efficient capsid than abbey five in terms of delivery to the deliver side is one feature of the improvement, but thats not related the platform, but just the choice of capsid. The platform itself allows us to produce the Avi.

Using the normal biology, and using and of ours recovery and that allows the biology means we get.

It really acts as it normally would in nature and the vector being made has a higher fill rate right off the call them right off the the production and that allows us to create a better consistent avi that way. So there is a a quality benefit in doing it with HILA system, and I think that could trends.

Emil D. Kakkis: So there is a quality benefit in doing it with the HeLa system, and I think that could translate into, you know, a cleaner product that might have less issues. We know with plasmid transfection systems, there can be plasmids, and managing pre-DNA is a factor, and so that's one thing we think the HeLa system would also reduce. So we think there is both a quality effect and there's also the choice of cats that are probably going to contribute to the effect of the HEMA program on hemophilia. So if it's different in quality, does that complicate the bridging on a post-approval basis?

Played into.

Cleaner product that might have less issues, we know with plasmid transfection system, there can be plasmid and managing free DNA is a factor and so that's one thing we think the he'll assist them would also reduced.

So we think there is the both the quality effect and there's also the choice of cast that are probably going to contribute to the.

The effect of the key May program on hemophilia.

So if it's different in quality does that complicate the bridging.

On a post approval basis would you need an extensive new study or.

Emil D. Kakkis: Would you need an extensive new study, or can you help us understand what the process is? I mean, so you're talking about bridging in GlaxoSterosis Type 1 if we're going to bridge the crossing over? No, no, no. Does it change the quality of the vector that you're using to transduce?

Can you help us understand what the process as we did so you're talking about bridging and blacks and started you type one if we're going to bridge crossing over and then I know Youre change.

Does it change the quality of the vector to use using two transduce and if so.

Emil D. Kakkis: And if so, does it change sort of the PKPD or biology of how the drug works as a product? Yeah, well, the actual product, remember, gets purified; the full versions get purified. And so at the end of the day, you end up with something closer. But remember, if you start with a better quality product right off the reactor, purifying it is easier, and you get a better product; you get a higher yield.

Does it change sort of the PK PD or biology of how does the drug works that's product.

Well the actual product remember gets purify the full versions get purified and so we end the day you end up with something closer, but remember if you start with a better quality product right off the reactor than purifying it is easier and you get a better.

Higher yield so I don't think that we're not expecting we've looked at HILA versus Tonight, three we havent seen the significant difference in distribution PK PD of the product, what we're saying as the Manufacturability. How you how much you can make how much you get is easier to achieve is so we think it will be potentially safer.

Emil D. Kakkis: So I don't think that we do not expect, and we've looked at HeLa versus 293. We haven't seen a significant difference in the distribution PKPD of the product. What we're saying is that manufacturability, how much you can make, how much you can get, is easier to achieve, and so we think it will be potentially safer. We would expect... Going from 293 to HeLa, truly, the drug, which is the DNA, is the same, so the cast is the same, so it's really the process, so we would expect that we could do the same kind of traditional non-clinical work, as well as some limited human bridging work in order to demonstrate some more safety and efficacy in order to move that forward. It doesn't entail more work, generally.

And we would expect.

Going from Tonight, Threed HILA that the truly the drug which is the DNA is the same sort of the cast is the same so it's really the process. So we would expect that we could do the same kind of traditional nonclinical work as well as some limited human bridging work in order to demonstrate similar safety and efficacy in order to move.

Forward, we would still need to talk with regulatory authorities about that but we don't think its fundamental change in the vactor and if anything the quality could be better not worse I don't think that entails more.

Emil D. Kakkis: Thank you. And I just have one follow-up, sorry. It's a rather naive question, but for the 301 program, can you remind us why prophylactic steroids should lead to improvement? Transduction and Improved Expression.

It doesnt until more work generally thank you and I just have one follow up sorry.

Rather naive question, but for the three a one program can you remind us why prophylactic steroid steroids should lead to improved.

Reduction and improved expression is information a function of how much sector you put into the patient or is it more of a function of how much actually gets transduced and lead to productive expression of the gene product.

Emil D. Kakkis: Is inflammation a function of how much vector you put into the patient, or is it more of a function of how much actually gets transduced and leads to productive expression of the gene product? And I'm asking this partly because, based on your most recent data from the OTC program, women were just as well transduced as males, so I'm just curious what your latest thinking is there. Thank you. Yes, well, look, capsid quantity or dose does have an effect on inflammation. That is, the higher the dose, we've got more inflammation. That's just normal and expected.

And I am asking does partly because it seems like based on your most recent data LTC program, one more just as well Transduced esmail. So.

Just curious what your latest thinking is there. Thank you.

Yes, well look captive quantity or dose does have an effect inflammation that is the higher dose we've gotten more inflammation of just normal expected inflammation is a little bit downstream of the problem, what the steroids and prophylaxis or as we hope is actually the suppress innate immunity, which is in do reduces.

Emil D. Kakkis: But inflammation is a little bit downstream of the problem. What the steroids and prophylaxis steroids do is actually suppress innate immunity, which reduces the transduction efficiency of the vector, which we think would improve efficacy, which is what we're trying to do. improve efficacy That is, the number of liver cells that are expressing your transgene. By suppressing innate immunity, we expect more of those cells to be able to overcome their innate immunity on a cell-by-cell basis and get more cells expressing, which we think would result in more robust treatment. We base that, based on some of our own non-clinical work and some clinical work of others, that suppressing innate immunity through prophylactic steroids does have a significant benefit on expression. That will have the effect of reducing downstream inflammation, but it's really about preventing the silencing of gene copies, which is a common problem you see in non-human primates and adults but not so often seen in mice.

Transduction efficiency of the vector, which we think would improve advocacy is what we're trying to prove the efficacy that is the number of liver cells that are expressing your transgene by suppressing the innate immune we expect more of those cells to be to overcome their need immunity on the fell by cell based and get more cells expressing.

Which we think will result in more robust treatment, we base that based on some of our own non clinical work and some clinical work of others that it appears as surprising the immunity through prophylactic steroid does have a.

A significant benefit on expression that we'll have the effect of reducing downstream inflammation, but it's really about preventing the silencing of gene copies.

Which is a common problem you see in non human primates and adults, but not so often seen in mice.

Emil D. Kakkis: And that's probably why humans and non-human primates are harder to treat with AAV gene therapy than mice are. Thank you so much. Thank you. And our next question will come from the line of Vincent Chen from Bernstein. You may begin. Great.

And that probably why humans and non your privates are harder to treat with Avi gene therapy than my SAR.

Thank you so much.

Thank you and our next question on topline Vincent Chen from Bernstein, you may begin.

Vincent Chen: Thank you very much for taking the questions. A couple on CRISPR-Beta, if I may. I was wondering if you could provide us with a little more color on where CRISPR-Beta patient growth in North America is coming from. What, well, maybe in the U.S. specifically, what's your sense of the balance between adult and pediatric patients? And within the adult portion, what portion of folks who are newly diagnosed compared to folks who are previously known in clinics? And how is this mix trending over time? Very good. It's good to talk to you, Vincent.

Great. Thank you very much for taking the question a couple interest Vienna, if I may I was wondering if you could provide us with a little more color on where tribunal patient growth in North America is coming from.

What well maybe in the U.S, specifically, what's your sense sort of balancing adult and pediatric patients and within the adult portion what portion of folks who are newly diagnosed compared to folks who were previously known in clinics and houses mix trending overtime.

Very good good to talk to you Vincent so.

Emil D. Kakkis: So, in CRISPIDA, we've been seeing some steady shift toward adults with the most recent ratios, 45% adults and 55% PEDS. We expect that to steadily shift further as we continue to find adults that have been lost to follow-up. I don't have a breakdown for you on how many are newly diagnosed, and you'd have to define what newly diagnosed means. There are a lot of patients who were diagnosed clinically 20 years ago and told they had a disease, and they know they have a disease, but then we get them genetically tested and confirm it's XLA. So which one of them, the guy that said you have a bone disease or us that gave you a genetic diagnosis?

In crispy that we've been seeing as some steady shift toward adults with the most recent ratios, 45% dolphin, 55% PD.

When we would expect that to steadily shift further as we.

Continue to find adults that are the loss to follow up I don't have a breakdown for how many are newly diagnosed and you have to define our newly diagnosed means there's a lot of patients were diagnosed clinically 20 years ago told to have a disease.

And they know they have a disease, but then we then get them genetically tested and confirm its exelate, so which who diagnosed and the guy that said you have a bone disease or us that gave you generics. So there's a number of patients in that kind of group that were diagnosed but there were diagnosed at a time when no one knew what the gene was right and so.

Emil D. Kakkis: So there's a number of patients in that kind of group that were diagnosed, but they were diagnosed at a time when no one knew what the gene was, right? And so we're doing a lot of work on free genetic testing to take those patients diagnosed with BRCAs that have ongoing problems that turn out, in a pretty high fraction, to be XLH patients. So that is something that's happening now and finding what I would call those patients. I would say to you that those patients were diagnosed, they had the bone disease, and they were aware of it. It's just that they weren't confirmed as being XLH.

We're doing a lot of work on free genetic testing to take those patients diagnosed with.

Rick it's the have ongoing problems that are turned out in a pretty high fraction to be exelate patients. So that that is something that is happening now and finding what I would call. Those patients I would say to you that those patients were diagnosed they have the bone disease may know of it is just they weren't confirmed as being EXL Asian, I think thats a lot of the.

Emil D. Kakkis: And I think that's a lot of the effort we're doing. What is harder to know is how many adults out there had some disease that wasn't really figured out correctly. They're truly undiagnosed as having rickets as a child. I don't know what that number is for sure.

Effort, we're doing what is harder to know how many adults out there had a some disease that were really figured out correctly. They are truly undiagnosed as having records as a child I don't know that number is for sure. What we can save so far those were pretty confident that are 12000 patient number for all exelate.

Emil D. Kakkis: What we can say so far, though, is that our 12,000 patient number for all XLH is probably about right, and that the 9,000 adults, we still have a significant fraction of those adults to work on getting the therapy, and our target is to get at least half of those adults on therapy over time, not next year, but over time as we find them. So it's a little less about.

It's probably about right and that the 9000 adults, we still have a significant fractionals adults to work on getting a therapy in our target is to get at least half of those adults on therapy overtime.

Next year, but overtime as we find them so it's a little less about.

Emil D. Kakkis: I think it's more about finding the patients who have the medical problems and know they have rickets but are no longer going to those centers that would normally treat them. And that's going to those secondary specialties, and that's what the PDL team is actually out there doing right now. That team is out there calling on those doctors that are out and about who appear to be treating someone with Ricketts disease or bone disease and helping them finalize that diagnosis. I see And if you think about this population, which I guess is the maybe known to have disease but newly confirmed, I was wondering if you could give us some sense for how the number of patients that fall into that bucket, sort of the maybe known, newly confirmed, how is that number trending in terms of like the quarterly clip over time? Is that some, would you say that's been responsible for driving the last couple of quarters of growth and is sort of proceeding at Well, it's only a fraction of the growth.

I think it's more about finding the patients who have the medical problems and know the have records, but are no longer going to those centers that would normally treated and thats going those secondary specialties and that's what the PDL team has actually out there doing right now at the teams out there calling on those doctors that are out in about who appear to be true.

Eating.

Someone with a records disease or bone disease.

And helping them finalize that diagnosis.

Hi, So if you think about this population, which I guess is the main maybe nodes of disease by newly confirmed I Wonder if you could give us some sense for how that the number of patients a fall into buckets or the mid may be known newly confirmed.

How is that number trending terms like the quarterly clip overtime is that something would you say that there's been response, we're driving the last couple of quarters of growth and is proceeding at a similar to clip or would you say that sort of trending one way or the other.

Well, it's a fraction of the growth I think theres been a lot of patients that we have diagnosed at centers that were still are been driving the growth. The first six quarters ones that were already there are known yes that are doing it and over time those patients are going to be an increasing part of the story is finding more and more.

Emil D. Kakkis: I think there's been a lot of patient, Transcripts provided by Transcription Outsourcing, LLC. Unknown to the clinic. But obviously, you try to focus the launch on the low-hanging fruit that is already in hand, and the PDLs are starting to look, you know, climb the branches for the other fruit, but in this process. Is there much more room to run on that sort of low-hanging fruit than known to Con

For those rather the ones are already had a known to the clinic, but obviously you try to focus the launch on the low hanging fruit that are already in hand, and the PDL is are starting to look climb the branches for the other fruit but.

In this process.

Is there much more room to run on the that sort of low hanging fruit to known to going forward on your six months into nor six quarters rather into into the launch which is usually when things start to Peter out, but it sounds like it was actually still more and more room to run from from your comments just now.

Emil D. Kakkis: You're six quarters into the launch, which is usually when things start to peter out, but it sounds like there's actually still more room to run from your comments just now. Oh, there are still more patients out there. There are definitely more patients that we know about that are already in those centers, but there are some centers that have actually written prescriptions for almost every single patient they have. So our top prescribers have written 40, 50 scripts or more. So that's a lot of patients. So there's definitely some that have already prescribed everything they have, which I think is actually a testament to their commitment, like their experience commitment, that they're gonna put every single patient they have on it. But there are some that haven't.

There are still more patients out there they are definitely more patients that we know about that are already in those centers, but where there are some centers that have actually written prescriptions for almost every single patients they have.

So a smart top prescribers have.

Written 40, 50 scripts or more.

So thats a lot of patient so there's definitely some that have already prescribed everything we have which I think is actually a testament their commitment like their experience commitment that theyre going to put every single patient they have on it but there are some of the habit and one of the question says well some people think maybe oral phosphate work, okay for their kids well Doug.

Emil D. Kakkis: And one of the questions is, well, some people think maybe oral phosphates work okay for their kids. Well, in October, we got a label update that says that head-to-head with oral phosphates, CRISV is way better. And we think that's something we can take out to those docs who may have some paid patients who think they are doing okay with oral phosphate and maybe change their mind about the value of switching. And then we have to look at the question for some adults, some doctors who don't treat adults for safety reasons and have gotten in the mode of thinking that maybe adults don't need to be treated. And that is where speaker programs and patient ambassador programs are helping people understand that those adults that may not be complaining that much but are not doing well. And once they get treated, they realize how much better they could be. And we're seeing a lot of good stories like that, and communication is important to get out of the mindset that. Not treating adults is the right thing when they often have very significant diseases.

If we got a label update that says that head to head with oral phosphate precedes way better and we think thats something we can take out to results may have some paid.

Were they think are doing o'kane oral phosphate and maybe change your mind about the value of switching and then we have to look at the question for some adult some doctors, who didnt treat adult for safety reasons and have gotten the motor thinking maybe adults don't need to be treated.

And that is where using speaker programs and patient ambassador programs are helping people understand that those adults that may not be complaining that much but are not doing well and once they get treated they realize how much better they could be we're seeing a lot of good stories like that and that communications part and to get out of the mindset that.

Not treating adults is the right thing when they often have very significant disease. So that piece of the other part where they know the patients are there has now getting people to understand why really they should put all their patients on or the majority of their adults on on drug and that's another part of the story that we're working on so far.

Emil D. Kakkis: So that piece is the other part where they know the patients are there, and it's now getting people to understand why really they should put all their patients on or the majority of their adults on this drug. And that's another part of the story that we're working on. So far, we're impressed that once doctors start prescribing Reseda, they then start prescribing more because the feedback is always really strong and positive, and that incents them to continue moving forward with putting their patients on Reseda. Great, thank you so much for all the color.

Impressed that once Dr. star prescribing.

The then start to prescribing more because the feedback is always really strong and positive in that that incents them to continue moving forward with putting their patients on the SITA.

Great. Thank you so much for all the color.

Jeff Hung: Thank you. And our next question will come from the line of Jeff Hung from Morgan's Family. You may begin. Thanks for taking the question. For UF701, you mentioned that it's in the manufacturing scale. Can you talk about what else remains outstanding before you file the IND? Well, we have done our preliminary TOCS work, but generally, you want to use the scaled-up material for the final TOCS, right? So that's some piece of it.

Thank you.

Thank you and our next question will come from line of Jeff Hong from Morgan Stanley You may have against.

Okay. Thanks for taking the question for you X seven to one you mentioned that it's in the manufacturing scale stage can you talk about what else remains outstanding 40 file the R&D.

Well, we have done our preliminary talks work, but generally you want to use the scale at material. The final Cox rates that some piece, but we've done our preliminary so we understand the comfortable with the the tox profile looks looks excellent. So we'll have to do that as well and.

Emil D. Kakkis: But we've done our preliminary work, so we understand, are comfortable with the TOCS profile looks excellent. So we'll have to do that as well. And we're also, you know, working toward our pre-ID and our discussion on the design of a trial that would be, A more streamlined design that will allow us to move quickly ahead, that requires both understanding the trial design, the patient population, and the endpoints. Now there are established endpoints for Wilson disease. Including Free Serum Copper, as well as, you know, Liver Copper by Imaging. And while those are established and valid.

We're also.

So working toward our pre Andy and our discussion on the design of a trial that would be.

A more streamlined design that allow us to move quickly had that requires both understanding the trial design the patient population and the endpoints now there are establish endpoints were wilson's disease, including free CRM copper as well as liver copper by imaging.

And while those are the established invalid.

Emil D. Kakkis: Question on gene therapy: how do we, what do we do to help substantiate? Tazeen Ahmad, Yigal Nochomovitz, Christopher Raymond, Gena Wang, Anupam Rama, Kristen Kluska, Maury Raycroft, Joseph Schwartz, Emil Kakkis, Yaron Werber, Jeff Hung, Camille Bedrosian, Laura Chico, Jack Allen, Aaron Olsen, Joori Park, Howard Horn, Howard Horns, Ultragenyx Pharmaceutical Inc., and making sure that we build a Transcripts provided by Transcription Outsourcing, LLC. Clinical Study Plan; that part is ongoing right now as well. The manufacturing is really controlling the timeline.

Question on the gene therapy is how do we what do we do the health substantiate.

The cost and price of gene therapy for as a life changing treatment that requires also capturing aspects and caused wise neurologic function liver injury another asset for disease.

And making sure that we build a trial that captures the breadth of the efficacy of the treatment.

And creates the case required to this transformative and also verify for us if that's true but the drug is transformative we think it can be in so we want to make sure. We trial design of the endpoints and we're doing a lot of work on service studies and other things to help devolve are there are.

Clinical study plan that part is ongoing right now as well the manufacturing is really controlling the timeline.

Danielle Keeley: Non-clinical, the clinical study plan, meeting with regulators, and that puts us on a timeline toward the end of the year to get an IND filed and be ready to go. Great, thanks. Thank you. And I'm not asking any further questions. I'd like to turn the call back to Danielle Keatley for any closing remarks. This will conclude our call, and a replay will be available soon if you have any questions. Thank you. Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect. Transcript Emily Beynon

Nonclinical clinical study plan meeting with regulators and that puts the some timeline towards the end of year to get R&D filed and be ready to go.

Great. Thanks.

Thank you.

Im not showing any further questions I'd like to turn the call back to Daniel Keatley for any closing remarks.

Thank you for joining US today. This will conclude our call and a replay will be available and if you have any questions. Please give us to call or you can reach out that IR at Ultragenyx dotcom. Thanks for joining.

Ladies and gentlemen, this concludes todays conference call. Thank you for parts. This meeting you may now disconnect.

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