Q1 2021 Ultragenyx Pharmaceutical Inc Earnings Call

Good day and thank you for standing by for will come to the first quarter 2021 financial results and corporate update conference call.

This time, all participants are in a listen only mode.

Started speaker's presentation, and there will be a question and answer session to ask a question. During the session you will need to press star one on your telephone.

If you require any further assistance. Please press star Zero I would now like behind the conference over at the yards Speaker today, Josh where he got please go ahead.

Thank you good afternoon, and welcome to the Ultra <unk> financial results and corporate update conference call for the first quarter 2021.

And issued a press release detailing our financial results, which you can find on our website and ultra <unk> Dot com I and Josh and he got a director of Investor Relations. Joining me on this call are Emil <unk>, Chief Executive Officer, and President Camille Bedrosian, Chief Medical Officer, Eric Harris, Chief Commercial Officer, and Marty Dear Chi.

<unk> financial officer.

I would like to remind investors that this call will include forward looking statements within the meaning of the safe Harbor provisions of the private Securities Litigation Reform Act from 1995, including but not limited to the types of statements identified as forward looking and our annual report on form 10-K that was filed on February 12 2021.

Our quarterly report on form 10-Q that will be filed soon and our periodic subsequent reports filed with the SEC, which will all be available in the investors section on our website. These forward looking statements represent our views only as of the date of this call and involves substantial risks and uncertainties, including many that are beyond our.

Control.

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

For a further description of the risks and uncertainties that could cause actual results to differ materially from those expressed and 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 him.

Thank you, Josh and welcome to everyone on the phone.

So far 2021, and it's been a productive year for ultra genetics.

We've made great progress towards initiation of for pivotal clinical studies with novel therapies for rare genetic diseases, and a broad portfolio of six clinical stage programs.

The clinical progress was complemented by continued advances in our free commercial franchises.

In 2020, one as an important inflection point in our growth as a company.

Starting with gene therapy, we've made significant regulatory and operational and benefits towards the initiation of the D. T X 301 D T X for O, one and UX seven and one pivotal studies.

Most recently, we completed a successful regulatory discussions for D. T X 301, our aviate gene therapy for OTC deficiency.

One of the last key steps for initiating that phase III study.

We've also completed all the formal regulatory discussions for the D. T X for O. One phase III and are working with sites to get and the study started soon.

Early in the year, we announced that the idea is active for innovative phase 123 study for U S. Seven and one and the 89 gene therapy for Wilson disease.

We're currently on track to launch all three of these pivotal studies this year with the GST, one a and Wilson stays on track to begin earn for rolling early and the second half.

In addition to the late stage gene therapies, we are pushing ahead with UX one for three of the monoclonal antibody for osteogenesis imperfecta that we recently licensed from Mario Biopharma.

We are and planning process for the phase three study for this program and we're currently on track to kick off this pivotal study in pediatric patients by the end of the year.

As a reminder, osteogenesis imperfecta. He was one of the largest groups of rare genetic bone disorders and is an excellent complement to christy either with respect to the clinical and commercial capabilities needed to craft and execute the top notch development and launch plan.

Moving to Gtx, one or to the anti sense oligonucleotide program for Angelman syndrome.

We're continuing to make progress towards resuming the phase one two study.

Our goal for the program and just specific time is two fold first to move forward as quickly as possible and we start dosing at the low doses it showed activity.

With and and visually monitor dose titration plan to assure safety.

And second to broaden the scope of the program to allow the program to accelerate once the safe and active dose level has been determined given the strong activity, we have seen with the molecule so far.

To those goals our partner G T genetics submitted and amendment to the existing approved Canadian filing to initiate study and Canada.

Genetics also submitted a new clinical trial.

For the second ex U S regulatory agency to open clinical sites outside of the us.

We have and encouraging we had encouraging discussion with that European regulatory agency regarding GTH, one or two including all of the detailed efficacy safety and non clinical data along with the same dosing and monitoring plan that was provided to the F. D. A.

European and agency agreed in principle with us analysis and planned and a full filing has been made on this basis to that agency.

Based on this interaction and we're confident we can start and study outside of the U S us here.

Our discussions are continuing with the FDA and removing the clinical hold.

Have submitted additional clinical information requested and the meeting is pending with the F. D. A.

Camille will provide a little more detail on this later in the call.

And we look forward to providing updates as definitive milestones are made and the Angelman program.

Moving to our newest clinical stage program and U S. All five three is our mrna candidate for GSD three year glycogen storage disease type three.

The branch for deficiency. This is the first clinical program to come out of our collaboration with Arcturus through which we have rights to 12 programs were working on two other earlier project and the mrna space that we will discuss as they mature we're always evaluating additional opportunities and harnesses promising technology for patients with rare genetic diseases.

And the last year and Marnie has come forward and it's not just a theory, but a viable strategy based on the highly successful COVID-19 vaccine programs.

And we are also very encouraged with what we see with this technology.

You had so far three programs received clearance from the FDA to start the phase one two study and glycogen storage disease type three or deep branch and deficiency and this program will further build and our experience with gene therapy, and glycogen storage disease type one eight for but I'm gerke as disease and is expected to start later this year.

Yeah.

Turning to our commercial portfolio, we had a good Q1 that Eric and Marty will describe further.

Kristina and North America continues to do well now that we're three years into launch us.

As COVID-19 restrictions have eased somewhat and clinics further reopened in 2021, we have seen an increase and diagnosis of actual age patients that we expect to help drive long term growth for Christy that we.

We have and initiate our strength and a number of efforts to support this increased diagnosis and X L. H. This includes increasing our digital and social media activities.

And the set of physicians, we meet with and using patient education and genetic counseling to improve diagnosis across a broad family tree.

And Latin America. The team continues to make good progress and establishing the value of Chris for you to for patients with <unk> and we continue to see more and more patients winning injunctions to receive reimbursed therapy for just started to generate meaningful revenue.

Turning to <unk>, which has been off to a great start.

We saw strong demand and the third and fourth quarter of 2020, driven by conversion of 80 clinical trial and existing compassionate use patients and the most severe of diagnosed patients.

We see a solid growth rate of new starts going forward and we're encouraged by the great positive feedback we are receiving purpose scrubbers and the U S.

And Europe, our discussions with regulators continue but we're also seeing strong named patient demand for <unk>.

Recent longer term efficacy data and safety from 18, eight EU patients and France, either named patient treated patients.

Were published and molecular genetics and metabolism.

Camille will get into the details later in this call, but it's good to see our phase two data corroborated by and independent French investigate and team and their patients and France.

And then I'll hand, the call off to Eric to provide more detail on our commercial progress.

Thank you Emil and good afternoon, everyone and 2020, the commercial team was able to find success and the face of many unprecedented challenges and and the first quarter of 2021 and continue to build on the momentum.

Start with for Sweden.

Our leading indicators, including patient fines start forms and reimbursed patients from the first quarter were strong and we are confident about our trajectory for the rest of the year.

As expected, we did see some seasonality and the first quarter driven by the annual reauthorization process.

At this time, we are reaffirming our 2021 guidance for revenue and Ultra Genesis territories.

$180 million to $190 million.

Based on where we finished 2020 this would represent strong growth, 30% to 37% year over year.

And the United States, we are continuing to hear positive feedback from the medical and patient communities.

Once patients with <unk> or <unk> start therapy with Chris meter very few discontinue.

This is mostly due to the benefits patients are experiencing while receiving christina as well as to support our patient support services team provides us.

At this 0.3 years and to launch.

We have established strong relationships with all of the major endocrinology and metabolic bone centers.

Stronger growth will come from our patient finding efforts and the community clinics, where the majority of our new adult start forms originate.

We are increasing investments and successful tactics that we piloted during the pandemic.

And our modest.

Expanding our field teams to reach more of those community clinics.

Just a quick comment on the launch of course meter for Tio.

Operator: Welcome to the first quarter 2021 Financial Results Incorporate Update Conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star one on your telephone. If you require any further assistance, please press star zero. I would now like to hand the conference over to your speaker today, Joshua Higa. Please go ahead.

We continue to see and steady flow of new starts for them for patients with this ultra rare disease. Many of these patients are seen by the same physicians, who treat patients with <unk> and <unk>.

Hi.

Over time, we expect the launch to continue this trajectory, while leveraging our current fields and patient support teams.

The demand, we're seeing across Latin Americans for breast meat and that remains strong the base of patients continues to expand and as more are granted injunctions.

And access to named patient sales.

Joshua Higa: Thank you. Good afternoon and welcome to the Ultragenyx financial results and corporate update conference call for the first quarter 2021. We have issued a press release detailing our financial results, which you can find on our website at ultragenyx.com. I am Joshua Higa, Director of Investor Relations. Joining me on this call are Emil Kakkis, Chief Executive Officer and President, Camille Bedrosian, Chief Medical Officer, Erik Harris, Chief Commercial Officer, and Marty Deer, Chief Financial Officer.

And just typical within the region, we do expect Latin America ordering patterns to be uneven as our team continues to make significant progress.

Full reimbursement approval within the region.

Turning now to the zone.

Which was approved for the treatment of long chain fatty acid oxidation disorders by the FDA and June 2020 by Health, Canada and February 2021.

And the United States, approximately three quarters and since the launch almost 10%.

Joshua Higa: I would like to remind investors that this call will include forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, the types of statements identified as forward-looking in our

Estimated low end and the range for the prevalent population and the United States have been prescribed <unk>.

No.

We believe that many of these patients are the most severe phenotypes.

And we received approximately 230 start forms from approximately 115 unique prescribers of <unk>.

Annual Report on Form 10-K that was filed on February 12, 2021; our quarterly report on Form 10-Q that will be

And have approximately 100 and PD patients on reimbursed commercial therapy.

[inaudible]

This continues to speak to the broad interest we are seeing from the physician community and strong support from payers.

, which will all be available in the investors section on our website. These forward-looking statements represent our views only as of the date of this call. They involve substantial risks and uncertainties, including many that are beyond our control.

As of the end of March 2021 over 135 million lives and the US have the Dolby coverage from over 50 policies for.

Please note the actual results could differ materially from those projected in any forward-looking statement. For a further description of the risks and uncertainties that could cause actual results to differ materially from those expressed in the forward-looking statements, as well as risks relating to our business, see our periodic reports filed with the SEC.

And as important as this broad coverage, we're seeing the time it takes from receiving and completed start for them to a patient beginning reimbursed therapy to be less and 45 days. This.

And this is a faster turnaround time, and we saw with Chris meter and a similar stage of launch.

Emil D. Kakkis: Thank you, Josh, and welcome to everyone on the phone. So far, 2021 has been a productive year for Ultragenyx. We've made great progress toward the initiation of four pivotal clinical studies with novel therapies for rare genetic diseases in a broad portfolio of six clinical stage programs. This clinical progress is complemented by continued advances in our three commercial franchises, marking 2021 as an important inflection point in our growth as a company. Starting with gene therapy, we made significant regulatory and operational advancements toward the initiation of the DTX-301, DTX-401, and UX-701 pivotal studies.

And it's great and see so many of these patients in the us with.

<unk> successfully navigating their insurance policies.

Emil D. Kakkis: Most recently, we completed successful regulatory discussions for DTX301 or AAV8 gene therapy for OTC deficiency as one of the last key steps before initiating that Phase 3 study. We've also completed all the formal regulatory discussions for DTX-401 Phase 3 and are working with sites to get the study started soon.

Despite the pandemic and the challenges patients are faced with and trying to get in to see their doctor and launches and exceeding our expectations as restrictions continue to ease and we are confident and the current trajectory of new start forms across all three brands for Christina Yoga and <unk> seven.

With that I will turn the call over to Marty to share the financial results.

Thanks, Eric Good afternoon, everyone and thank you for joining today's call. We issued a press release earlier today that included a financial update which I will briefly summarize.

<unk> revenue for the quarter, ending March 31, 2021 and totaled $99 $4 million.

Christy that revenue and ultra Genex territory with $42 $1 billion, including $36 3 million from North and from the North America profit share territory and net product sales at five 9 million and other regions.

Early in the year we announced that the IND is active for our innovative Phase 1-2-3 study for UX701 and the AV9 gene therapy for Wilson disease. We're currently on track to launch all three of these pivotal studies this year with the GSD-1A and Wilson studies on track to begin rolling early in the second half. In addition to the late-stage gene therapies, we are pushing ahead with UX143, the monoclonal antibody for osteogenesis imperfecta that we recently licensed from Muriel Biopharma.

Total royalty revenue related to the sales of Christina and the European territory with $3 9 million.

And as Eric alluded to earlier, there are really two factors to keep in mind when looking at the first quarter Crispy net revenue first and then North American profit share territory. We saw the anticipated seasonality from the annual reauthorization process that occurs at the beginning of each year. We're pleased that day that the first quarter revenue the north and north.

And America profit share territory grew 33% versus the first quarter 2020.

We are in the planning process for the Phase 2-3 study for this program, and we are currently on track to kick off this pivotal study in pediatric patients by the end of the year. As a reminder, Osteogenesis Imperfecta is one of the largest groups of rare genetic bone disorders and is an excellent complement to CRISPR with respect to the clinical and commercial capabilities needed to craft and execute a top-notch development and launch plan. Moving to GTX-102, the antisense oligonucleotide program for Angelman syndrome.

Second we received a large order from the Brazil from Brazil Ministry of health towards the end of the quarter that reflects our success and identifying more <unk> patients.

We're able to get reimbursement for the injunction process and Brazil.

And with the case with Brazil's Ministry of Health, We expect continued uneven ordering pattern for this territory.

<unk> revenue for the quarter was $79.

As we have stated before and we will not be providing revenue guidance printed Java and the first quarters of launch we believe the metrics Eric just discussed better described.

We are continuing to make progress towards resuming the Phase I-II study. Our goal for the program at this specific time is twofold: to move forward as quickly as possible. We will start dosing at the low doses that showed activity, with an invisibly monitored dose titration plan to assure safety.

We are having that we are saying and this launch so far.

Net revenue for the quarter first quarter of 2021 was 369 and we expect these revenues may modestly increase over time.

Second, to broaden the scope of the program to allow the program to accelerate once a safe and active dose level has been determined, given the strong activity we have seen with the molecules so far. To those goals, our partner GT Genetics submitted an amendment to the existing approved Canadian filing to initiate the study in Canada. Ultragenyx also submitted a new clinical trial application with a second ex-U.S. regulatory agency to open clinical sites outside of the U.S. We had an encouraging discussion with that European Regulatory Agency regarding GTX-102, including all the detailed efficacy, safety, and non-clinical data, along with the same dosing and monitoring plan that was provided to the FDA. European Agency agreed in principle with this analysis and plan and a full filing has been made on this basis to that agency.

First quarter 2021 revenue also included $42 8 million related to the tech transfer.

And as part of our strategic manufacturing partnership with Daiichi Sankyo around our Hela, PCL and heck $2 93 technologies.

And the total contract value of approximately $185 million, we have recognized close to 132 million per day.

The remaining amount allocated to the intellectual property and tech transfer services, most likely will be recognized over the rest of this year and will taper significantly over the next three quarters and as the tech transfer activities wind down additional.

Additional details on this revenue recognition can be found in our annual and quarterly reports filed with the SEC.

Our total operating expenses for the quarter were $206 million, which includes research and development expenses of 147, five SG&A expenses of $53 3 million and cost of sales of $5 2 million.

Emil D. Kakkis: Based on this interaction, we are confident we can start the study outside the U.S. this year. Our discussions are continuing with the FDA on removing the clinical hold. We have submitted additional clinical information requested, and a meeting is pending with the FDA. Camille will provide a little more detail on this later in the call.

And the R&D cost and the first quarter of 2021 included the $50 million upfront payment for the closing of the Maria license and collaboration agreement.

As a reminder, we expect our R&D cost this year to increase as we support the three pivotal gene therapy clinical trials. The UX one for three phase three clinical study and osteogenesis imperfecta and the phase one two study for their most advanced mrna program and UX.

We look forward to providing updates as definitive milestones are made in the Angelman program. Moving to our newest clinical stage program, UX-053 is our mRNA candidate for GSD-3 or Glycogen Store Disease Type 3, debranch or deficiency.

This is the first clinical program to come out of a collaboration with Arcturus, through which we have rights to 12 programs. We're working on two other earlier projects in the mRNA space that we will discuss as they mature. We're always evaluating additional opportunities to harness this promising technology for patients with rare genetic diseases. In the last year, mRNA has come forward as not just a theory, but a viable strategy based on the highly successful COVID vaccine program.

Free and TST, three and a number of other preclinical activities as we get ready to advance the next programs and to the clinic.

And I also expect SG&A to modestly increase over 2021, as we continue to support the expansion and launches and crispy that day, Josie and savvy.

For the quarter ended March 31, 2021, net loss was $136 1 million or $2 and <unk> <unk> per share.

And we are also very encouraged with what we see with this technology. The USO-5.3 program has received clearance from the FDA to start the Phase I-II study in Glycogen Steroid Disease Type 3 or Deep Branching Deficiency, and this program will further build on our experience with gene therapy in Glycogen Steroid Disease Type 1a or von Gierke's disease, and is expected to start later this year. Turning to our commercial portfolio, we had a good Q1 that Erik and Marty will describe further. Chris Vita in North America continues to do well now that we are three years into launch.

This compares to a net loss for the same period, and 2020 of $119 million or $2 and five pence per share and.

Net loss for the first quarter 2021 includes the $50 million upfront payment from morale and a $26 million decrease and the fair value of investments and equity securities.

Net cash used in operations for the quarter was 153 $159 $3 million, which includes the upfront payment to morale as compared to the $95 $2 million for the same period and 2020.

Emil D. Kakkis: As COVID restrictions have eased somewhat and clinics further reopen in 2021, we have seen an increase in diagnosis of XLH patients that we expect to help drive long-term growth for CRISFIDA. We have initiated or strengthened a number of efforts to support this increased diagnosis of XLH. This includes increasing our digital and social media activities; broadening the set of physicians we meet with; and using patient education and genetic counseling to improve diagnosis across a broad family tree.

We ended the quarter with over $1 billion and cash cash equivalence and marketable securities. This puts us and our strong capital position to reach key clinical and commercial milestones as we continue executing our development and commercial strategy.

Now all of that can you touch on some of our clinical programs.

Thank you Marty and I too wish everyone. Good afternoon.

I would like to start by providing a regulatory update on Gtx, one O two which is being developed with our partner genetics for the treatment of Angelman syndrome.

Emil D. Kakkis: In Latin America, the team continues to make good progress in establishing the value of CRISPR for patients with XLH, and we continue to see more and more patients winning injunctions to receive reimbursed therapy, which has started to generate meaningful revenue. Turning to Oshaldi, who has been off to a great start.

Angelman syndrome is a devastating neural genetic disorder with a broad spectrum of disease manifestations, including speech and cognitive impairment.

CEA or balance issues.

Growth and fine motor dysfunction sleep dysfunction and seizures.

We saw a strong demand in the third and fourth quarter of 2020, driven by conversion of 80 clinical trial and existing compassionate use patients and the most severe of diagnosed patients. We see a solid growth rate of new starts going forward and we're encouraged by the great positive feedback we are receiving from prescribers in the U.S. In Europe, our discussions with regulators continue, but we're also seeing strong inpatient demand for Dojovi.

Last year, we reported positive efficacy data from the first five patients treated and the phase one two study indicated substantial improvements and multiple domains and all patients.

We also reported all five patients had a grade one or two serious adverse event of lower extremity weakness.

Recent longer-term efficacy data and safety from 18 ATU patients in France, these are named patients treated with ATU, were published in Molecular Genetics and Metabolism. Camille will get into the details later in this call, but it's good to see our Phase 2 data corroborated by an independent French research team in their patients in France. I'll now hand the call off to Erik to provide more detail on our commercial progress.

That now has fully resolved, we paused dosing and enrollment at the first presentation of the event.

And supportive resuming the clinical study we have provided the FDA with additional non clinical data showing the effects of Gtx 102, and nonhuman primate models at single and repeat doses at levels far exceeding and equivalent dose that would be expected to be used and our clinical program.

The delayed onset weakness, we saw and the phase one two was not observed and the nonhuman primates with single doses as high as 10 milligrams or a 110 milligram human equivalent dose.

Erik Harris: Thank you, Emil. And good afternoon, everyone. In 2020, the commercial team was able to find success in the face of many unprecedented

in the face of many unprecedented challenges. And in the first quarter of 2021, we continue to build on that moment.

Nor was it observed with seven monthly doses at four milligrams or an equivalent cumulative dosing humans of 314 milligrams.

Erik Harris: Our leading indicators, including patient fines, start forms, and reimbursed patients in the first quarter, were strong, and we are confident that

And importantly, we did see a strong knockdown of the <unk> anti sense and very low monthly doses, beginning at one milligram or approximately 10 milligram dose equivalent and humans.

Our trajectory for the rest of the year. As expected, we did see some seasonality in the first quarter driven by the annual reauthorization process. At this time, we are reaffirming our 2021 guidance for revenue in Ultragenyx territories of $180 to $190 million. Based on where we finish 2020, this would represent strong growth of 30 to 37% year over year.

We also saw a measurable though not as strong effect at zero point.

And five milligrams dose monthly.

We recently requested a meeting with the FDA following multiple submissions that substantial non clinical and clinical data, including data confirming that the serious adverse event and the previously treated patients has fully reversed.

In the United States, we are continuing to hear positive feedback from the medical and patient communities. Once patients with XLH or TIL start therapy with Crisvita, very few discontinue it. This is mostly due to the benefits patients are experiencing while receiving CRIS VITA, as well as the support our patient support services team provides.

This meeting has been granted for later this quarter.

Following the meeting we hope to have fully satisfy the fda's questions around the SAE and to have approval to resume dosing and patients in the U S.

Now I'd like to shift to our strategy outside of the U S.

We have established strong relationships with all of the major endocrinology and metabolic bone centers. Further growth will come from our patient-finding efforts in the community clinics where the majority of our new adult star forms originate. We are increasing investments in successful tactics that we piloted during the pandemic and our modest, expanding our field teams to reach more of those community clinics. Just a quick comment on the launch and procedure for TIL. We continue to see a steady flow of new start forms for patients with this ultra rare disease. Many of these patients are seen by the same physicians who treat patients with XLH and

Earlier this year, we held a pre application meeting with a national regulatory authority and Europe, where we presented detailed safety.

Efficacy and non clinical information about Gtx one O two.

The authority has agreed in principle on the expansion of the trial to Europe using our proposed modified study design dosing and administration strategy pending review of the application.

The application to enroll clinical studies and this country was recently submitted.

Separately, we also recently submitted and amended dataset and protocol to the Canadian authorities in order to begin enrolling patients there.

This submission is currently being reviewed by health Canada.

Over time, we expect the launch to continue this trajectory while leveraging our current field and patient support team. The demand we are seeing across Latin America for the perspirator remains strong, and the base of patients continues to expand as more are granted injunctions, gaining access to many patient cells.

Our modification to the study protocol include and amended administration and dose titration plan.

10, denenberg and and artificial CSF flush should help reduce the local contact time and helped me a ASO weeks for cisterna Magna as it is diluted and.

As is typical within the region, we do expect Latin America ordering patterns to be uneven as our team continues to make significant progress on full reimbursement approval within the region. Turning now to The Joke, which was approved for the treatment of long-chain fatty acid oxidation disorders by the FDA in June 2020 and by Health Canada in February 2021. In the United States, approximately three quarters into the launch, almost 10% of the estimated low end of the range for the prevalent population in the United States have been prescribed the Joby.

And so circulation distributed to the brain.

Patients will be divided into two starting dose cohorts based on age.

Under eight years old well receive a starting dose of 3.3 milligrams and while those eight years and older will start at five milligrams.

Titration to higher doses will be evaluated on an individual basis. After several repeat doses have been administered.

This new dosing plan is within the observe range of clinical and non clinical activity, but below the doses associated with S. H E.

With this three pronged approach, we feel confident we will be able to us in this important study and share additional clinical data before the end of this year.

We believe that many of these patients are the most severe phenotype. We received approximately 230 initial forms from approximately 115 unique prescribers.

Turning now to <unk> 401, our gene therapy for the treatment of glycogen storage disease type, one a or GSD one day.

of the Jogi, and have approximately 180 patients on reimbursed commercial therapy. This continues to speak to the broad interest we are seeing from the physician community and strong support from payers. As of the end of March 2021, over 135 million lives in the U.S. have been recovered from over 50 policies. Perhaps as important as this broad coverage, we are seeing the time it takes from receiving a completed start form to a patient beginning reimbursed therapy to be less than 45 days.

We previously completed the scientific advice process with the European Medicines agency and held the end of Phase II meeting with the F D. A.

Following these regulatory discussions we submitted the study protocols two months ago to the F D. A.

As of this call. The FDA has not provided any objections to starting the study.

And we await some informal feedback from the agency, we simultaneously I'm moving forward with study startup.

This is a faster turnaround time than we saw with CRISPR at a similar stage of launch. It is great to see so many of these patients in the U.S. with LC-FAODs successfully navigating their insurance policies. Despite the pandemic and the challenges patients are faced with in trying to get in to see their doctor, the launch is exceeding our expectations.

As we finalize and timing of IRB submissions and approvals, we expect the study to be up and running soon and anticipate dosing the first patients and the early part of the second half of this year.

Next I'll turn to D. T X 301, our gene therapy for the treatment of ornithine transcribe families or OTC deficiency.

At the end of the first quarter, we held a successful and the phase two meeting with the FDA and together with feedback from the EMA. We now have a finalized phase III <unk> study design and endpoints.

As restrictions continue to ease, we are confident in the current trajectory of new start forms across all three brands. Chris Vita, Yovi, and Mep7.

Erik Harris: With that, I'll turn the call over to Marty to discuss the finances.

The study will enroll approximately 50 patients ages 12 years and older.

Maurice Thomas Raycroft: Thanks, Erik. Good afternoon, everyone, and thank you for joining us on today's call.

Patients will be randomized one to one to either <unk> or placebo.

The dose of one seven times 10 to the 13 genome copies per kilogram defined by the digital drop assay is the same dose that we studied and the third and fourth cohorts of the phase one two study.

Maurice Thomas Raycroft: We issued a press release earlier today that included a financial update, which I will briefly summarize. Company revenue for the quarter ending March 31, 2021 totaled $99.4 million. CRECETA revenue in Ultragenyx territory was $42.1 million, including $36.3 million from North America profits.

For the Phase III study, we will have co primary endpoints.

The first is this change and 24 hour plasma ammonia levels and the second co primary is the percentage of patients who achieve a response, which we measure by 50% or more discontinuation for reduction and baseline disease management.

Total royalty revenue related to the sales of CRISPR-Vita in the European territory was $3.9 billion. As Erik alluded to earlier, there are

really two factors to keep in mind when looking at the first quarter Crispita revenue. First, in the North America Profit Share Territory, we saw the anticipated seasonality from the annual reauthorization process that occurs at the beginning of each year. We are pleased that the first quarter revenue in the North America Profit Share Territory grew 33% versus the first quarter, 2020. Second, we received a large order from Brazil's Ministry of Health towards the end of the quarter that reflects our success in identifying more XLH patients that are able to get reimbursement through the injunction process in Brazil.

We did lengths and the phase III durations slightly 48 weeks to 64 weeks to allow more time for patients to be weaned off of their ammonia scavenger medications and protein restricted diet.

From our experience with the phase one and two study we know that it can take some time to establish normal ammonia and metabolism and to be able to safely reduce baseline treatment.

By moving to 64 weeks, we expect there will be enough time to assure success and the baseline treatment reduction co primary endpoint and.

And still proceed to development as rapidly as possible.

As with the case with Brazil's Ministry of Health, we expect continued uneven ordering patterns for this territory. The Joby revenue for the quarter was $7 million. As we have stated before, we will not be providing revenue guidance for the JOVI in the first quarters of launch. We believe the metrics Erik just discussed better describe the situation.

With the Finalization of the phase III design that incorporates feedback from both FDA and EMA and we are rapidly moving forward towards initiation of the study and the second half of this year.

Lastly, I'd like to touch on data that were recently published and molecular genetics and metabolism.

Success that we are seeing in this launch so far. MFSEBI revenue for the quarter, first quarter of 2021 was $3.6 million. We expect these revenues may modestly increase over time. First quarter 2021 revenue also included $42.8 million related to the tech transfer as part of our strategic manufacturing partnership with Daiichi Senkyo around our HeLa-PCL and HEC-293 technologies. Of the total contract value of approximately $185 million, we have recognized close to $132

Describe the clinical outcomes of 18, pediatric and adult patients with long chain fatty acid oxidation disorders, or LC S. E. O D who were treated with don't tell me or do I have to knowing for a median duration of 22 months.

The remaining amount allocated to intellectual property and tech

And this paper 18 early access French cases showed that two I have to know and reduce the need for medical intervention.

Patients in this cohort were followed for a range of nine to 228 months.

Similar to the published and towards the Phase two data the accumulative annual number of days of emergency home care was reduced from a total of 286 days to 51 days during the 12 months on therapy.

Tech Transfer Services most likely will be recognized over the rest of this year and will taper significantly over the next three quarters as the tech transfer activities wind down. Additional details on this revenue recognition can be found in our annual and quarterly reports filed

Notably 13 of these patients who acquired zero days of emergency home care. During this time.

Other reported clinical improvements included reduced fatigue and my Alger.

And elimination of the need for wheelchair us and five of the six patients who had required it.

Family Reports filed with the SEC.

Our total operating expenses for the quarter were $206 million, which includes research and development expenses of $147.5 million, SG&A expenses of $53.3 million, and cost of sales of $5.2 million. The R&D cost in the first quarter of 2021 included the $50 million upfront payment for the closing of the Moreo License and Collaboration Agreement. As a reminder, we expect our R&D costs this year to increase by $1.3 billion.

And the year prior to receiving <unk>.

With these updates I will now turn back the call to Emil Thank you.

Thanks Camille.

After completing for approvals and our first 10 years, we've built out our pipeline and ultra genetics. These last few years to put us and positioned to have both for full pipeline of late stage assets and multiple products in launch mode.

With all of our us as one of the broadest and most diverse portfolios and the rare disease space.

U.S. Centers for Disease Control and Prevention.

Our clinical pipeline now includes six program is well balanced across modes and come through gene therapies, and antibody and anti sense oligonucleotide and mrna and.

Phase II-III Clinical Study in Osteogenesis Infracocta Phase I-II Study for the Most Advanced mRNA Program, UX-053 in GSD-3 and a number of other preclinical activities as we get ready to...

And include smaller rare diseases, where we're essentially the only drug development, but also includes more competitive and much larger opportunities.

Advanced, the next program is in the clinic. We also expect SG&A to modestly increase over 2021.

Over the long term, we will continue the strategy of using our insights and relationships and rare disease defined as advance a diverse set of compelling opportunities.

Thank you everyone, as we continue to support the expansion and launches of CRISPR-DigitalVMF7. For the quarter ended March 31, 2021 net loss was $136.1 million or $2.03 per share. This compares to a net loss for the same period in 2020 of $119 million or $2.05 per share. The net loss for the first quarter 2021 includes the $50 million upfront payment to Morayo and a $20.6 million decrease in the fair value of investments and equity security.

We will focus most of our efforts now on executing on the new studies and data Readouts that we have laid out for 2021 and beyond.

And with that let's move on to the Q&A portion of the call. Operator, please provide the instructions for asking questions.

Thank you to ask a question you will need to press star Linda and number one on your telephone to withdraw your question press the pound key.

And by while we compile the Q&A roster.

Net Cash Use and Operation

Your first question comes from the line of Joseph Schwartz.

The total number of operations for the quarter was $159.3 million, which includes the upfront payment to Moreo, as compared to the $95.2 million for the same period in 2020. We ended the quarter with over a billion dollars in cash, cash equivalents, and marketable securities. This puts us in a strong capital position to reach key clinical

As we believe Inc. Your line is now open.

Hi, I'm, Jerry dialing in for Joe and Thank you for taking our questions. My question and D. T X 301 for OTC deficiency.

Typically when you have a co primary endpoint it can be analyzed several different ways and usually you have to hit both endpoints, but sometimes you can just hit one of the two or the hurdle can be higher for one over the other endpoints. So I was just wondering if you could discuss the statistics for your phase III study.

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

Camille L. Bedrosian: Now I'll let Camille touch on some of our clinical programs.

Camille L. Bedrosian: Thank you Marty and I too wish everyone good afternoon. I would like to start by providing a regulatory update on GTX-102, which is being developed with our partner, Genetics, for the treatment of Angelman syndrome. Angelman syndrome is a devastating neurogenetic disorder with a broad spectrum of disease manifestations including speech and cognitive impairment, ataxia or balance issues, gross and fine motor dysfunction, sleep dysfunction, and seizures.

Yes, well, we are expecting to have to hit both endpoints the ammonia.

Control is easy, but I think the question with the responder enough and we think as the clinical meaningfulness of the result, and the clinical meaningfulness, we think.

It's quite dependent on being able to get off of existing therapies. So if we control ammonia, but can't get people off therapies and.

It doesn't mean much but our view would be based and everything we've seen so far that if we control ammonia maintain.

Last year, we reported positive efficacy data from the first five patients treated in the Phase I-II study that indicated substantial improvements in multiple domains in all patients. We also reported all 5 patients had a grade 1 or 2 serious adverse event of lower extremity, that now has fully resolved. We pause dosing and enrollment at the first presentation of the event.

And maintain their monier and get it below a certain level, we will be able to reduce their diet and drugs. So we feel confident and putting both and point forward.

Okay, great. Thank you and then.

How are you defining a responder I know that for the and your opening remarks, you mentioned and 50% plus reduction and the baseline disease management, but I guess I'm curious about the ammonia component are you assuming is there like a threshold you have to meet or are you trying to get their patients down to the normal normal range.

In support of resuming the clinical study, we have provided the FDA with additional non-clinical data showing the effects of GTX-102 in non-human primate models at single and repeat doses, at levels far exceeding an equivalent dose that would be expected to be used in our clinical program. The delayed onset weakness we saw in the Phase 1-2 was not observed in the non-human primates with single doses as high as 10 mg or a 110 mg human equivalent dose.

Now the ammonia analysis is really a continuous variable reduction and ammonia level. So it is not a responder determined analysis for ammonia and since we will let relax the entry criteria for ammonia and we've seen very sharp declines and pneumonia, we'd expect a spread of ammonia levels across a range and we expect that varies.

And to compress us among patients who are treated so it's a continuous variable ammonia level will be measured not a responder and the diet and the reduction and care the fishing and threshold.

Nor was it observed with 7 monthly doses of 4mg or an equivalent cumulative dose in humans of 314mg. Importantly, we did see a strong knockdown of the UBE3A antisense at very low monthly doses, beginning at 1mg or approximately 10mg dose equivalent in humans. We also saw a measurable, though not as strong, effect at 0.5%.

You could think of it as if you have Fisher cent decrease will say if you get off your scavenger drugs.

Relax your diet that would be 50% reduction and your care for Ting scavenger drugs and diet.

If you get off both that's a 100% if you get off one and 50% and the way. The responder analysis will goes will account for 50% and it was getting off the drugs alone will count as a response for that endpoint and getting up everything will count.

5 mg dose monthly. We recently requested a meeting with the FDA following multiple submissions of substantial non-clinical and clinical data, including data confirming that the serious adverse event in the previously treated patients has fully reversed. This meeting has been granted for later this quarter.

You know as a complete responder and it would be 100%.

And so we'll look at the percent reduction in response and treatment requirement.

Okay, great. Thank you so much.

Following the meeting, we hope to have fully satisfied the FDA's questions around the SAE and to have approval to resume dosing in patients in the U.S. Now I'd like to shift to our strategy outside of the U.S. Earlier this year, we held a pre-application meeting with the National Regulatory Authority in Europe, where we presented detailed safety, efficacy, and non-clinical information about GTX-102. The authorities agreed in principle on the expansion of the trial to Europe using a proposed modified study design, dosing and administration strategy, pending review of the application. The application to enroll clinical studies in this country was recently submitted.

The next question comes from the line of Gena Wang from Barclays. Your line is now open.

Thank you for taking my questions I have two regarding the Angelman and one is for the U S and why and so for the ex U S for the U S. Thanks.

FDA did and ask you for additional animal data and EU submit additional clinical data.

Wondering you know what could hold FTE back.

And your second quarter meeting and then for the ex U S. A both Europe and Canada are pending review will you be able to start dosing in first half this year and I think you did mention that we will have some patient data by the end of this year can you.

Separately, we also recently submitted an amended data set and protocol to the Canadian authorities in order to begin enrolling patients there. This submission is currently being reviewed by Health Canada. Our modification to the study protocol include an amended administration and dose titration plan. Tandellenberg and an artificial CSF flush should help reduce the local contact time and help the ASO reach the cisterna magna as it is diluted and through circulation distributed to the brain.

Library, and a little bit what kind of data will be shared by the end of this year.

Very good I'll I'll go ahead and answer that so on the first part the Angelman and they asked for more data on the individual patients and that were treated and have the event mainly to deter us.

Third complete reversal and we've done some additional things and show that they are completely reversed.

The question is what could hold them up we think we've given them enough to get forward. So I'm not sure what else would hold them up but I think we are.

And responsive to their requests and we hope that we will move forward, but I don't have and my head right now what would be the reason not to go ahead.

Patients will be divided into two starting dose cohorts based on age. Those under 8 years old will receive a starting dose of 3.3 mg, while those 8 years and older will start at 5 mg. TITRATION TO HIGHER DOSES WILL BE EVALUATED ON AN INDIVIDUAL BASIS AFTER SEVERAL REPEAT DOSES HAVE BEEN ADMINISTERED.

However that said, we also know that sometimes.

You can't predict what regulatory authorities will do and we have initiated work to also initiate and steady ex U S.

Well, we said today is that one ex U S authorities said agreed with a planned given the knowledge about the serious adverse event and the efficacy and everything agree with our plan to move for the same plan, we had smoothed the F D. A Canadian stories I've seen that now we're waiting for their response.

This new dosing plan is within the observed range of clinical and non-clinical activity but below the doses associated with SAE. With this three-pronged approach, we feel confident we will be able to resume this important study and share additional clinical data before the end of this year. Turning now to DTX-401, our gene therapy for the treatment of Glycogen Storage Disease Type 1a or GSD-1a.

The timing of those responses from low threes will determine the timing when we can get going if they were happened within a shorter period of time, we could get going if they take their full.

Period required we may not dose there and the first half it's hard to know.

With the us of course, if depending on their response, we could dose now what we've said and the release, though is it given what we know now about the ex U S path.

We have previously completed the scientific advice process with the European Medicines Agency and held the End of Phase II meeting with the FDA. Following these regulatory discussions, we submitted the study protocol two months ago to the FDA. As of this call, the FDA has not provided any objections to starting the study. While we await some informal feedback from the agency, we are simultaneously moving forward with study start-ups.

One way or another we will have some data and some patients this year and that's the.

Point were making for everyone Gina, but you can't precisely say, how those although we're going to play out as they undergo three different regulatory authorities are looking at reviews.

Okay, and then what kind of data with the ship.

Well, we're talking about us as the first patients re dosing again at the going through since they're dosing once a month, we would expect to have several months of dosing on a set of patients are first our plan currently that we're proposing is 12 patients six below age eight or six above.

As we finalize timing of IRB submissions and approvals, we expect the study to be up and running soon and anticipate dosing the first patients in the early part of the second half of this year. Next, I'll turn to DTX301, our gene therapy for the treatment of ornithine transcarbamylase, or OTC, just, At the end of the first quarter, we held a successful end of phase 2 meeting with the FDA, and together with feedback from EMA, we now have a finalized phase 3 study design and end, The study will enroll approximately 50 patients ages 12 years and older.

And so we'd be looking for some fraction of those patients be treated at least few times based on our response, we have seen before that within us.

Patients will be randomized one-to-one to either DTX301 or placebo. The dose of 1.7 times 10 to the 13 genome copies per kilogram defined by the digital drop assay is the same dose that we studied in the third and fourth cohorts of the Phase I-II study. For the phase three study, we will have co-primary MD. The first is a change in 24-hour plasma ammonium levels, and the second co-primary is the percentage of patients who achieve a response, which we measure by 50% or more discontinuation or reduction in baseline disease management.

One or two Modo says, we started seeing things and so we think within the timeframe with three or four doses. We would have the opportunity to see if we're seeing the clinical effect and whether we are getting the adverse effect.

It wouldn't be definitive information, but at least tell you are we dosing is it safe and are we seeing some activity and that's the kind of ratio will give you a sense of where we're going.

Next question comes from the line of <unk> Ahmad from Bank of America. Your line is now awesome.

Hi, good afternoon, and thanks for taking my question and as.

And as it relates to Angelman and.

I guess when would you need to start for assumption of the study this year in order to meet your targeted goal of having some clinical data available on patients by the end of this calendar year.

And as it relates to the safety profile of the drug is that kind of a make or break situation based on any discussions that you've had with the agency and the reason I'm asking us Angelman is an area of under met need if you are showing us.

We did lengthen the Phase III duration slightly, 48 weeks to 64 weeks, to allow more time for patients to be weaned off of their ammonia scavenger medications and protein-restricted diet. From our experience with the Phase 1-2 study, we know that it can take some time to establish normal ammonia metabolism and to be able to safely reduce baseline treatment.

And efficacy in these patients.

And what is the tolerance do you think that the agency and or physicians would have to.

A safety profile that might not be 100% clean thank you.

Sure so.

On the when started our expectations, we'd need to get started either late this half or early next half and order to have a few at least a few doses of and a number of patients right before the end of the year. So it would have to be late this half early next half and order to accumulate enough data.

Camille L. Bedrosian: By moving to 64 weeks, we expect there will be enough time to assure success in the Baseline Treatment Reduction Co-Primary MPR, and still proceed through development as rapidly as possible. With the finalization of the Phase III design that incorporates feedback from both FDA and EMA, we are rapidly moving forward toward initiation of the study in the second half of this year. Lastly, I'd like to touch on data that were recently published in Molecular Genetics and Metabolism, that described the clinical outcomes of 18 pediatric and adult patients with long-chain fatty acid oxidation disorders, or LC-SAOD, who were treated with Dojovi or Triheptanoin for a median duration of 22 months.

Whatever data, we were gonna say us whatever data we have we will put out some an update on that information. However, many patients how it works much time.

So we will commit to doing that.

With regard to the safety profile.

We think that having low extremity weakness wouldn't be a good profile to have for a chronic treatment like this so what really we believe we can get past that because its not a drug pharmacologic effect, it's like a local irritation inflammation effect, which is something that should be very manageable. So we're confident we can get past that.

Camille L. Bedrosian: In this paper, 18 early access French cases show that triheptanoin reduced the need for medical intervention. Patients in this cohort will follow for a range of 9 to 228 days. Similar to the published Dojovi Phase 2 data, the cumulative annual number of days of emergency home care was reduced from a total of 286 days to 51 days during the 12 months on therapy. Notably, 13 of these patients required zero days of emergency home care during this time.

And even so if once we know that and a ASO can have this kind of effect. There are many avenues ahead of us even if this all ago, we had to change it we could we could of course do us.

Now that we're in this space and we have this ability to change clinical future Angelman and it's something worth fighting for and we will fight for getting this done with a drug that gives patients and important efficacy.

And our safety, that's appropriate and I don't think having low extremity weaknesses and.

Successful is a long term safety outcome.

Okay. Thank you and maybe a quick question on Wilson.

Emil D. Kakkis: Other reported clinical improvements include reduced fatigue and myalgia and elimination of the need for wheelchair use in five of the six patients who had required it in the year prior to receiving triheptanol. With these updates, I will now turn back the call to Emil. Thank you.

You are expected to start your study and the second half of this year.

How big of a study do you plan on this being given that you are describing it as a single protocol.

And I think one through three study.

Yeah. So the Wilson Phase III study is a phase one two study bolted on to a phase III study to be most accurate Seamlessness US we don't go back to the regulatory authorities between the decision, making us all preset.

After completing four approvals in our first 10 years, we've built out our pipeline, Ultragenyx, these last few years to put us in position to have both a full pipeline of late stage assets and multiple products in launch mode. The result of our S is one of the broadest and most diverse portfolios in the rare disease space. Our clinical pipeline now includes six programs, is well balanced across modes encompassing gene therapies and antibody and antisense oligonucleotide and mRNA, includes smaller rare diseases where we are essentially the only drug development, but also includes more competitive and much larger opportunities.

So the way it's going to go as we're doing cohorts in stage one courts.

At three different dose levels and sequence the randomized for the placebo group.

And those cohorts will be six and three so there'll be.

A total of 27 patients and that the second half for this study is on the order of 60 to 70 patients.

At this point and time, that's our expectation.

Over the long term, we will continue the strategy of using our insights and relationships in rare disease to find and advance a diverse set of compelling opportunities. We'll focus most of our efforts now on executing on the new studies and data readouts that we have laid out for 2021 and beyond. Now with that, let's move on to the Q&A portion of the call. Operator, please provide the instructions. Thank you for asking questions.

Okay. Thank you.

Next question comes from the line of Yaron Werber from Colin Your line is now open.

Great. Thanks for taking my question.

Two questions from me if you don't mind one is.

And do you have to go day, one actually see the the weakness recapitulated in animal models.

Operator: Thank you. To ask a question, you will need to press star, then the number 1 on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Your first question comes from the line of Joseph Schwartz. From S. V. B. Lirenk, your line is now open. Hi, I'm Joori dialing in for Joe. Thank you for taking our questions. My question is on DTX 301 for OTC deficiency. Typically, you know, when you have a

And to show resolution for them to move forward or is that not one of the things because its hard to recapitulate that I'm trying to get a sense of what would get them comfortable and then and then secondly, when you look at the the structure. This is a cyclic base GAAP and more rights of the it becomes true a little different from spinoff.

And how valid and the chemistry. Thank you.

Well the FDA has not asked us to recreate anything and animals frankly at all and they did not ask us do any more work. They recognize we've used higher dose and animals and for many repeated doses with very high load and not seen it. So it's clearly not a toxicity of this all ago.

Co-Primary Endpoint. It can be analyzed in several different ways.

Transcription by Transcription Outsourcing, LLC.

And I'll go is not shouldnt be talks and on premise and so I think that's really important.

the other end point. So I was just wondering if you could discuss the

What else can say with regard to the chemistry.

If you could discuss the statistics for your Phase 3 study,

Is it <unk> Ken of toxicities, but this particular I'll go does not have toxicities that we see.

Emil D. Kakkis: Yeah, so we're expecting to have to hit both endpoints. The ammonia control is easy, but I think the question with the responder analysis we think is the clinical meaningfulness of the results. And the clinical meaningfulness we think is quite dependent on being able to get off of existing therapies. So if we control ammonia but can't get people off therapies, then it doesn't mean much. But our view would be, based on everything we've seen so far, that if we control ammonia... Maintain their ammonia or get it below a certain level, we will be able to reduce their diet and drugs. So we feel confident in putting both endpoints forward.

And the pathology of and on your prime rates given repeat doses.

So we feel comfortable at the chemistry is us being appropriate I do think the ability of aso's to cause irritation or injury is not and.

It's not new it's.

It's been seen Theres been high protein and CSF and a number of ASO programs, including the recent H D. One I think the key here is what's the therapeutic index how much efficacy do you get for the dose and in this case, we have with this LMA extraordinarily potent and Illinois.

Okay, great. Thank you.

Drug that is actually achieving.

Beginning achieve efficacy and the three to 10 milligram range. So a very potent and we think that that range. We can avoid those secondary contact assist for the issues. We think that's a distinct advantage of that based on that the true high potency of this particular one.

Emil D. Kakkis: And then How are you defining responder? I know that for the, in your opening remarks, you mentioned 50% plus reduction in the baseline disease management, but I guess I'm curious about the ammonia component. Are you assuming, is there like a threshold you have to meet or are you trying to get the patients down to the normal range?

So right now we're comfortable the chemistry, we think it's.

Particular choices made we're very potent we are aware of a lot of variations that we've made and others have made.

Now, the ammonia analysis is really a continuous variable reduction in ammonia level, so it is not a responder-determined analysis for ammonia. And since we will let relax the entry criteria for ammonia, and we've seen very sharp declines in ammonia, we'd expect a spread of ammonia levels across a range, and we expect that variation to compress among patients that are treated. So it's a continuous variable ammonia level will be measured, not a responder.

Dr Jindo sense exceptionally high quality work and if so we will good about where we're at.

And we're of course, we're also looking at making small variations that might.

And it changed the profile, but we feel pretty good about this existing and efficacy were seeing and.

And right now the FDA is just waiting more confirmation about the clinical situation and have not asked for any other animal data from us.

In the diet, in the reduction in care, the 50% threshold, you could think of it as if you have 50% decrease, let's say if you get off your scavenger drugs, but not relax your diet, that would be 50% reduction in your care. So think of the scavenger drugs and diet. If you get off both, that's 100%. If you get off one, it's 50%. And the way the responder analysis will go is we'll count 50%.

With that matures for long term follow up clinically and how do you control the risk mitigation because that would have us.

And they just wanted a more definitive proof that the patients didn't have any residual neurological effects.

Because I think this is a benefit risk question. They were trying to assess if they put more patients at risk will they have and irreversible harm from that right.

Is that fundamental we've said no. They just wanted further information to confirm that that's true.

That is, getting off the drugs alone will count as a response for that endpoint. And getting off everything will count. You know, it's a complete responder, and it would be a hundred percent. And so we'll look at the percent reduction in response over treatment requirements.

And we have good reasonably but it's not because we don't think it's the direct neurotoxicity issue I think it's just and your flattish inflammation issue.

And it resolved the majority in fact resolve and then.

A few weeks.

And so they just wanted more definitive quantitative measure that help prove that they are reversed and we have done those measures, including mris and more.

Okay, great. Thank you so much.

And final you know a lumbar punctures.

I have two regarding the Andrew Mann. One is for the U.S. and one is for the ex-U.S.

Special Neurophysiological test and found that patients are normal.

Great. Thank you.

Next question comes from the line of Bank and half from Stifel. Your line is now open.

Good afternoon, and thanks for taking my question and maybe I'll just touch on one more angelman question. So.

At your second quarter meeting and then for the ex-US both Europe and Canada are pending review Will you be able to start dosing in first half this year? And I think you did mention that we'll have some patient data by the end of this year Can you elaborate a little bit what kind of data will be shared by the end of this year?

Recognizing you have three parallel paths with the ex U S sites as well as the US I was wondering if you can comment on potential alignment between the three regulatory discussions I mean do you see a lot of concordance between the three or do you see quite a bit of disparity.

In terms of what they are requesting and then second question is more commercial I was wondering perhaps it's for Eric given that U S has been easing up you and your prepared remarks talked about the irregular ordering patterns and Latam, but now COVID-19 also seems to be somewhat more ramp and and the ex U S sites. So I was wondering.

Emil D. Kakkis: Very good. I'll go ahead and answer that.

So on the first part, the Angeman, they asked for more data on the individual patients in that were treated and had the event mainly to assess their complete reversal. And we've done some additional things and showed they're completely reversed. The question is what can hold them up?

And what you guys are currently is saying and that development front. Thanks.

We think we've given them enough to get forward, so I'm not sure what else would hold them up, but I think we've been responsive to their requests and we hope that we'll move forward. But I don't have in my head right now what would be the reason not to go ahead. However, that said, we also know that sometimes, We can't predict what regulatory authorities will do and we have initiated work to also initiate and study Ex-U.S. What we said today is that one ex-US authority said, agreed with the plan, given the knowledge about the serious adverse event and the efficacy and everything, agreed with our plan to move forward with the same plan we had submitted to the FDA.

Very good thanks for the question, Doug and I'll, let Eric and a moment you can talk about COVID-19 around the world Eric.

Eric So prepare for that I'll do the first part so.

One of the Great Tech.

Techniques and rare disease regulatory is to exploit the actual differences between regulatory authorities and find the best answer somewhere and or to move forward and that is extremely important part of moving.

Very complex diseases forward and the drug development. So it was very often that we will go to another authority in order to get started and get going and Boston.

Canadian authorities have seen that now. We're waiting for their response. The timing of those responses from the authorities will determine the time when we can get going. If they happened within a shorter period of time, we could get going. If they take their full period required, we may not dose them there in the first half. It's hard to know for sure. With the U.S., of course, depending on their response, we could do so. Now, what we have said in the release, though, is that given what we know now about the ex-U.S. path, we will have some data in some patients this year. And that's the point we're making for everyone, Gina. But we can't precisely say how all those are going to play out as they unfold. Three different regulatory authorities are looking into the reviews.

Bob and three programs that did that and the and all came back to the US all got approved in the US. So it's just a normal thing we don't really look for Concord and see.

Okay, and then what kind of data will be shared?

We are proposing ex U S. The same study and the same design, we have not had any negative feedback from the.

Other European authority does not give us any changes to the protocol that were fundamental and whatever the Canadians are seeing are actually in line with what we submit it to our other European So that's the same and we don't have any further feedback with.

With the FDA right now we're highly focusing in on the current five patients and re dosing them and just getting their understanding about doing that piece.

And by limiting the scope, we think will give us an opportunity to kind of generate a little bit of.

And more narrow and safe path for getting started and the U S and the existing five patients.

Well, what we're talking about is the first patients redosing again at the going through since they're dosing once a month, we would expect to have several months of dosing on a set of patients. Our first our plan currently that we're proposing is 12 patients, six below age eight or six above. And so we'd be looking for some fracture of those patients to be treated at least a few times.

So that's our approach right now.

So let me hand, this off now to Eric to talk a little about I think the question was Eric on.

COVID-19, maybe easing up and the us but house COVID-19 affecting.

South America.

Yeah, a couple of things I'd point out first when you consider 2020, we put out our guidance and advance of the COVID-19 pandemic and we ended up and the upper end and that's because.

Based on our response we've seen before that within, One or two doses, we started seeing things, and so we think within the time frame of three or four doses, we would have the opportunity to see if we're seeing the clinical effect and whether we are getting the adverse effect. It wouldn't be definitive information, but at least tell you, are we dosing? Is it safe? And are we seeing some activity? And that's the kind of information will give you a sense of where we're going.

And the team did a great job.

And for the situation and maintaining them at the same level of engagement with both.

Physicians and patients from.

Virtual and digital means so we learned a lot.

In 2020 and.

And we will continue to leverage those successful tactics as we move into 2021 which is why we've taken into account.

Emil D. Kakkis: Hi, good afternoon. Thanks for taking my question. As it relates to Angelman, Emil, I guess, when would you need to start the resumption of the study this year in order to meet your targeted goal of having some clinical data available on patients by the end of this calendar year? And as it relates to safety

Our ability to us.

Operate and this pandemic environment as well as.

Central for hypertension reported easing restrictions throughout the year across the globe that hasn't been said.

No doubt the situation varies region by region and in some instances country by country.

And the Latam team has done a great job just us.

And U S team has done and adapting to this situation. So we feel confident that with our projections as we move forward.

Emil D. Kakkis: Angelman is an area of undermined need. If you are showing efficacy in these patients, what is the tolerance do you think that the agency and or physicians would have to a safety profile that might not be 100% clean? Thank you. Sure, so.

Eric.

We are getting obviously.

We are receiving.

And orders, we have received order from Brazil, Despite the pandemic because I know, Brazil has been hard hit and there's no doubt, it's going to put pressure on the world, including Latin America, but.

On the when started, our expectations, we need to get started either late this half or early next half in order to have at least a few doses of in a number of patients right before the end of the year. So we'd have to be late this half, early next half in order to accumulate enough data. Whatever data we, what we're gonna say is whatever data we have, we will put out some an update on that information.

Patients with these diseases are also and severe need and so we're pleased to see some order and continuing and I think your team just like in the U S will do all the work to make sure that plays outright.

Great. Thanks for the clarity.

Next question comes from the line of you've done this from events from Citigroup. Your line is now open.

However, many patients, how it works much time. So we'll commit to doing that. With regard to the safety profile, we think that having low extremity weakness wouldn't be a good profile to have for a chronic treatment like this, so we believe we can get past that because it's not a drug pharmacologic effect, it's like a local irritation inflammation effect which is something that should be very manageable, so we're confident we can get past that.

Hi, I'm, Melanie and thank you for taking the question could you expand a bit on why you opted for a single seamless protocol for Wilson's disease spanning baseball and two phase III and just curious if there's something specific about Wilson's disease, that's better suited to doing a stainless protocol for a separate protocols.

Well, yes, there are some very distinct differences for some number one it's been well studied well treated so they're actually well established endpoints, which we could define and choose upfront.

And even so, once we know that an ASO can have this kind of effect, there are many avenues of research. So now that we're in this space and we have this ability to change the clinical future of management, it's something worth fighting for, and we will fight for getting this done with a drug that gives patients important efficacy and safety that's appropriate. And I don't think having lower extremity weakness is.

So urinary copper accretion, which is a measure of how much koppers essentially dumping out and your urine and where it's not supposed to be as a relatively good measure of whether your copper is being routed to the correct place since that's well accepted and Wilson.

Transcription by CastingWords Transcription by CastingWords

We're able to get a green with authorities on that as a primary endpoint and so I think it's the issue the endpoint has been.

Defined and studies before that allows us to pick and points right upfront.

And <unk> are experienced and doing gene therapy of the liver and now in two other programs gives us confidence in the dosing range you would like to hit right. So we're more confident and what the dosing range would likely need to be and that we can hit that range and our phase one two trial and be able to pick three doses confidently. So.

Okay, thank you. And maybe a quick question on Wilson. You are expected to start your study in the second half of this year.

Transcripts provided by Transcription Outsourcing, LLC.

Phase 1 through 3. Yeah, so the Wilson phase three study.

And that experience liberty and therapy ability to pick doses and endpoints that we can get agreement on and then the only thing we need to decide what the FDA is.

Yeah, so the Wilson Phase 3 study is like a Phase 1-2 study bolted on to a Phase 3 study, just to be most accurate. The seamlessness is, we don't go back to regular authorities between the decision making is all pre-set.

How big those studies and how long they are.

And with that the all the decisions required to go from phase II to phase III are done we'll do the phase one two and we'll look at the dose data will pick the dose and we will begin enrolling phase III without having to go back to the store and he will have pre defined the administrative criteria to make those choices.

The way it's going to go is we're doing cohorts in stage one, transcripts provided by Transcription Outsourcing, LLC, and those cohorts will be six and three. So there'll be a total of 27 patients in that. The second half of the study is on the order of 60 to 70 patients at this point in time. That's our expectation.

You can't do this kind of thing is a disease. That's never been studied with no history of endpoints right and where you don't know the dosing response rate. So it is not something you can do with most programs, but in this case being a bigger disease with a lot of history, we have an opportunity to take advantage of that and do something that would be smoother and faster.

Next question comes from the line of Yaron Werber from Colin. Your line is now open.

That makes a lot of sense and then I had one other question on the French study that Camille described I was really intrigued by the upper and the size and range of median follow up of 228 months because that would imply 19 years of follow up so I want to make sure I'm understanding that correctly and if so the study and if I have to Atlanta.

Emil D. Kakkis: Great, thanks for taking my question.

I got two questions for you if you don't mind. One is, do you have a sense, did the FDA, did they want to actually see the weakness recapitulated in animal models for them and to show resolution for them to move forward? Or is that not one of the things, because it's hard to recapitulate that. I'm trying to get a sense.

Actually been running for almost two decades.

And we all do you want to answer that yeah sure. Thank you. Thank you for the question. Yes, you are correct and in fact before ultra and <unk>.

Emil D. Kakkis: would get them comfortable. And then, and then secondly, when you look at the, the structure, this is a cyclic base, a Gapmar, right? So the chemistry is a little different from Spinarasa. And how valid is the chemistry? Thanks.

And I took on the development program for dry up to now and our adult Tobey that program was being study by academics for a dozen years or so before that time and even before that so you are correct and physicians, even then understood the biochemistry and and metabolism.

Well, the FDA has not asked us to recreate anything in animals, frankly, at all. And they did not ask us to do any more work.

Emil D. Kakkis: They recognize that we've used higher doses in animals and for many repeated doses with a very high load and not seen it. So Clearly, not toxicity of this oligo. This oligo is not shown to be toxic to your primates, and so I think that's really important. Now, what I can also say with regard to the chemistry is that LNAs can have toxicities, but this particular oligo does not have the toxicities that we see in the pathology of the non-E primates given repeat doses.

And the potential for <unk> to now.

Alright, Thank you very much.

Mhm.

Next question comes from the line of Karri <unk> from Jpmorgan. Your line is now open and it good.

Afternoon, guys. Thanks for taking the question two for me as well.

First one on <unk> 301, just wanted to ask again about the rationale for going from 48 to 64 weeks for the endpoint.

Emil D. Kakkis: So, we feel comfortable about the chemistry as being appropriate. I do think the ability of ASLs to cause irritation or injury is not new. It's been seen, there's been high protein in CSF and a number of ASL programs, including the recent HD one. I think the key here is what's the therapeutic index, how much efficacy do you get for the dose. In this case, we have an extraordinarily potent LNA.

And so patients can wean off of prior therapies was that.

And I guess I'm curious if that was driven by you or by regulators and if there was anything you saw it and the phase one two data that led you to think this additional time could be beneficial and then I have a follow up on angelman.

Well the debate with the regulators like it has been for a number of programs for both not ours and all of them out. There is whether you should be studying these diseases for up to two years right and phase III, we didn't feel that was necessary and so and the discussion of time.

Emil D. Kakkis: Drugs that is actually achieving, Beginning to achieve efficacy in the 3 to 10 milligram range, so a very potent, and we think at that range we can avoid those secondary contact toxicity issues. I think that's a distinct advantage based on the true high potency of this particular one.

We were agreeing to add another quarter, another 12 weeks essentially to the plan.

Yes.

If we're now going to include a and endpoint, which resolved with required the titration or maximal titration of their drugs and diet.

So right now, we're comfortable with the chemistry. We think it's.., particular choices made were very potent. We are aware of a lot of variations that we've made and others have made.

We saw and phase one two and some patients responded a little later like it and say six months or so which would leave a little less time, if they responded and the six to 12 weeks is a few did then we'd have enough time, but if they respond at six months, then you're giving them a little less time to titrate their drugs down and die down and you don't want it.

Emil D. Kakkis: Dr. Dindo has done some exceptionally high-quality work in this, so we feel good about where we're at. And we are, of course, we're also looking at making small variations that might, might change the profile, but we feel pretty good about the succicity and efficacy we're seeing. And right now, the FDA is just waiting more confirmation about the clinical situation. Have not asked for any other animal data, with them it's just a long-term follow-up clinically and and how do you control the risk mitigation is that what it is?

Doing it precipitously right you want them to do it steadily and to verify that they're not having problems with their ammonia.

So just another few weeks would help us and also.

Manage the regulators desire for longer studies without taking it out two years, we get.

A little benefit to us in terms of that endpoint and we manage the fda's desire for the length of study.

Emil D. Kakkis: Now they just want a more definitive proof that the patients didn't have any residual neurological effects, because I think this is a benefit-risk question. They are trying to assess if they put more patients at risk, will they have an irreversible harm from that, right? Is that fundamental?

Okay that makes sense and then just to go back to Angelman and for a second I just want to make sure I understand when you restart this program how should we be thinking about the accrual strategy and in terms of whether you would enroll one patient treat them and then watch and wait before enrolling another or will it happen at a faster pace and that.

We've said no. They just wanted further information to confirm that that's true. And we have good reason to believe it's not because we don't think it's a direct neurotoxicity issue. I think it's just an inflammation issue. And it resolved, the majority of the effect resolved within a few weeks, and so, They just wanted more definitive quantitative measures that help prove that they are reversed. And we have done those measures, including MRIs and more final, you know, lumbar punctures, as well as special neurophysiological tests and have found the patients are normal.

Well there is a staging scattered and propose there's two younger ones two older ones that would get a few doses and if they are okay. Then we enroll the rest of the two cohorts. So theres some staging for two and two and then.

Moving up to what was the total of six and six patients to get through before doses. So that that is low it is staged a little bit that would slow up the enrollment of the second group, but.

But we would have for patients that we think will reasonable short period of time could get started and then be able to expand that to total of 12.

If the 12 look good.

Next question comes from the line of Dagan How from Staple. Your line is now open.

And then we have the option and their protocols to expand to include another 40 patients at the dose now that appears to be sufficient to have efficacy and also appears to be safe. So that would give us a lot more data than to learn more about the particular dose that we've hit with our first 12 patients.

Good afternoon. Thanks for taking that question. Emil, maybe I'll just touch on one more Angelman question. So, recognizing you have three parallel paths with the ex-US sites as well as the US, I was wondering if you can comment on potential alignment between the three regulatory discussions. I mean, do you see a lot of concordance between the three or do you see quite a bit of disparity on this in terms of what they're requesting? And then second question is more commercial.

Okay. It makes us very helpful. Thank you Emil.

Next question comes from the line of moving across from Jefferies. Your line is now open.

Hi, everyone. Thanks for taking my questions.

First one is on Angelman and I think you mentioned on the for Q call that the five angelman patients were losing efficacy benefit after being off treatment can you confirm if the five patients fully reverted on efficacy and could this lawsuit benefit factor into your discussion with FDA.

Emil D. Kakkis: I was wondering, perhaps it's for Erik, you know, given that US has been easing up, you, in your prepared remarks, talked about the irregular ordering patterns in LATAM, but, you know, COVID also seems to be somewhat more rampant in the ex-US sites. So, I was wondering what you guys are currently seeing on that development front. Thanks. Very good. Thanks for the question, Dagon. I'll let Erik in a moment, you can talk about COVID around the world. Eric, so prepare for that. I'll do the first part. So, One of the great.

Yes, the patients have lost.

A lot of benefit I think there may have been some that still retaining a little bit of the words that they gained but it's clearly substantially resolved at this point and reversed.

So yes, it's been a factor and our discussions of the agency because the effects were not subtle they were life changing so.

Next slide please. So, I think the number one thing we have to do in order to implement these techniques in rare disease regulatory is to exploit the actual differences between regulatory authorities and find the best answer somewhere in order to move forward. And that is an extremely important part of moving very complex diseases forward in the drug development. So, it's very often that we will go to another authority in order to get started or get going. I was involved in three programs that did that.

And we hope to make that part of the whole benefit risk assessment question. If we can show them the risk and we were.

Russell change is really not there that it is reversible than I think we can open the door to seeing that patient and losing efficacy. It's not great I do think the Fca's always first rules about.

In the end, all came back to the US. All got approved in the US. So, it's just a normal thing.

No doing no harm and safety.

If we can demonstrate that that I think the efficacy story becomes relevant.

We are proposing, ex-US, the same study and the same design. We have not had any negative feedback from the other European authorities. It did not give us any changes to the protocol that we were fundamental in whatever the Canadians are seeing are actually in line with what we submitted to our other Europeans.

Got it that's helpful and then one quick one.

I think you've mentioned potential for and Angelman publication from Skype and knows lab and I'm. Just wondering if you have a status update on that.

I don't have an immediate update on it I thought it was submitted its a tour de force of.

Emil D. Kakkis: So that's the same, and we don't have any further feedback. With the FDA right now, we're highly focusing in on the current five patients and re-dosing them, just getting their understanding about doing that piece. And by limiting the scope, we think will give us an opportunity to kind of generate a little bit of, a more narrow and safe path for getting started in the U. on the existing five patients. So that's our approach right now.

Research by the way I was just.

So it's one of those special like.

Very large papers that requires a special journal so I think it's.

Still and review and I don't have an update at this point in time, but it is.

Truly exciting and.

I think actually redefined the whole angelman and biology.

And more clearly and a little more precisely which is what led them to us discovery of the right place to knockdown and and defense.

Emil D. Kakkis: So let me hand this off now to Eric to talk a little about, I think the question was, Eric, on. COVID may be easing up in the U.S., but how is COVID affecting? South America. Yeah, a couple of things I'll point out. First, when you consider

Got it okay. Thank you for taking my questions.

Next question comes from the line of Jimmy <unk> from <unk> Securities. Your line is now open.

Hi, Thanks for taking my question and congrats on the progress.

For the GSD three why have you decided on mrna as opposed to DNA <unk> 301 and for one.

And I have a follow up question.

Yeah, there's a good reason for it I think GST three as a day branch and officially it's a very complex large enzyme has two activities.

[inaudible] So we learned a lot in 2020.

It wouldn't fit normally inside and AAV vector is too large.

We will continue to leverage those successful tactics as we move forward.

and to 2021, which is why, you know, we've taken into account. [inaudible] operate in this pandemic environment, as well as Potential for high potential for easing of restrictions.

The second thing that's for unique about GSE three is that you're creating a limit dextera and like a little piece of glass, which is us leftover when the enzyme doesn't work.

That is actually toxic and you accumulate and every single liver cell.

And so as gene therapy, very often and won't hit every single liver cell, you'll still have the problem. If you hit 10, or 15% and whoever they have a lot of liver, that's not detoxified right and that's because there's a cytoplasmic enzymes. So.

Erik Harris: Transcript by Rev.com Page of Note that the situation varies region by region, and in some instances, country by country. And the LATAM team has done a great job, just as the U.S. team has done in adapting to this situation. So we feel confident with our projections as we move forward. It would appear that we are getting, obviously, we are receiving orders. We have received orders from Brazil despite the pandemic, because I know Brazil has been hard hit.

Vantage mrna then is twofold, one it conclude a larger protein as we needed here and secondly, we've shown a very nice delivery to essentially every pad site and clear it.

And last thing I'll note is because it's a storage toxic effect, if you're clear that the toxic dextran and it could take some months to accumulate so the actual dosing frequency could not be driven necessarily by the loss of the enzyme but by the time it takes for toxic accumulation of dextran to occur.

Erik Harris: And there's no doubt it's going to put pressure on the world, including Latin America, but patients with these diseases are also in severe need, and so we're pleased to see some ordering continuing, and I think your team, just like in the U.S., will do all the work to make sure that plays out right. Great, thanks for the clarification.

And so we think those are some features that make gene therapy.

Challenging, but maybe for mrna maybe a better opportunity and that's why we've gone ahead with mrna for that indication.

Got it and for one or two Angelman and <unk>.

There are several players now following your strategy of stopping to stop.

Next question comes from the line of Yigal Nochomovitz from Citigroup. Your line is now open.

And then Roche I think has a study up and.

And running.

Emil D. Kakkis: Hi, I'm Millentine. Thank you for taking the question. Could you expand a bit on why you opted for a single seamless protocol for Wilson's disease, or spanning Phase I through Phase III? Just curious, is there something specific about Wilson's disease that's better suited to doing a seamless protocol versus separate protocols? Well, yes, there are some very distinct differences.

And I think they've got past two.

Additional doses does that play a factor and Sba's decision and.

What can we learn from that.

I'm curious if you know what.

The latest us on Roche, yeah, well I Havent seen Roche put out any information on their trials and I can't really comment and I don't think the F D. A.

Well, some number one, it's been well studied, well treated. So they're actually well established endpoints, which we could define and choose up front. So urinary copper excretion, which is a measure of how much copper is, Transcription by Transcription Outsourcing, LLC.

Makes a decision between program winners or losers based on early data that's not their role their roles look ear program should you be treating if youre asking well if they have another win if they can get treated from other ways that safer. It was an approved treatment I would say that may be a factor right. If they are and approved treatment and worked very well and yours is not working.

Cause and safety problems. There is a difference but in this case, it's not approved and nor have we heard any efficacy of the drug working.

We believe we're in a much more potent area and based on the non clinical data put out we think our molecules and much more potent and there. So if anything I would expect them to have more risk and safety issues.

Emil D. Kakkis: Transcription by https://otter.ai, So given that experience with liver gene therapy, ability to pick doses, and endpoints that we can get agreement on, then the only thing we need to decide with the FDA is... You know, how big the studies and how long they are. And with that, all the decisions required to go from phase two to phase three are done. We'll do the phase one, two.

And then we did so we will see what happens, but I don't think it's a factor right now its all up to us and Gtx 102.

Got it and then one more if I can squeeze and.

It seems like so they are all targeting the same gene, but you mentioned something about.

You know.

Your drug targeting all of the Spice ISO forms or more thorough suppression of the Yankee sense that are transcribed.

Is that and IP strategy or and can you talk to that differentiation between other multiple other players and the same thing but.

We'll look at the dose data. We'll pick the dose and we'll begin enrolling phase three without having to go back to the authorities. We'll have predefined administrative criteria to make those choices.

<unk> be doing the same thing, but maybe a little differently.

Well, there is hard and trying to turn a theme and a sense, but they're targeting a different patented region. So the generics team and Scott and they'll have patented a region near the five prime and at the end it sends a message.

Emil D. Kakkis: You can't do this kind of thing in a disease that's never been studied, with no history of endpoints, right, and where you don't know the dosing response, right? So, it is not something you can do with most programs, but in this case, being a bigger disease with a lot of history, we have an opportunity to take advantage of that and do something that would be smoother and faster. That makes a lot of sense.

That is not covered by the Roche patent alright, the Roche patent and is further three try and downstream.

There are regions unique and that region for some reason was not included in the Roche patents. So it is unique exclusive intellectual property and what the use.

Emil D. Kakkis: And then I had one other question about the French study that Camille described. I was really intrigued by the upper end of the cited range of median follow-up of 228 months because that would imply 19 years of follow-up.

Of all goes within that region, the target and defense.

The key value that uniqueness is the fact that it's way more potent and potency is involved and knocking down all the isoforms, which were not fully recognized by everyone. There were people think of this as a single and defense message and what Scott's work showed and fact that there's a number of and defense.

Camille L. Bedrosian: So I want to make sure I'm understanding that correctly. And if so, that this study of triheptanone has actually been running for almost two decades. Camille, do you want to answer that?

Molecules and some of them are spliced and therefore, how you pick your targeting maybe in the Andersons, where it may not be and picking towards the five prime and he found a particularly unique potency there and.

Yeah, sure, thank you. Thank you for the question. Yes, you are correct. In fact, before Ultragenyx took on the development program for triheptanolone or dolzolvi, the program was being studied by academics for a dozen years or so before that time, and even before that. So you are correct. And physicians even then understood the biochemistry and the metabolisms and the potential for triheptanolone. Thank you very much.

And that is patented so I do think we have and intellectual property position on a superior insight and the message and honestly. That's why we did the deal with genetics, we did the deal because as.

As we told our team.

It wasn't really wanted to get and a foot race or a muscle match with Roche or Biogen I own. This is our big players and ESO play for the questions did was there a scientific insight that gave US gave us an edge and I think Scott didn't Dow had the insight and genetics and the <unk>.

The next question comes from the line of Kari Kashimov from JP Morgan. Your line is now open. Hey, good afternoon.

Emil D. Kakkis: Hey, good afternoon guys. Thanks for taking the question. Two for me as well. First one on DTX-301, just wanted to ask again about the the rationale of going from 48 to 64 weeks for the endpoint so patients can wean off of prior therapies. Is that, I guess I'm curious if that was driven by you or by regulators, and if there was anything you saw in the phase 1-2 data that led you to think this additional time could be beneficial, and then I have a follow-up on it.

Right to it.

Okay. Thank you.

Next question is from Geoff Hoon from Morgan Stanley. Your line is now open.

Hi, guys. This is hannah on for Jeff.

What for such roadmap is there a particular profile Oh I patients within the pediatric population that you guys think would respond and then what do you see us likely the key differences between potential pivotal studies within the pediatrics and adults and for.

Beyond the primary endpoint.

Alright, well right now and asking that question, we really focus on the pediatric pivotal study.

Emil D. Kakkis: Well, the debate with the regulators, like it has been for a number of programs, both not ours, but all of them out there, is whether you should be studying these diseases for up to two years, right, in phase three. We didn't feel that was necessary.

And as kind of the core drivers of the application and the pediatric patients have the highest unmet need there the core of the driver and what we'll do to cover adults may depend a little bit and what we see there, but the pediatric phase III is really our core focus.

According to the profile if you look across the day to day do have now and adults and peds.

And so in the discussion of time, we were agreeing to add another quarter, another 12 weeks, essentially, to the plan. If, If we're now going to include a an endpoint which result which required the titration or maximal titration of the drugs and diet. What we saw in Phase 1 and 2 is some patients responded a little later, like say six months or so, which would leave a little less time. If they responded in the 6 to 12 weeks, as a few did, then we'd have enough time. But if they respond at six months, then you're giving them a little less time to titrate their drugs down and diet down. And you don't want to be doing it precipitously, right?

See the bone.

Bone marrow density improvements and potential improvements from both Oi type one type three and type for we know type threes and type for it and we'll have more fractures and then type ones and they're just more severe and general well.

Well, we will focus on and this study is patients who have a lot of fractures and because they have the unmet need and obviously it is part of our rare formula and rules and that you'd have to treat sick people.

And with drugs and so in this case we.

We will focus on patients who have had more fractures and bones or more and need of a improved strength, which is where <unk> can be very beneficial in terms of enhancing and anabolic bone activity, increasing bone density, but not just any bone density bone density and the places require.

You want to do it steadily and to verify that they're not having problems with their ammonia. So just another few weeks would help us and also manage the regulators' desire for longer studies without taking it out two years. We get a little benefit to us in terms of that endpoint, and we manage the FDA's desire for the length of the study. Okay, it makes sense.

<unk> strength and that the way that bone is directed would allow us and I think the strength and bone and certainly in animal models allow us a mutant college and animal models.

Emil D. Kakkis: And then just to go back to Angelman for a second, I just want to make sure I understand, when you restart this program, how should we be thinking about the accrual strategy and in terms of whether you'd enroll one patient, treat them and then watch and wait before enrolling another or will it happen at a faster pace? Well, there is a staging strategy proposed. There's two younger ones, two older ones that would get a few doses.

To achieve near normal strength.

After some true them up so for it.

High School, Ross and antibody, so where we're focused on the high fracture patients and peds and demonstrating that bone marrow density and fracture proven can occur.

With that core data, we'll leverage that to adults.

And if they're okay, then we enroll the rest of the two cohorts. So there's some staging for two and two and then moving up to what was a total of six and six patients to get through the four doses. So that is, it is staged a little bit that would slow up the enrollment of the second group, but we would have four patients that we think would be a reasonable short period of time to get started and then be able to expand that to a total of 12. If the 12 looks good,

For which we already have good day to 90 patients showing dose dependent improvement and bone mineral density and and number of locations and those patients.

Next question is from Laura Chico.

From Wedbush Your line is now open.

Hi, good afternoon, and thanks for taking the question I have one on us.

701, I'm just wondering if you could comment a little bit on who might be appropriate candidates for gene therapy, and I guess I asked this and the context of one your observational study and Wilson's disease. If there's any learnings there, but then also astrazeneca and Alexia and have expanded enrollment and their study. So just thinking about the impact on your efforts thanks very much.

And then we have the option in that protocol to expand, to include another 40 patients at the dose now that appears to be sufficient to have efficacy and also appears to be safe. So that would give us a lot more data then to learn more about the particular dose that we've hit with our first 12 patients. Okay. Makes sense. Very helpful. Thank you.

Sure.

Well we are.

And there's obviously a lot of people and the space Wilson right now all the lexi on as well as.

The answer to that.

There's also a lot of Wilson patients the trial will take more stable patients from the beginning patients because we haven't established the safety, but we are looking for ultimately for patients who have enough significant illness to measure.

Emil D. Kakkis: Next question comes from the line of Maury Raycroft from Jefferies. Your line is now open.

Emil D. Kakkis: Hi, thanks for taking my questions. First one is on Angelman. I think you mentioned on the 4Q call that the five Angelman patients were losing efficacy benefit after being off treatment. Can you confirm if the five patients fully reverted on efficacy, and could this loss of benefit factor into your discussion with FDA?

With the disease and.

We're not particularly restricting for example, the CNS or other types of manifestations, but we are accepting people have seen us manifestations and after the first stage, we will accept people that have some level of liver injury within a certain bound we don't want to take the war and very severe late stage kind of liver problems because we don't the gene therapy can have an impasse.

Yes, the patients have lost a lot of benefit. I think there may have been some that still retaining a little bit of the words that they gained. But it's clearly substantially resolved at this point and reverse. So yes, it's been a factor in our discussion of the agency because the effects were not subtle. They were life-changing.

On the liver.

But those kind of patients would be something we'd want to look at it. After the study so it'll be people have figured out for measure, but not so sick that the liver the gene therapy might harm them and we'd look to see.

Both liver manifestations as well as seen us manifestation and some patients.

We hope to make that part of the whole benefit-risk assessment question. If we can show them the risk of a reversal change is really not there, that it is reversible, then I think we can open the door to seeing that patient. And losing efficacy is not great. I do think the FDA's always first rule is about, No Doing No Harm and Safety. So if we can demonstrate that, then I think the efficacy story becomes relevant.

Since of the efficacy and the endpoints, we evaluate and the program.

Emil D. Kakkis: Got it. That's helpful. And then, one quick one.

Next question is from solving and Mr. From Goldman Sachs. Your line is now open.

Good afternoon, and thanks for taking my questions on Angelman and you mentioned potential variations for the program if need be.

Are those and and what are your updated thoughts from on the age factor and then just a second question and therapy does change and just give us an update there.

Yeah, I think you mentioned potential for an Angelman publication from Scott Dindo's lab, and I'm just wondering if you have a status update on that.

Okay, So and Angelman.

Ex U S. There are no previously treated patients. So we're focused on treating naive patients and the protocol for Canada and the other country are basically based on us.

Emil D. Kakkis: I don't have an immediate update on it. I thought it was submitted.

And treating naive patients at the low dose and regimen and the US we're focusing the programme now on retreat and existing patients. If that is okay. Then with the FDA, we'd move to adding more patients at the point of time when it makes sense.

It's a tour de force of research, by the way. So it's one of those special like, very large papers. It requires a special journal. So I think it's still in review, and I don't have an update at this point in time, but it is truly exciting, I think actually redefines the whole Angerman biology a little bit more clearly and a little more precisely, which is what led him to his discovery of the right place to knock down the antithes.

All the programs, we would hope would converge at some point on a larger phase II cohort, but right now were focusing us on retreating the five and the ex U S and treating naive and then eventually will expand so that's a difference we were talking about.

Emil D. Kakkis: Got it. Okay, thank you for taking my question.

The age factor.

The next question comes from the line of Joon Lee from Truvy Securities. Your line is now open.

Is an important one I think from the beginning of Angelman and science and analysis, there was a sense that.

Emil D. Kakkis: Hi, thanks for taking my question and congrats on the progress.

Only young patients would respond and there was many people think that need to be very young patients.

For the GST-3, you know, why haven't we decided on mRNA as opposed to DNA like DTX-301 and 401, and I have a follow-up question.

Based on mouse data, but one of the important things is mice are not people.

Mice live only two years, so humans have to live decades, and our brains are just different for that reason.

Emil D. Kakkis: Yeah, there's a good reason for it. I think GST-3 is a D-branch or deficiency. It's a very complex, large enzyme. It has two activities.

So I wasn't so surprised that our brains have to continue to evolve and improve with our life.

It wouldn't fit normally inside an AAV vector. It's too large. The second thing that's unique about GSK3 is that you're creating a limit dextran, like a little piece of glycogen that's left over when the enzyme doesn't work, that is actually toxic and you accumulate that in every single liver cell. And since gene therapy very often won't hit every single liver cell, you'll still have the problem if you hit 10 or 15% of the liver, they have a lot of liver that's not detoxified, right?

So we what we've observed already has the two youngest patients had the most potent effect of the treatment and we saw they also had the stronger side effect. The older patients took a little longer and had to get a little higher dose before they saw the effect.

But they clearly did have an effect including teenagers so.

The fact, you do a teenager I would say was completely unexpected by many people in fact denied that it would happen and.

That's because it's a cytoplasmic enzyme. So the advantage of mRNA then is twofold. One, it can include a larger protein as we need here. And secondly, we've shown a very nice delivery to essentially every hepatocyte and clear it. The last thing I'll note is because it's that storage toxic effect, if you clear the toxic dextran, it could take some months to accumulate, so the actual dosing frequency could not be driven necessarily by the loss of the enzyme, but by the time it takes for toxic accumulation of dextran to occur. And so we think those are some features that make gene therapy, challenging but maybe for MRNA may be a better opportunity and that's why we've gone ahead with MRN for that indication.

And I, just believe and human neurology and need to have them open minded and what can really happened because honestly everyone thinks they know, but they don't know.

So you Gotta do the experiments and that's why we strongly believe and safety studies that have wider criteria, let yourself worn and not prejudge who's going to respond and who won't respond because you'll be surprised sometimes so we think a wide age range can respond can adults respond potentially it might be slower it might be different.

But we think there is room for improvement across a range of Angel and patients and we still believe that young patients will probably have a more potent effect.

And then we will see and older patients, but the fact that all respond I think.

It's important.

Emil D. Kakkis: For one or two Angelman's, there are several players now following your strategy of stopping the stop, and then Roche I think has a study up and running, and I think they've advanced to additional doses. Does that play a factor in SBA's decision? You know, what can we learn from that? I'd be curious if you know what, The latest is on. We'll see.

The final institution, we are making progress with our partner thawed, and we've been making contracts successfully and designed and finalize the contracts and are doing the work and creative and manufacturing system, which is all going well and so we're on track and will prevail and fried and uptake later in the year about where we're at on the menu.

Factoring of the new strategy and any other work, we will have put together, but so far it's gone very well very good collaborative teams and the contracts creation has occurred and we're moving forward on our on our vector production.

Emil D. Kakkis: Yeah, well, I haven't seen Roche put out any information on their trials, so I can't really comment on that.

The next question is from Chris Raymond from Piper Sandler Your line is now open.

Hi, this is going to progress key anchor Chris Thanks for taking the question.

I don't think the FDA makes a decision between program winners or losers based on early data. That's not their role. Their role is to look at your program, should you be treating. If you're asking, well, if they have another win, if they can get treated some other way that's safer, if it was an approved treatment, I would say that may be a factor, right? If they have an approved treatment, it works very well, and yours is not working and causing safety problems, there is a difference.

Just one and.

Five three I know you're on track to start the study and the second half of this year.

But in this case, it's not approved, and nor have we heard any efficacy of the drug working. We believe we're in a much more potent area, and based on the nonclinical data put out, we think our molecule is much more potent than theirs. So, if anything, I would expect them to have more risk of safety issues than we did. So, we will see what happens, but I don't think it's a factor. Right now, it's all up to us and GTX-102. Unknown Speaker One more second squeeze in, you know, it seems like so they're all targeting the same gene.

Just curious going back to your 2019 R&D day, you turn a lot of data around 053, and we're projecting to file the IMD and 2020 I guess can you just talk a little bit about the path to getting and factory into the clinic was there something specific that was getting for that program and and.

And I guess, given your comments today and you have to other programs and the mrna space under development are there any range you might be able to apply to these future programs.

Sure well.

2020, it was a difficult year, obviously, so are running a lot of non clinical things and other things are definitely impaired our ability to operate whereas impaired and so.

All targeting the same gene, but you mentioned something about.

Non clinical and pre IND stage programs were difficult.

Difficult to move ahead at the same pace, we tried to keep our main clinical programs operating from the non clinical ones had to take whatever time. They had to take so it was kind of normal there certainly was learning, though one of the things is learned is optimizing production of mrna for these longer and Martin as we're using for translation.

Emil D. Kakkis: [inaudible] Well, they're trying to target the same antisense, but they are targeting a different patented region. So the genetics team and Scott Dindo have patented a region near the five prime end of the antisense message. 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, of all goes within that region, the target and defense.

A pretty large protein and so we've been doing a lot of work and optimizing and producing and learnings that are low of low immune stimulating capacity and.

And the team has done a dramatic drop actually and improving.

The cost of manufacturing and the scale and manufacturing and so those are features that would help us and our other programs for sure and we've also improved and scaling making the LNP for this particular LNP for this particular cannot flip it.

The key value of that uniqueness is the fact that it's way more potent and potency is involved in knocking down all the isoforms, which were not fully recognized by everyone. They were, people think of this as a single antisense message, and what Scott's work showed, in fact, that there's a number of antisense, [inaudible] I wasn't really wanting to get in a foot race or a muscle match with Roche or Biogen Ionis. There's our big players in the ESO play. So the question is, was there a scientific insight that gave us an edge? I think Scott Dindo had the insight in genetics, had the rights to it.

And that information and also will be very useful and the other programs. So I would we looked at this first program was putting all the efforts and the developing it and getting it ready but to do the second and the third one I think is gonna be substantially easier given that all of that other technology will been figured out and so we decided to put all our effort on one program.

And with the first get it prove and get into the clinic and then we can open the door on and bringing other ones forward.

Next question comes from the line of and tobacco from Evercore ISI. Your line is now open.

Hi, just two quick questions. The first one on Angelman and says the FTA and excuse me I'm, sorry, if I apologize if you answered this before I hopped on a little late but does that mean for.

And for any additional clinical data generated from other regions before kind of.

And you.

And so kind of allowing the process ran mistakes here and.

Is there anything along those lines and there should be thinking about.

Emil D. Kakkis: Next question is from Jeff Hung from Morgan Stanley Alliance.

Well first of all the FDA would never say that it's at now we're Americans search are two precious go test it on some foreign nurse and then come back and how they would never sit that's not there for a few they're looking at us and our view.

Emil D. Kakkis: Hi guys, this is Hannah on for jobs. What, for CitrusMab, is there a particular profile of OI patients within the pediatric population that you guys think would best respond? And then what do you see is likely the key differences between potential pivotal studies within the pediatrics and adults and perhaps beyond the primary? All right.

The reality is this and sometimes what happens is because they're being conservative were and are moving and elsewhere and as I've.

I've been involved and the Morpheus program.

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Seal and two program and the net savvy program, which actually started ex U S. Because the various questions that couldnt get answered in a timely way and we went ex U S. And then came back to us. So it's there's nothing there about that they're not waiting for the other to do it that may be what happens, but they certainly are not would never ask something.

Emil D. Kakkis: Well, right now, to answer that question, we're really focused on a pediatric pivotal study as kind of the core drivers of the application. The pediatric patients have the highest unmet need. They're the core of the driver.

And that Theyre, just want to look at what's going on and I really think their issue is irreversibly reversible and it's really a big deal if they feel like it is a reversible problem and they feel they are taking less risk, but they wouldn't want to see you know irreversible damage from kids right. That's served their main issue, which we get and we think we have.

What we'll do to cover adults may depend a little on what we see there, but the pediatric phase three is really our core focus. With regard to the profile, if you look across the data they do have now in adults, not in peds, you see, Bone Marrow Density Improvements and Potential Improvements in both OI Type 1, Type 3, and Type 4. We know Type 3s and Type 4s will have more fractures than Type 1s.

What we will focus on in this study is patients who have a lot of fractures, and this is because they have an unmet need. And obviously, it's part of our unique formula and rules that you have to treat sick people with drugs.

They are able to show them that.

Okay, that's not happening alright.

Alright that makes sense. Thank you and then.

M D and gene therapy, I think Pfizer made an interesting announcement, saying that it's taking them a little longer to and to get their pivotal study up and running day to some I think requirements for additional as you know.

Emil D. Kakkis: And so in this case, we'll focus on patients who have had more fractures, the bones are more in need of improved strength, which is where citruzumab can be very beneficial in terms of enhancing an anabolic bone activity, increasing bone density, but not just any bone density, bone density in the places require increased strength. And that the way that bone is directed would allow us and I think to strengthen bone and certainly nanomodels allows a mutant collagen nanomodel, to Achieve Neuronormal Strength or an Antisklerosin Antibody.

Testing and whatnot can you maybe just kind of speak to how you see the opportunity for PMT and the context of you know.

Developments.

You know leading companies to Raptor and also Pfizer and and how that makes you think about your own program and and what you need to do and sort of what the opportunity and Els coming up little later to the game, but.

Right well.

First of all I wouldn't consider us a haul.

Race, we're not racing.

It was a horse race, it's like a 10 mile course, because it's not your typical mine and a quarter, but and and.

Emil D. Kakkis: So we're focusing on the high fracture patients in PEDS and demonstrating that bone marrow density and fracture improvement can occur. With that core data, we'll leverage that to adults, for which we already have good data, 90 patients showing a dose-dependent improvement in bone marrow density in a number of locations in those patients.

And that context, we're at sea biscuit right, because we're going to come in at the end but.

The truth is all of the programs are different and ultimately our efficacy.

And safety will will will win the day and for US. We think we have some advantages because we can scale manufacturing, which would produce a higher quality product really with the hela platform at a higher dose at a lower costs and allow us to be a lot more competitive and to produce really are higher I think the quality of the product is starting to matter.

Next question is from Laura Chico. From Red Bush, your line is now open.

Emil D. Kakkis: Good afternoon, thanks for taking the question. I have one on UX701. I'm just wondering if you could comment a little bit on who might be appropriate candidates for gene therapy, and I guess I ask this in the context of, one, your observational study in Wilson's disease, if there's any learnings there, but then also AstraZeneca and Alexia have expanded enrollment in their studies, so just thinking about the impact on your efforts. Thanks very much.

And how well full at us.

And with his presence of trace plasmid and it or other things, we get a much higher quality product out of the Hewlett price, we believe and that will I think make the difference.

And with all of the things we're planning to do we think we can achieve potency its equal or greater and also scale and cost that would be much improved and therefore come and long run us a better product profile.

Emil D. Kakkis: Well, we're, there's obviously a lot of people in the space, Wilson, right now, but Alexion, as well as Pfizer, but there's also a lot of Wilson patients. The trial will take more stable patients in the beginning because we haven't established safety, but we are looking ultimately for patients who have enough significant illness to measure with the disease and We're not particularly restricting, for example, to CNS or other types of manifestations, but we are accepting people who have seen this manifestation.

I think for Pfizer Duchenne announcement related to the potency assay, which has been the.

This is for many gene therapy programs and the FDA rightly. So is concerned about potency variations and manufacturing runs and once.

A very high quality thorough.

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Our other programs, we have resorted to using and vivo assays for that purpose, while we still further developed in vitro us, but we'd have to have those assays in place as well for our three programs and.

Emil D. Kakkis: And after the first stage, we'll accept people that have some level of liver injury within a certain bounds. We don't want to take people who are in very severe late stage kind of liver problems because the gene therapy can have an impact on the liver. But those kind of patients would be something we'd want to look at after the study. So it'll be people who are sick enough to measure, but not so sick that the liver, that the gene therapy might harm them. And we'd look to see both liver manifestations as well as CNS manifestations in some patients as signs of efficacy in the endpoints we evaluate in the program.

And the Duchenne story is tricky because of the nature of the protein and proving its activity and so it's not surprising to see some challenges and developing and activity assay for a structural protein.

So.

What I think it does tell us that the.

The past us rocky, but the importance of this treatment and can't be underestimated. So.

And why so many people are trying to work and solve it and I think Mike just drugs and the strategy I think it's real and the data are strong and I'm very.

I'm very excited to be part of that race, because I think we do have some new things to offer and.

Emil D. Kakkis: Next question is from Salveen Richter from Goldman Sachs. Your line is now open. Good afternoon. Thanks for taking my questions on Angelman's you mentioned potential

And the patients deserve to have every possible paths going forward for them as rapidly as possible and not just for to seven year olds, all the kids with Duchenne and not just U S patients but.

As you mentioned, potential variations to the program if need be. What are those?

Emil D. Kakkis: And what are your updated thoughts on the age factor? And then just a second question on being therapy inducing. So just give us an update there.

Elsewhere as well.

Thank you.

There are no further question at this time, let me turn the call over back to Josh for Cisco.

Emil D. Kakkis: Okay, so an Angeman, Ex-U.S. there are no previously treated patients, so we're focused on treating naive patients and the protocol for Canada and the other country are basically based on, Treating Naive Patients at the Low Dose in the Regimen. In the U.S., we're focusing the program now on retreating the existing patients. If that is okay, then with the FDA, we'd move to adding more patients at the point of time when it makes sense. But all the programs we'd hope would converge at some point on a larger phase two cohort. But right now we're focusing U.S. on retreating the five and ex-U.S. on treating naive. And then eventually we'll expand.

Thank you. This concludes today's call for additional questions. Please contact us by phone or at IR and ultra <unk> Dot com. Thank you for joining us.

This concludes today's conference call. Thank you all for your participation you may now disconnect.

And.

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So that's the difference we were talking about. The age factor is an important one. I think from the beginning of Angelman science and analysis, there was a sense that only young patients would respond. And there were many people thinking it needed to be very young patients. That's based on mouse data, but one of the important things is mice are not people. Mice live only two years, so humans have to live for decades.

Yeah.

Okay.

And then.

Yeah.

And then.

And then.

Emil D. Kakkis: And our brains are just different for that reason. So I wasn't so surprised that our brains have to continue to evolve and improve with our life. So what we've observed already is the two youngest patients had the most potent effect, of the treatment that we saw, they all said the stronger side effect. The older patients took a little longer and had to get a little higher dose before they saw the effect.

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Emil D. Kakkis: [inaudible] So you got to do the experiments. That's why we strongly believe in phase two studies that have wider criteria. Let yourself learn and not prejudge who's going to respond and who won't respond because you'll be surprised sometimes.

Okay.

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So we think a wide age range can respond. Can adults respond? Potentially. It might be slower. It might be different, but we think there is room for improvement across a range of age-old patients. And we still believe that young patients will probably have a more potent effect.

Emil D. Kakkis: [inaudible] But finally, in Duchenne, we are making progress with our partner, Solid, and we've been making constructs successfully and designed and finalized the constructs and are doing the work and creating the manufacturing system, which is all going well. And so we're on track, and we'll provide an update later in the year about where we're at on the manufacturing of the new strategy and any other work we'll have put together. But so far, it's gone very well. We're very good collaborative teams, and the constructs creation has occurred, and we're moving forward on our.., on our vector production.

Emil D. Kakkis: Next question is from Chris Raymond from Piper Sandler, your line is now open. Hi, this is Nicole Gabreski on for Chris.

Thanks for taking the question. So just one on UX-053. I know you're on track to start the study in the second half of this year, but just kind of curious, going back to your 2019 R&D day, you had shown a lot of data around UX-053 and were projecting to file the IND in 2020. I guess, can you just talk a little bit about the path to getting 053 into the clinic? Was there something specific that was gating for that program? And I just, I guess, given your comments today that you have two other programs in the mRNA space under development, are there any learnings that you might be able to apply to these future programs?

So running a lot of non-clinical things and other things was definitely impaired. And so the non-clinical pre-IND stage programs were difficult to move ahead at the same pace. We tried to keep our main clinical programs operating; some of the non-clinical ones had to take whatever time they had to take, so it was kind of normal. There certainly was learning, though.

One of the things that was learned is optimizing production of mRNA for these longer mRNAs we're using for translation of a pretty large protein, so we've been doing a lot of work on optimizing and producing mRNAs that have low immune-stimulating capacity, and the team has done a dramatic job, actually, in improving the cost of manufacturing and the scale of manufacturing. So those are features that would help us in our other programs, for sure.

We've also improved on scaling, making the LNPs for this particular LNP, for this particular cationic lipid, and that information also will be very useful in the other programs. So we looked at this first program as putting all the effort into developing it, getting it ready, but to do the second and the third one, I think, is going to be substantially easier, given that all that other technology will have been figured out, and so we decided to put all our effort on one program at the first, get it proven, get in the clinic, and then we can open the door on bringing other ones forward.

The next question comes from the line of Liisa Bayko. From Evercore ISI, your line is now open.

Emil D. Kakkis: Hi, just two quick questions. The first one, Angel, is the FDA, and excuse me, sorry if I apologize if you answered this before I hopped on the light, but is FDA waiting for any additional clinical data, you know, generated from other regions before kind of You know, kind of allowing the process to reinitiate here, are you, is there anything along those lines we should be thinking about? Well, first of all, the FDA would never say that it said now we're Americans are, are too precious, go test it on some foreigners, and then come back, you know, they would never say that's not their view. They're looking at us in our view. The reality is this is sometimes what happens is because they're being conservative, we're in the moving and elsewhere.

Emil D. Kakkis: And as I said, I've, I've been involved in the Morphe program, the, Unknown Speaker, Unknown Attendee, Unknown Attendee, Unknown Attendee, Unknown Attendee, [inaudible] Okay. All right, that makes sense. Thank you. And then on DMD and gene therapy, you know, I think Pfizer made an interesting announcement saying that it's taking them a little longer to get their pivotal study up and running due to some, I think, requirements for additional, you know,

Testing and whatnot. Can you maybe just kind of speak to how you see the opportunity for DMD in the context of, you know,

Emil D. Kakkis: Unknown Speaker, Unknown Speaker, Unknown Speaker, First of all, I wouldn't consider this a horse race. We're not racing. If it was a horse race, it would be like a 10 mile course because it's not your typical mile and a quarter.

Emil D. Kakkis: But, and in that context, we're Seabiscuit, right? Because we're gonna come in at the end. The truth is all the programs are different and ultimately our efficacy, you know, and safety will win the day and for us we think we have some advantages because we can scale manufacturing which will produce a higher quality product really with the HeLa platform at a higher dose at a lower cost that will allow us to be a lot more competitive and to produce really a higher quality.

Emil D. Kakkis: I think the quality of the product is starting to matter how well full it is. With this presence of trace plasmid in it, or other things, we get a much higher quality product out of the HeLa process, we believe. And that will, I think, make the difference.

Combined with other things we're planning to do, we think we can achieve potency is equal or greater and also scale and cost that will be much improved and therefore come in the long run as a better product profile. I think the Pfizer-Duchenne announcement related to the potency assay, which has been, The FDA, rightly so, is concerned about potency variations in manufacturing runs and wants, A very high-quality, thorough, activity-based protein potency assay from GeneTherapy products.

In our other programs, we have resorted to using in vivo assays for that purpose, while we still further developed in vitro, but we've had to have those assays in place as well for our three programs. And the Duchenne story is tricky because of the nature of the protein and proving its activity. And so it's not surprising to see some challenges in developing an activity assay for a structural protein. So, what I think it does tell you is that the...

The path is rocky, but the importance of this treatment can't be underestimated. So that's why so many people are trying to work and solve it. And I think micro strobes as a strategy, I think it's real. The data are strong and I'm very. I'm very excited to be part of that race because I think we do have some new things to offer. And the patients deserve to have every possible path going forward to them as rapidly as possible. And not just four to seven year olds, all the kids with Duchenne and not just US patients, but.

Joshua Higa: If there are no further questions at this time, let me turn the call over back to Joshua Higa.

Joshua Higa: Thank you. This concludes today's call. If there are additional questions, please contact us by phone or at IR at Ultragenyx.com. Thank you for joining.

Operator: Thank you for joining us.

This concludes today's conference call. Thank you all for your participation. You may now disconnect.

Tazeen Ahmad, Yigal Nochomovitz, Yaron Werber, Gena Wang, Anupam Rama, Emil Kakkis, Yaron Werber, Joseph Schwartz, Emil Kakkis, Laura Chico, Jack Allen, Eric Crombez, Maurice Raycroft, Unknown Executive, Unknown Attendee, Huidong Wang, Aaron Olsen, Joori Park, Howard Horn, Howard Horns, Ultragenyx Pharmaceutical Inc Tazeen Ahmad, Yaron Werber, Gena Wang, Anupam Rama, Emil Kakkis, Yaron Werber, Joseph Schwartz, Unknown Attendee, Huidong Wang, Aaron Olsen, Joori Park, Howard Horns, Ultragenyx Pharmaceutical Inc