Ultragenyx Pharmaceutical Inc (RARE) 2021 Q1 法說會逐字稿

Good day, and thank you for standing by. Welcome to the first quarter 2021 financial results and corporate update conference call. (Operator Instructions)

I would now like to hand the conference over to your speaker today, Joshua Higa. Please go ahead.

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 Mardi Dier, Chief 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 of 1995, including, but not limited to, the types of statements identified as forward-looking in 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 involve substantial risks and uncertainties, including many that are beyond our control. Please note the actual results could differ materially from those projected in any forward-looking statement. For a further description of the risks and uncertainties that could cause actual results to differ materially from those expressed in the forward-looking statements as well as risks relating to our business, see our periodic reports filed with the SEC.

I'll now turn the call over to Emil.

Thank you, Josh, and welcome to everyone on the phone. So far, 2021 has been a productive year for Ultragenyx. We've made great progress towards the initiation of 4 pivotal clinical studies with novel therapies for rare genetic diseases in a broad portfolio of 6 clinical stage programs. The clinical progress is complemented by continued advances in our 3 commercial franchises, marking 2021 as an important inflection point in our growth as a company.

Now starting with gene therapy. We made significant regulatory and operational advancements toward the initiation of the DTX301, DTX401 and UX701 pivotal studies. Most recently, we completed successful regulatory discussions for DTX301, our AAV8 gene therapy for OTC deficiency as one of the last key steps before initiating that Phase III study. We've also completed all the formal regulatory discussions for the DTX401 Phase III and are working with sites to get the study started soon. Early in the year, we announced that the IND is active for our innovative Phase I/II/III study for UX701, an AAV9 gene therapy for Wilson disease. We're currently on track to launch all 3 of these pivotal studies this year with the GSDIa and Wilson studies on track to begin enrolling 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 Mereo BioPharma. We are in the planning process for the Phase II/III 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 Crysvita 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. We are continuing to make progress towards resuming the Phase I/II study. Our goal for the program in this specific time is twofold: first, to move forward as quickly as possible, we start dosing at the low doses that showed activity with an individually monitored dose titration plan to assure safety; and 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 molecule so far. To those goals, our partner, GeneTx, submitted an amendment to the existing approved Canadian filing to initiate the study in Canada. GeneTx 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 have an encouraging -- we had encouraging discussion with that European regulatory agency regarding GTX-102, including all the detailed efficacy, safety and nonclinical data, along with the same dosing and monitoring plan that was provided to the FDA. The European agency agreed in principle with this analysis and plan, and a full filing has been made on this basis to that agency. Based on this interaction, we are confident we can start the study outside of 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. We look forward to providing update as definitive milestones are made in the Angelman program.

Moving to our newest clinical stage program. UX053 is our mRNA candidate for GSDIII or Glycogen Storage Disease Type III, debrancher deficiency. This is the first clinical program to come out of our collaboration with Arcturus, through which we have rights to 12 programs. We're working on 2 other earlier projects in the mRNA space that we will discuss as they mature. We are 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. And we are also very encouraged with what we see with this technology. The UX053 program has received clearance from the FDA to start the Phase I/II study in Glycogen Storage Disease Type III or debrancher deficiency, and this program will further build on our experience with gene therapy in Glycogen Storage Disease Type Ia 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 Mardi will describe further. Crysvita in North America continues to do well now that we are 3 years into launch. As COVID restrictions have eased somewhat and clinics further reopened in 2021, we have seen an increase in diagnosis of XLH patients that we expect to help drive long-term growth for Crysvita. We have initiated or strengthened a number of efforts to support this increased diagnosis in 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. In Latin America, the team continues to make good progress in establishing the value of Crysvita 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 Dojolvi, which has been off to a great start. We saw 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 named patient demand for Dojolvi. Recent longer-term efficacy data and safety from 18 ATU patients in France, either named patients or treated patients, 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 II data corroborated by an independent French investigating team and their patients in France.

I'll now hand the call off to Erik to provide more detail on our commercial progress.

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

I'll start with Crysvita. Our leading indicators, including patient fines, start forms and reimbursed patients in 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 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 million to $190 million. Based on where we finished 2020, this would represent strong growth of 30% to 37% year-over-year.

In the United States, we are continuing to hear positive feedback from the medical and patient communities. Our -- once patients with XLH or TIO start therapy with Crysvita, very few discontinue. This is mostly due to the benefits patients are experiencing while receiving Crysvita as well as the support our patient support services team provides. At this point, 3 years into launch, 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 start forms originate. We are increasing investments in successful tactics that we piloted during the pandemic and are modestly expanding our field teams to reach more of those community clinics.

Just a quick comment on the launch of Crysvita for TIO. We continue to see a steady flow of new start forms for patients with this ultrarare disease. Many of these patients are seeing the same physicians who treat patients with XLH and OI. Over time, we expect the launch to continue this trajectory while leveraging our current field and patient support teams.

The demand we are seeing across Latin America for Crysvita remains strong. The base of patients continues to expand as more of our branded injunctions are gaining access to named patient sales. 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 Dojolvi, 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 3 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 Dojolvi. We believe that many of these patients are the most severe phenotypes. We received approximately 230 start forms from approximately 115 unique prescribers of Dojolvi 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 Dojolvi coverage 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. This is a faster turnaround time than we saw with Crysvita at a similar stage of launch. It's 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 restrictions continue to ease, we are confident in the current trajectory of new start forms across all 3 brands for Crysvita, Dojolvi and Mepsevii.

With that, I'll turn the call over to Mardi to share the financial results.

Thanks, Erik. 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.

Company revenue for the quarter ending March 31, 2021, totaled $99.4 million. Crysvita revenue in Ultragenyx territory was $42.1 million, including $36.3 million from the North America profit share territory and net product sales of $5.9 million in other regions. Total royalty revenue related to the sales of Crysvita in the European territory was $3.9 million.

As Erik alluded to earlier, there are really 2 factors to keep in mind when looking at the first quarter Crysvita 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. As is with the case with Brazil's Ministry of Health, we expect continued uneven ordering pattern for this territory.

Dojolvi revenue for the quarter was $7 million. As we have stated before, we will not be providing revenue guidance for Dojolvi in the first quarters of launch. We believe the metrics Erik just discussed better describes the success we are having -- that we are seeing in this launch so far. Mepsevii 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 Sankyo around our HeLa PCL and HEK293 technologies. Of the total contract value of approximately $185 million, we have recognized close to $132 million to date. 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 3 quarters and as the tech transfer activities wind down. 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 $147.5 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 Mereo license and collaboration agreement. As a reminder, we expect our R&D costs this year to increase as we will support the 3 pivotal gene therapy clinical trials: The UX143 Phase II/III clinical study in osteogenesis imperfecta; and the Phase I/II study for the most advanced mRNA program, UX053 in GSDIII; and a number of other preclinical activities as we get ready to advance the next programs into the clinic. We also expect SG&A to modestly increase over 2021 as we continue to support the expansion and launches of Crysvita, Dojolvi and Mepsevii.

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 Mereo and a $20.6 million decrease in the fair value of investments in equity securities. Net cash used in operations for the quarter was $159.3 million, which includes the upfront payment to Mereo as compared to the $95.2 million for the same period in 2020. We ended the quarter with over $1 billion in cash, cash equivalents and marketable securities. This puts us in a strong capital position to reach key clinical and commercial milestones as we continue executing our development and commercial strategies.

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

Thank you, Mardi, 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, GeneTx, 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.

Last year, we reported positive efficacy data from the first 5 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 weakness that now has fully resolved. We paused dosing and enrollment at the first presentation of the event.

In support of resuming the clinical study, we have provided the FDA with additional nonclinical data showing the effects of GTX-102 in nonhuman 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 I/II was not observed in the nonhuman primates with single doses as high as 10 milligrams or a 110-milligram human equivalent dose, nor was it observed with 7 monthly doses of 4 milligrams or an equivalent cumulative dose in humans of 314 milligrams. And importantly, we did see a strong knockdown of the UBE3A antisense at very low monthly doses, beginning at 1 milligram or approximately 10-milligram dose equivalent in humans. We also saw a measurable, though not as strong, effect at 0.5 milligrams dose monthly.

We recently requested a meeting with the FDA following multiple submissions of substantial nonclinical 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. 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 a national regulatory authority in Europe, where we presented detailed safety, efficacy and nonclinical 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.

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. Trendelenburg 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. Patients will be divided into 2 starting dose cohorts based on age. Those under 8 years old will receive a starting dose of 3.3 milligrams, while those 8 years and older will start at 5 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 observed range of clinical and nonclinical activity but below the doses associated with SAEs. With this 3-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 DTX401, our gene therapy for the treatment of Glycogen Storage Disease Type Ia or GSDIa. We 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 2 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 simultaneously are moving forward with study start-up. 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 deficiency. At the end of the first quarter, we held a successful end of Phase II meeting with the FDA. And together with feedback from EMA, we now have a finalized Phase III study design and end points. The study will enroll approximately 50 patients ages 12 years and older. Patients will be randomized 1:1 to either DTX301 or placebo. The dose of 1.7 x 10^13 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 III study, we will have co-primary end points. The first is the change in 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 or reduction in baseline disease management. 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 diets. From our experience with the Phase I/II study, we know that it can take some time to establish normal ammonia 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 in the baseline treatment reduction co-primary end point and still proceed to development as rapidly as possible. With the finalization of the Phase III design that incorporates feedback from both the 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 describe the clinical outcomes of 18 pediatric and adult patients with long-chain fatty acid oxidation disorders or LC-FAOD, who were treated with Dojolvi or triheptanoin for a median duration of 22 months. In this paper, 18 early-access French cases showed that triheptanoin reduced the need for medical intervention. Patients in this cohort were followed for a range of 90 to 228 months. Similar to the published Dojolvi Phase II 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 0 days of emergency home care during this time. Other reported clinical improvements included reduced fatigue and myalgia and elimination of the knee for wheelchair use in 5 of the 6 patients who had required it in the year prior to receiving triheptanoin.

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

Thanks, Camille. After completing 4 approvals in our first 10 years, we've built out our pipeline in Ultragenyx in the 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 efforts is one of the broadest and most diverse portfolio in the rare disease space. Our clinical pipeline now includes 6 programs. It is well balanced across modes, encompassing gene therapies and antibody and antisense oligonucleotide and mRNA. It includes smaller rare diseases where we are essentially the only drug in development but also includes more competitive and much larger opportunities. 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 for asking questions.

(Operator Instructions) Your first question comes from the line of Joseph Schwartz from SVB Leerink.

I'm Joori dialing in for Joe. My question is on DTX301 for OTC deficiency. Typically, when you have a co-primary end point, it can be analyzed several different ways. Usually, you have to hit both end points. But sometimes you can just hit 1 of the 2, or the hurdle can be higher for 1 over the other end point. So I was just wondering if you could discuss the statistics for your Phase III study.

Yes. So we're expecting to have to hit both end points. The ammonia control is easy. But I think the question with the responder analysis, we think, is the clinical meaningfulness of the result. 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 drug. So we feel confident in putting both end points forward.

Okay. Great. 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?

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

In the reduction in care, this issue of 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 if you think of the scavenger drugs and diet, if you get off both, that's 100%. If you get off 1, it's 50%. And the way the responder analysis will go is we'll count 50% -- that is getting off the drug alone will count as a response for that end point. And getting off everything will count as a complete responder and would be 100%. And so we'll look at the percent reduction in response in treatment requirement.

Our next question comes from the line of Gena Wang from Barclays.

I have 2 regarding the Angelman. One is for the U.S. and one for the ex U.S. For the U.S., since the FDA didn't ask you for additional animal data and you submit additional clinical data, just wondering what could hold FDA back at your second quarter meeting?

And then for the ex U.S., 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?

Very good. I'll go ahead and answer that. So on the first part, the Angelman, they asked for more data on the individual patients that were treated and had the event mainly to assess their complete reversal. And we've done some additional things and showed that they're 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 -- 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 the study ex U.S. What we said today is that one ex U.S. 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. Canadian authorities have seen that now, and we're waiting for their response. The timing of those responses from the authorities will determine the timing when we can get going. If they were to happen within a shorter period of time, we could get going. If they take their full period required, we may not dose there in the first half. It's hard to know. With the U.S., of course, if depending on the response, we could dose.

Now what we have said in the release, though, is that given what we know now about the ex U.S. path, that one way or another, we will have some data in some patients this year. And that's the point we're making for everyone, Gena. But we can't precisely say how those all are going to play out as they undergo. Three different regulatory authorities are looking at reviews.

Okay. And then what kind of data will be shared?

Well, what we're talking is about 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, 6 below age 8 and 6 above. And so we'd been looking for some fraction of those patients to be treated at least a few times.

Based on the response that we've seen before that within 1 or 2 doses, we start seeing things. And so we think within the time frame of 3 or 4 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 it will tell you, are we dosing? Is it safe? And are we seeing some activity? And that's the kind of range, what will give you a sense of where we're going.

Next question comes from the line of Tazeen Ahmad from Bank of America.

As it relates to Angelman, Emil, I guess when would you need to start 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 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 is Angelman is an area of undermet 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?

Sure. So on the -- once started, our expectation is 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 it would have to be late this half or early next half in order to accumulate enough data. Whatever data we've -- what we're going to say is whatever data we have, we will put out some -- an update on that information, however many patients, how it worked, how 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, an inflammation effect, which is something that should be very manageable. So we're confident we can get past that. And even so, if -- once we know that an ASO can have this kind of effect, there are many avenues ahead of us. Even if this oligo, we had to change it, we could, of course, [use].

So now that we're in this space and we have this ability to change the clinical future with Angelman, it's something worth fighting for. And we will fight for getting this done with a drug that gives patients an important efficacy and a safety that's appropriate. And I don't think having low extremity weakness is acceptable as a long-term safety outcome.

Okay. And maybe a quick question on Wilson. You are expected to start your study in the second half of this year. How big of a study do you plan on this being, given that you're describing it as a single protocol Phase I/II/III study?

Yes. So the Wilson Phase III study is like a Phase I/II study bolted on to a Phase III study, just to be most accurate. The seamlessness is we don't go back to regulatory authorities between -- the decision-making is all preset. So the way it's going to go is we're doing cohorts -- in stage 1 cohorts at 3 different dose levels in sequence. They're randomized with a placebo group, and those cohorts will be 6 and 3. 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.

Next question comes from the line of Yaron Werber from Cowen.

Great. So Emil, I got 2 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 -- 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 what would get them comfortable.

And then secondly, when you look at the structure, this is a cyclic base gapmer, right? So the chemistry is a little different from Spinraza. And how valid is the chemistry?

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. They recognize we've used higher dose in animals and for many repeated doses with very high load and not seen it. So it's clearly not the toxicity of this oligo. This oligo has not shown to be toxic on nonhuman primates. And so I think that's real important. Now what I also could say with regard to the chemistry is the LNAs can have toxicities, but this particular oligo does not have toxicities that we see in the pathology of the nonhuman primates given repeat doses. So we feel comfortable of the chemistry as being appropriate.

I do think the ability of ASOs to cause irritation or injury is not unknown -- not new. It's been seen. There's been high protein in CSF in a number of ASO 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. And in this case, we have, with this LNA, extraordinarily potent LNA, a drug that is actually achieving -- beginning to achieve efficacy in the 3- to 10-milligram range, so very potent. And we think at that range, we can avoid those secondary contact toxicity issues. We think that's a distinct advantage of the -- based on the true high potency of this particular one.

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. Dr. Dindot has done exceptionally high-quality work in this. So we feel good about where we're at.

And we're -- of course, we're also looking at making small variations that might change the profile. But we feel pretty good about the toxicity and efficacy we're seeing. 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.

So with them, it's just a long-term follow-up clinically? And how do you control the risk mitigation? Is that what it is?

No. They just wanted more definitive proof that the patients didn't have any residual neurological effects because I think this is a benefit/risk question they're trying to assess. If they put more patients at risk, will they have an irreversible harm from that, right? That is fundamental. We have 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 effect resolved within 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 lumbar punctures as well as special neurophysiological tests and have found the patients are normal.

Next question comes from the line of Dae Gon Ha from Stifel. .

Emil, maybe I'll just touch on one more Angelman question. So recognizing you have 3 parallel paths with the ex U.S. sites as well as the U.S., I was wondering if you can comment on potential alignment between the 3 regulatory discussions. I mean, do you see a lot of concordance between the 3? Or do you see quite a bit of disparity in terms of what they're requesting?

And then second question is more commercial. I was wondering -- perhaps it's for Erik. Given that U.S. has been easing up, you, in your prepared remarks, talked about the irregular ordering patterns in LatAm. But COVID also seems to be somewhat more rampant in the ex U.S. sites. So I was wondering what you guys are currently seeing on that development front.

Very good. Thanks for the question, Dae Gon. I'll let Erik -- in a moment, you can talk about COVID around the world, Erik, so prepare for that. I'll do the first part. So one of the great 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 and already get started or get going. I've been involved in 3 programs that did that. In the end, all came back to the U.S., all got approved in the U.S. So it's just a normal thing. We don't really look for concordancy.

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. They did not give us any changes to the protocol that were fundamental or whatever. The Canadians are seeing -- are actually in line with what we submitted to our other European. 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 5 patients and redosing them, just getting their understanding about doing that piece. And by limiting the scope, we think it 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.S. on the existing 5 patients. So that's our approach right now.

So let me hand this off now to Erik to talk a little about -- I think the question was, Erik, on COVID is maybe easing up in the U.S. But how is COVID affecting South America?

Yes. A couple of things I'll point out. First, when you consider 2020, we put out our guidance in advance of the COVID pandemic, and we ended up in the upper end. And that's because the team did a great job of adapting to the situation and maintaining the same level of engagement with both physicians and patients through virtual and digital means. So we learned a lot in 2020. And we'll continue to leverage those successful tactics as we move into 2021, which is why we've taken into account our ability to operate in this pandemic environment as well as the potential for -- high potential for easing of restrictions throughout the year across the globe.

That having 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 as the U.S. team has done, in adapting to the situation. So we feel confident that -- with our projections as we move forward.

Thank you, Erik. We are getting -- obviously, we are receiving orders. We have received an order from Brazil despite the pandemic because I know Brazil has been hard hit. 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 the team, just like in the U.S., will do all the work to make sure that plays out right.

Next question comes from the line of Yigal Nochomovitz from Citigroup.

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 for Wilson. Number one, it's been well studied, well treated. So they're actually well-established end points, which we could define and choose upfront. So urinary copper excretion, which is a measure of how much copper is essentially dumping out in your urine, where it's not supposed to be, is a relatively good measure whether your copper is being routed to the correct place. Since that's well accepted in Wilson, we're able to get agreement with authorities on that as the primary end point. So I think it's the issue that the end point is being defined and studied before it allows us to pick end points right upfront.

Secondly, our experience in doing gene therapy of the liver now in 2 other programs gives us confidence in the dosing range you would like to hit, right? So we're more confident on what the dosing range would likely need to be and that we can hit that range in our Phase I/II trial and be able to pick 3 doses confidently. So given that experience with liver gene therapy, the ability to pick doses and end points that we can get agreement on, then the only thing we need to decide with the FDA is how big the studies and how long they are.

And with that, all of the decisions required to go from Phase II to Phase III are done. We'll do the Phase I/II. We'll look at the dose data. We'll pick the dose, and we'll begin enrolling Phase III. Without having to go back to the authorities, we'll have predefined administrative criteria to make those choices. You can't do this kind of thing in a disease that's never been studied, with no history of end points, 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. And then I had one other question on 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. So I want to make sure I'm understanding that correctly. And if so, that this study of triheptanoin has actually been running for almost 2 decades.

Camille, do you want to answer that?

Yes. Sure. Thank you. Thank you for the question. Yes, you are correct. In fact, before Ultragenyx took on the development program for triheptanoin or Dojolvi, 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 triheptanoin.

Next question comes from the line of Cory Kasimov from JPMorgan.

Two for me as well. First one on DTX301, just wanted to ask again about the rationale of going from 48 to 64 weeks for the end point 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 I/II 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, both not ours and all of them out there, is whether you should be studying these diseases for up to 2 years, right, in Phase III. We didn't feel that was necessary. And so in the discussion of time, we were agreeing to add another quarter, another 12 weeks essentially to the plan, if we're now going to include an end point which would require the titration or maximal titration of the drugs and diet.

What we saw in Phase I/II is some patients responded a little later, like, let say, 6 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 6 months, then you're giving them a little less time to titrate their drugs down and die it down. And you don't want to do it precipitously, right? You want them to do it steadily and to verify that they're not having problem with their ammonia.

So just another few weeks would help us and also manage the regulator's desire for longer studies without taking it out 2 years. We get a little benefit to us in terms of that end point, and we manage the FDA's desire for the length of study.

Okay. That makes sense. 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 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 than that?

Well, there is a staging strategy proposed. There's 2 younger ones, 2 older ones that would get a few doses. And if they're okay, then we enroll the rest of the 2 cohorts. So there's some staging for 2 and 2 and then moving up to what was the total of 6 and 6 patients to get through the 4 doses. So that is -- though it is staged a little bit, that would slow up the enrollment of the second group. But we would have 4 patients that we think with a reasonable short period of time could get started and then be able to expand that to a total of 12. If the 12 looked good, 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.

Next question comes from the line of Maury Raycroft from Jefferies.

First one is on Angelman. I think you mentioned on the 4Q call that the 5 Angelman patients were losing efficacy benefit after being off treatment. Can you confirm if the 5 patients fully reverted on efficacy? And could this loss of benefit factor into your discussion with the FDA?

Yes. The patients have lost a lot of benefit. I think there may have been some that's still retaining a little bit of the words that they have gained, but it's clearly substantially resolved at this point and reversed. So yes, it's been a factor in our discussion with the agency because the effects were not settled. They were life-changing. And so we hope to make that part of the whole benefit/risk assessment question. If we can show them the risk -- 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.

Got it. That's helpful. And then one quick one. Yes, I think you mentioned potential for an Angelman publication from Scott Dindot's 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. It's a tour de force of a research, by the way. I just -- so it's one of those special like very large papers that 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. And I think it actually redefines the whole Angelman biology a little more clearly and a little more precisely, which is what led him to his discovery of the right place to knock down the antisense.

Next question comes from the line of Joon Lee from Truist Securities.

Congrats on the progress. For the GSDIII, why have we decided on mRNA as opposed to DNA IP kit 301 and 401? And I have a follow-up question.

Yes. There's a good reason for it. I think GSDIII is a debrancher deficiency. It's a very complex, large enzyme. It has 2 activities. It wouldn't fit normally inside an AAV vector. It's too large.

The second thing that's unique about GSDIII is that you're creating a limit dextrin, 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, then you have a lot of liver that's not detoxified, right? 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 needed 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 a storage toxic effect, if you clear the toxic dextrin, 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 tox accumulation of dextrin to occur. 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 1 of 2 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 have advanced to additional doses. Does that play a factor in FDA's decision? And what can we learn from that? I'm curious if you know what the latest is on Roche.

Yes. Well, I haven't seen Roche put out any information on their trials. So I can't really comment on it. 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 and it works very well, and yours is not working and you're causing 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 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.

Got it. And one more, if I can squeeze in. It seems like -- so they're all targeting the same gene, but you mentioned something about your drug targeting all the splice isoforms or more thorough suppression of the antisense that are transcribed. Can you -- is that an IP strategy? Or -- and can you talk to that differentiation between other -- multiple other players doing the same thing but -- who appears to be doing the same thing but maybe a little differently?

Well, they're targeting -- trying to target antisense, but they are targeting a different patented region. So the genetics team and Scott Dindot have patented a region near the 5 prime end of the antisense message. That is not covered by the Roche patent, all right? The Roche patent is further the 3 prime downstream. That region is unique. And that region, for some reason, was not included in the Roche patent. So it is unique, exclusive intellectual property about the use of oligos within that region to target antisense.

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 molecules, and some of them are spliced. And therefore, how do you pick your target? It may be in the antisense or it may not be. And picking towards the 5 prime end, he found a particularly unique potency there, and that is patented. So I do think we have intellectual property position on a superior insight in the message.

And honestly, that's why we did the deal with GeneTx. We did the deal because, as we told our team, I -- it wasn't really we wanted to get in a foot race or a muscle match with Roche or Biogen Ionis. Those are the big players in the ASO play. So the question is if -- was there a scientific insight that gave us an edge. And I think Scott Dindot had the insight, and GeneTx had the rights to it.

Next question is from Jeff Hung from Morgan Stanley.

This is Hannah on for Jeff. What -- for setrusumab, 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 end point?

Right. Well, right now, answering your second 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. What we'll do to cover adults may depend a little bit on what we see there, but the pediatric Phase III is really our core focus.

With regard to the profile, if you look across the data they do have now in adults and non-peds, you see bone marrow density improvements and potential improvements in both OI type I, type III and type IV. We know type IIIs and type IVs will have more fractures and -- than type Is. They're just more severe in general. What we will focus on in the study is patients who have a lot of fractures, and this is because they have the unmet need. And obviously, it's part of our rare formula and rules that you have to treat sick people with drugs.

And so in this case, we will focus on patients who have had more fractures, whose bones are more in need of improved strength, which is where setrusumab can be very beneficial in terms of enhancing the anabolic bone activity, increasing bone density, but not just any bone density, bone density in the places that require increased strength. And that -- the way that bone is directed would allow us -- and I think the strength of the bone and certainly, in animal models, allows a mutant collagen animal model to achieve near-normal strength after setrusumab, so -- or an anti-sclerostin antibody.

So we're focused 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.

Next question is from Laura Chico from Wedbush.

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 Alexion have expanded enrollment in their study. So just thinking about the impact on your efforts.

Well, we're -- there's obviously a lot of people in the space, Wilson, right now, with Alexion as well as Pfizer with that. But there's also a lot of Wilson patients. The trial will take more stable patients in the beginning, patients -- because we haven't established the 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 CNS manifestations.

And after the first stage, we'll accept people that have some level of liver injury within a certain bound. We don't want to take people who are in very severe or late-stage kind of liver problems because we don't -- 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 will be people who have -- sick enough to 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 CNS manifestations, if some patients have signs of efficacy in the end points we evaluate in the program.

Next question is from Salveen Richter from Goldman Sachs.

On Angelman, you mentioned potential variations to the program, if need be. What are those? And what are your updated thoughts on the age factor?

And then just a second question on gene therapy in Duchenne, whether you could just give us an update there.

Okay. So on 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 treating naive patients at the low dose in the regimen. In the U.S., we're focusing the program now on re-treating 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. All of the programs we'd hope would converge at some point on a larger Phase II cohort. But right now, we're focusing U.S. on re-treating the 5 and ex U.S. in treating naive. And then eventually, we'll expand. 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 2 years So humans have to live decades, 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 we have observed already that the 2 youngest patients had the most potent effect. Of the treatment that 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 that you do a teenager, I would say, was completely unexpected by many people, in fact, denied that it would happen. And I just believe in human neurology, you need to have an open mind of what can really happen. Because honestly, everyone thinks they know, but they don't know.

So you got to do the experiments. That's why we strongly believe in Phase II 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. 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 Angelman patients. And we still believe that young patients will probably have a more potent effect than we will see in the older patients. But the fact that all responded, I think, is important.

But finally, in Duchenne, we are making progress with our partner, Solid. And we've been making constructs successfully and designed and finalize the constructs and are doing the work and creating a manufacturing system, which is all going well. And so we're on track. And we'll probably 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 have very good collaborative teams, and the construct creation has occurred. And we're moving forward on our vector production.

The next question is from Chris Raymond from Piper Sandler.

This is Nicole Gabreski on for Chris. So just one on UX053. 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 turned a lot of data around UX053 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 2 other programs in the mRNA space under development, are there any learnings that you might be able to apply to these future programs?

Sure. Well, 2020 was a difficult year, obviously. So running a lot of nonclinical things and other things were definitely impaired. Our ability to operate was impaired. And so the nonclinical 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 nonclinical 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 we've learned is optimizing production of mRNA. For these longer mRNAs, we're using for translation like of a pretty large protein. So we've been doing a lot of work on optimizing and producing mRNAs that are low -- 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. And 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, with this particular cationic lipid. And that information also will be very useful in the other program.

So I would -- we looked at this first program with putting all the efforts 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 approved and get it in the clinic. And then we can open the door on and bringing other ones forward.

Next question comes from the line of Liisa Bayko from Evercore ISI.

Just 2 quick questions. The first on Angelman's, is the FDA -- excuse me, sorry, if -- I apologize if you answered this before. I hopped on a little late. But is the FDA looking for any additional clinical data generated from other regions before kind of allowing the trial to reinitiate your -- are you -- is there anything along those lines we should be thinking about?

Well, first of all, the FDA would never say that. They had said, "No, Americans are too precious. Go test them on some foreigners and then come back." They would never -- that's not their view. They're looking at us in our view. The reality is, is that sometimes what happens is that because they're being conservative, we end up moving it elsewhere. And as I said, I've been involved in the Morquio program, the CLN2 program and the Mepsevii program, which actually started ex U.S. because of various questions that couldn't get answered in a timely way. And we went ex U.S. and then came back to the U.S.

So it's -- there's nothing there about that. They're not waiting for the others to do it. That may be what happens, but they certainly are not -- would never ask something like that. They just want to look at what's going on. I really think their issue is irreversibility and reversibility. It's really a big deal. If they feel like it is a reversible problem, then they feel they're taking less risk. But they wouldn't want to see irreversible damage to some kids, right? That's their main issue, which we get. And we think we have the evidence to show them that, that's not happening.

All right. That makes sense. And then on DMD and gene therapy, 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 testing and whatnot. Can you maybe just kind of speak to how you see the opportunity for DMD in the context of developments at both leading companies, Sarepta and also Pfizer? And how that makes you think about your own program and what you need to do and sort of what the opportunity is coming a little later to the game, but...

Right. Well, first of all, I wouldn't consider this a horse race. We're not racing. If it was a horse race, it's like a 10-mile course because it's not your 2 mile and a quarter. But -- and in that context, we're Seabiscuit, right, because we're coming at the end. But the truth is all the programs are different. And ultimately, our efficacy 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 -- I think the quality of the product is starting to matter. How well full it is, whether there's presence of trace plasma 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 that's 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 and Duchenne announcement is related to the potency assay, which has been the bane of existence for many gene therapy programs. And 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 gene therapy products.

In our other programs, we have resorted using in vivo assays for that purpose, while we still further develop in vitro. But we have had those assays in place as well for our 3 programs. And the Duchenne story is tricky because of the nature of the protein improving 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 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 microdystrophin is a strategy. I think it's real. The data are strong, and 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 4- to 7-year-olds, all the kids with Duchenne and not just U.S. patients but elsewhere as well.

There are no further questions at this time. Let me turn the call over back to Joshua Higa.

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

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