Ultragenyx Pharmaceutical Inc. Q2 FY2021 Earnings Call

Good day, and thank you for standing by. Welcome to the Second Quarter 2021 Financial Results and Corporate Update Conference Call. At this time, all participants are in a listen-only mode. After the speakers’ presentation, there will be a question-and-answer session. I would now like to hand the conference over to your first speaker today, Joshua Higa, Director of Investor Relations. Thank you. Please go ahead.

Good afternoon, and welcome to the Ultragenyx financial results and corporate update conference call for the second 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 today are Emil Kakkis, Chief Executive Officer and President; Camille Bedrosian, Chief Medical Officer; Erik Harris, Chief Commercial Officer. Mardi Dier, our Chief Financial Officer had an unavoidable flight delay and is not able to join us on today’s call. I would like to remind investors that this call will include forward-looking statements within the meaning of the Safe Harbor provisions of the Private Securities Litigation Reform Act of 1995, including but not limited to, the types of statements identified as forward-looking in our 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 subsequent periodic 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 related to our business, please see our periodic reports filed with the SEC. I will now turn the call over to Emil.

Thanks, Josh, and good afternoon, everyone. I want to quickly reflect on our progress mid-year and note that we're approaching a period of significant execution on our clinical programs in the second half of this year. For those who are newer to our story, we're a diversified global commercial rare disease company with three products approved for four indications. We now have one of the broadest clinical portfolios among rare disease companies in terms of modalities and indications, and one of the most prolific late-stage pipelines of both gene therapy and rare disease. It is a testament to our ability to identify great science and do effective deal transactions to drive that work forward in the development of our 11 years as a company. We are now on track to initiate four pivotal clinical trials over the second half of this year. And these include Phase 3 studies for two of our gene therapy programs DTX401 and DTX301 in GSDIa and OTC, respectively. Two, a seamless Phase 1/2/3 study for gene therapy target UX701 in Wilson Disease. Finally, a Phase 2/3 pivotal study for UX143 in osteogenesis imperfecta.

Thank you, Emil, and good afternoon, everyone. Before I get into the details of the commercial performance for the quarter, I'd like to thank all of the teams for their work and dedication during what are still uncertain times. While most states have reopened, the teams have shown an ability to adapt and overcome challenges within this new environment of conducting business. Crysvita had another strong quarter growing 6% versus the first quarter of 2021, and 38% over the second quarter of 2020. Within the North American region, second quarter revenue grew 15% versus the prior quarter, as the seasonal reimbursement effects normalized. Crysvita revenue in Latin America declined quarter-over-quarter, but this is driven by uneven ordering patterns and is not reflective of the underlying demand. Given the strong demand and execution we have seen in the first half of the year, we continue to affirm the 2021 guidance range we previously provided for revenue in Ultragenyx territories of $180 million to $190 million. In the United States, we are continuing to make inroads beyond major endocrinology and metabolic bone centers, and into the community clinics where we are finding more and more adult patients. Early on in the launch, adults made up 40% of the patients treated with Crysvita. Today, as the total number of patients on therapy has grown significantly, so too has the portion of adults who have received Crysvita. We are now at approximately a 50/50 split between adults and pediatric patients on Crysvita therapy, mainly driven by the work the team has done in the small, harder-to-reach community clinics. As the teams leverage and expand upon investments that were made over the last year, we are confident we will continue to find more patients with XLH and TIO who could benefit from Crysvita.

Thanks, Erik. We issued a press release earlier today that included a financial update, which I will briefly summarize. Company revenue for the quarter ending June 30, 2021 totaled $87.0 million. Crysvita revenue in Ultragenyx territories was $44.7 million, including $41.8 million from the North American profit share territory, and net product sales of $2.9 million in other regions. Total royalty revenue related to the sales of Crysvita in the European territory was $4.9 million. As a reminder, ordering patterns in Latin America will vary from quarter to quarter. In the first quarter 2021, we received a large stocking order from Brazil's Ministry of Health to support the patient demand in that region. We are confident revenue from this region will continue to grow over time, driven by strong underlying demand. But ordering patterns will be uneven in the near term as we work through the reimbursement process. Dojolvi revenue for the quarter was $10.0 million. As we have noted before, we will not be providing revenue guidance for Dojolvi in these first quarters of launch. We believe the metrics Erik discussed better describe the success we are seeing so far. Mepsevii revenue for the second quarter 2021 was $5.4 million. We expect these revenues may modestly increase over time. Second quarter 2021 revenue also includes $22.0 million related to tech transfer as part of our strategic manufacturing partnership with Daiichi Sankyo, around our HeLa PCL and HEK293 Technologies. Through the rest of this year, the revenue recognized will taper significantly, as the tech transfer activities come to a close. 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 $169.8 million, which includes research and development expenses of $113.2 million, SG&A expenses of $53.4 million, and cost of sales of $3.1 million. As a reminder, we expect our R&D costs this year to increase versus 2020, as we support three pivotal gene therapy studies, the UX143, Phase 1/2 clinical study in OI, the Phase 1/2 study for our most advanced mRNA program, UX053 and GSDIII, and a number of other pre-clinical activities as we get ready to advance the next programs into the clinic. We also expect SG&A to modestly increase in 2021, as we continue to support the expansion and launches of Crysvita, Dojolvi, and Mepsevii. For the quarter ended June 30, 2021, net loss was $122.4 million, or $1.81 per share. This compares to net income in the same period of 2020 of $25.3 million, or $0.42 per share basic and $0.41 per share diluted. The net loss for the second quarter 2021 includes a $31 million decrease in the fair value of investments in equity securities, as compared to a $95 million gain in Q2 '20. Net cash used in operations for the six months ended June 30, 2021 was $224.7 million, compared to $7.8 million for the same period in 2020. Net cash used in the first half of '21 includes the $15 million upfront payment for the closing of the Mereo license and collaboration agreement, compared to net in the first half of 2020, which included $134.9 million of operating cash received from Daiichi Sankyo related to collaboration and license agreements. We ended the second quarter with approximately $974 million 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. I'll now turn the call over to Camille.

Thank you, Josh. And I too wish everyone a good afternoon. Today, I will focus my remarks on providing an update on GTX-102, being developed with our partner GeneTx for the treatment of Angelman syndrome. Angelman syndrome is a devastating neuro genetic disorder, with a broad spectrum of disease manifestations that affect multiple important domains. Last year, we reported surprisingly early positive efficacy data from the first five patients treated in the Phase 1/2 study of GTX-102 that indicated substantial improvements in multiple domains in all patients. We also reported all five patients had either one or two serious adverse events of lower extremity weakness that have fully resolved. At the first presentation of the SAE, we paused dosing and enrollment in the clinical study. Since then, we have run extensive tests to confirm that this SAE has been fully resolved in all five patients. Furthermore, we shared extensive clinical and non-clinical data with regulators and have had productive discussions with regulatory agencies, including Health Canada, the Medicines and Healthcare Products Regulatory Agency, or MHRA in the UK, and the FDA. Outside of the U.S., both regulatory agencies have reviewed our data and have given us the green light to begin treating patients with GTX-102. The agencies agreed with our plan to begin dosing in two parallel cohorts with a modified dose titration and administration plan. One cohort will start at 3.3 milligrams for patients under eight years old, and the other at 5.0 milligrams for patients aged eight to 17 years. Trendelenburg or a head-down tilted positioning of the body, and an artificial CSF flush should help reduce local contact time and help the ASO reach the cisterna magna as it is diluted, and through circulation distributed to the brain. Careful titration to higher doses may be evaluated on an individual basis after two repeat doses have been first administered to allow the exploration of a dose that is both substantially effective in at least two domains without causing a safety event. Dose escalation is capped at 14 milligrams for a single dose. This new dosing plan is within the observed range of clinical and non-clinical activity, but below doses associated with SAE. In the U.S., we have had a number of productive discussions with the FDA, where we discussed the nature and complete resolution of the SAE, as well as our plan to resume dosing patients in the United States. Following a Type A meeting, we submitted a protocol amendment. Based on feedback we received on this amendment, we believe we have agreement with the agency on a dose and dose administration strategy to treat naive patients. The agency asked that a few specific additional neurological assessments be added to the protocol before we resume dosing in the U.S. We will make these changes and look forward to resuming the treatment of patients with Angelman syndrome in the U.S. We and the GeneTx team have received numerous inquiries from families looking to enroll their children in this study. The data generated will confirm we can safely dose patients with GTX-102 and will inform the loading and maintenance dose regimens as we move to the next phase of development. With this update, I will now turn back the call to Emil. Thank you.

Thank you, Camille. Before we close out, I'll provide a quick reminder of the key upcoming milestones for Ultragenyx. For GTX-102 and Angelman syndrome, we will dose patients in Canada later this quarter and provide some summary data by the end of the year. We also expect to resume the study in the U.S. adapted to the FDA’s request. For our three pivotal gene therapy studies, DTX401, DTX301 and UX701, all the products have been manufactured and released for use in studies in sites around the globe and identified and patient-finding efforts are underway as the final operational tests are completed before we begin dosing patients. For UX143 osteogenesis imperfecta, we reached agreement with the FDA on a final pivotal study in pediatric and adult patients, and we will initiate that study by year-end. For UX053 and GSDIII, we intend to move our first mRNA therapy in the clinic with a Phase 1/2 study. As you can see, we're executing on all fronts, with early and late-stage clinical trials in various disease areas and therapeutic modalities as well as in commercial. This will set us up for multiple important clinical readouts over the coming 12 months, as well as pivotal study data from at least four programs over the next couple of years. With that, let's move on to your questions. Operator, please provide the Q&A instructions.

Definitely. Your first question is from Maury Raycroft with Jefferies. Your line is open.

Hi, thanks for taking my questions. So I was wondering if you could elaborate on what the additional neuro assessments are that the FDA is asking you to use for Angelman? And how many patients and how much follow-up you could have to report later this year?

Sure. Well, we've agreed on what the assessments are, the sorts they want, how we're documenting what the training for the person is, who administers it. They just want a little more logistical detail. But these are just really careful neuro exams. And we're doing some deliberate electrophysiology, and we'll also have the imaging when necessary. They also want us just to be certain of what triggers what kind of action on our part, what to do when we find things. So it's a bit of logistical management detail. But I think fundamentally, we have the big pieces put together; it's why we're confident we'll get that figured out. It's unfortunate it's taking time to do this. But I think we're finally there. Now on how many patients, it depends a little bit on how many patients get treated in the UK and in Canada. The sites already have patients inquiring and have gone through some of the ethics committee approvals. So it's a little bit more of the last logistical steps. We said before, we’d expect to have a few patients treated through a few doses, and that we would report, by the end of the year. The exact number, I think it's hard for us to say, but we'll have some data on a few patients. And we should probably have most of the patients in the first two cohorts, at least receive one dose by the end of the year. So we'll put out whatever we do have, but it will be limited. It won't be an extensive amount of data. But we do believe it'll give us at least a sense of are we moving in the right direction with the program. Our confidence is that if we give patients three or four low doses that load them, we will begin seeing the clinical effects we saw before, so without any adverse events. So we'll get to start to get a read on that before the end of the year.

Great. Okay. Thanks for taking my questions.

The next question is from Tazeen Ahmad with Bank of America. Your line is open.

Hi, good afternoon. Thanks so much for taking my questions. Emil, another one on Angelman, if I may. So you made in your prepared remarks the comment that the agency has asked you not to start redosing the previous patients. Is that pending approval for what you're going to do for protocol for the new patients that you would add? Or is that something that would have to be separately discussed? And then I have a follow-up?

Yeah, I think their view right now is that we don't have perfect knowledge of what the reaction will be from, and so they'd want us to treat patients that haven't seen higher doses and just see if it's safe to do. Then we could rediscuss what to do with retreating patients. But we don't have perfect knowledge of the mechanism. What we have said and we believe the data we have suggests it's a local chemical irritation type effect because there's no cellular response. There's no antibody response; it's really kind of a local contact issue. But we don't have perfect knowledge of the mechanism. So, it's mainly about going into naive patients with a lower dose. That way we know it's nothing about the history of exposure; we're now dealing with the lower dose alone and can look at it in a clean way. After that, we'll certainly have to get back to retraining the same patients we saw before. But we don't think this changes our overall timeline of what we do. I think we can get the data that we need. It just is tough for those patients who were so excited and want to get retreated. For them to have to wait more time is disappointing for them, but it won't affect the overall program. But we do feel for them, and we're going to work at getting them treated as soon as we can.

Okay. And then, as a follow-up, is it safe to say that the FDA is asking for additional information relative to what the UK and Canada asked for? And if that's the case, what's prompting that?

Well, the actual method we're using in Canada and in the UK regarding evaluations and safety monitoring is actually the same. It's the same. It's a question of how much detail we provide them; do we have a checklist form, or is there some other, let's say, operational structure regarding verification and training, etc. They sort of want more detailed rigor around the same things that we're doing there and doing here. So it's not like they're making us do extra things; really, it's the same safety assessments. So I think they're just being very conservative. And they want great assurance that we're going to be careful about what we do, but of course, we will. But I think you can be careful by having great neurologists who are insightful to take care of patients carefully. And then the question is how much documentation makes that better or not. And I think you can do it. If you have great people, they'll do a good job. So that's the difference.

Your next question is from Gena Wang with Barclays. Your line is open.

Thank you. I have one question regarding Angelman clinical endpoints. Some doctor feedback suggests CGI has some limitations and rely too much on parents' feedback. What other measurements would you include for the Phase 1/2 such as Bailey's or Violin, that's what doctors recommended? And then, quickly another question regarding DMD. Just wondering, are you on track for the R&D filing in the second half of this year?

Did you say DMD?

Yeah. DMD.

Alright, we'll follow up on that. Regarding the CGI and patient feedback, the information provided is not fully comprehensive because our trial evaluations involve multiple parties. There are caregivers, psychologists who administer standardized tests like the Bailey's, and investigators who directly observe the patients' performance rather than relying solely on their self-reports. We have three distinct sources providing data, all of which are supportive of our findings. Additionally, we utilize objective measures like Delta power, EEG assessments, and the Active Mayo test that yielded further insights. It's important to note that physician assessments also consider observable patient behaviors. While I appreciate the feedback, we prioritize using multiple verification methods to avoid being influenced solely by parental perspectives. I can confirm that our principal investigator in Chicago reviewed video recordings of patients demonstrating behaviors that their parents reported, highlighting that those recordings provide clear, objective evidence of the patients' actions. We are confident in the validity and significance of our findings. Now, concerning Duchenne Muscular Dystrophy, we plan to provide an update on our program's status. We are not filing an IND this year, as stated previously. This year, our focus is on establishing a large-scale commercial manufacturing system utilizing our HeLa technology. We anticipate sharing results from this production system later this year and will update you on our non-clinical program. At that time, we will discuss potential timelines for an IND, but it will not be completed by the end of this year.

Okay. Thank you.

Your next question is from Yaron Werber with Cowen. Your line is open.

This is Brendan on for Yaron. Congrats on the progress. Thanks for taking the questions. Just a quick one from us. I guess to keep on the same line on Angelman. I was hoping to see if you could give us a little bit more color on the timing for the UK study. I know you said things like Canada are pretty close to the first doses. Just wanted to see what's left in getting drug into some patients and the UK, and if we might get any of those interim data. And then just wanting to see also if you mentioned that you settled on the dosing scheme administration with the FDA, wanted to see if you can tell us if it's the same structure you're using in the UK, in Canada, or if you're thinking about a different design for that. Thanks.

Okay. So the UK is on track. I mean, it could be UK or Canada in terms of treat comparisons within weeks of each other, so it won't be that much different. We expect to have some UK patients treated; there's a great deal of enthusiasm from the UK patient community getting enrolled. Once the site's open, we expect them to be able to enroll. And remember that study will have two patients below 2.8 treated first, and then a couple of doses, and then additional patients will get treated. Alright, until they're six and then six get treated. So we expect some UK patients. Now you're asking about the U.S. protocol; the U.S. protocol will also have monthly dosing, but will involve different doses. However, the methodology will be simpler in the U.S., in fact, not identical to what the UK and Canada are doing because the FDA has made specific requests. We have an understanding with them about the dose administration strategy that we're going to use in the U.S. But it is a little bit different. It is monthly dosing similarly, but the method thus far will be a little bit different based on the FDA’s input.

Okay, great. Thank you.

Your next question is from Joon Lee with Truist Securities. Your line is open.

Hi, thanks for taking our questions, and for the updates. I have a question on UX053 GSDIII. We're interested to hear your views on the use of modified versus non-modified mRNA given the precedent set by Moderna, BioNTech, and CureVac. Curious if the signals some potential headwinds UX053 given Arcturus uses the unmodified mRNA. Some KOLs seem to think that urethane might have contributed to weak data for CureVac, and they also point out to double stranded RNA as a potential trigger for innate immunity. And so curious what your views are on that? And sort of what kind of biomarkers are you hoping to collect from this initial data to assuage any concerns there? Thank you.

Yeah. So, we think the issue of the innate immunity stimulation of mRNA is very important. And we actually do several things to design. We design the mRNAs very carefully to ensure that they don't induce innate immunity responses. We actually use peripheral blood monocytes, white cells from patients to actually test our mRNA to determine they're not having significant amounts of double-stranded RNA in how we purify and prepare them. We have used modified nucleotides. We're using mRNA. So we just have to make sure that they're translated efficiently. But we haven't disclosed all the details of that. However, we know our mRNA is not stimulating human white cells, which we think gives us a handle on that particular issue. And we know the expression is substantial in terms of how much enzyme can be made from the mRNA product. So, the whole issue regarding the COVID vaccines, I think, is more complex than just the RNAs, frankly. So I think there's a lot of other aspects like the lipid nanoparticles themselves which matter too.

Thank you.

Your next question is from Salveen Richter with Goldman Sachs. Your line is open.

Hi, good afternoon, and thank you for taking our question. This is Elizabeth on for Salveen. A question on the Angelman program, so I know previously, you've sort of discussed expanding the program to include other genetic types outside of the most severe solution-based patients. Just wondering how this would work in terms of the trials and progress or if it's more of a future consideration?

We definitely think the other genetic types deserve to be treated and we think the ASO could work in the deletion type, it may also work in the other types based on the mechanistic understanding. Our plan right now is to focus on the 77 patients with deletions for the program we're conducting. However, we would probably put a second study in place to look at other genetic types. The reason to focus the main pivotal study on the deletion type is because they are more severe. Therefore, any improvement you see in language communication which is one of the main things that patients are most interested in would be clearer if we have a mixture of patients who have varying degrees of communication skills and words, etc. It would just create difficulty in a pivotal randomized study. So we'll focus on those but we are not going to forget the other types and put some program in place to deal with the other types, as well. But creating heterogeneity in the main body of the big study is, is one of the ways you can create trouble for something that's doing great, so we wouldn't do that.

Thank you.

Your next question is from Joseph Schwartz with SVB Leerink. Your line is open.

Thanks very much. We noticed a couple questions on Crysvita. First, we noticed that the label was updated in Europe to allow patients to self-administer therapy. And we were wondering, what impact do you expect this to have, if any? And do you think we could see a similar change take place in the U.S. at any point in the foreseeable future?

Thank you, Joe. But in the U.S., right now, we actually have temporary authorization from the FDA to allow self-administration which is going on already because of the pandemic. We haven't submitted the change that at this point, but we have done the human factors study. The drug administration is very similar to what you might do for any other subcutaneous drugs, and there's nothing very special about the injections or problems. So it certainly could be added. It has complexity, though in the U.S. because we have to deal with the different systems whether it becomes a medical product, a hospital product, or home product or not a part B product. So there's some complexities in the U.S. at this point in time, but our patients are doing self-administration. In the long run, we would certainly move in that direction. We haven't had a big compliance issue. And I think one of the things that is important just to note is that we supported right up front and do include in the class of drugs getting home nurses that come to your home to inject you. So the 85-plus percent of patients are getting their treatment at home already. The benefit of self-administration is you don't have someone show up at your house. On the plus side, there's a lot more confidence that you're going to get your injection on time since it's an appointment. But we want to make sure it's as convenient as possible because this is a lifelong treatment. So we'll look at self-administration in the long run, but so far, the home nurses are working well and some of the patients are getting it, are doing it for now on the temporary authorization.

Okay. That's helpful color. Thanks. And then has the need for Brazilian patients to use the label system to gain access to Crysvita been holding back adoption there to an appreciable degree? Can you quantify the impact you'd expect to see on Crysvita Brazil sales from potential formal approval?

Well, we have the approval, and we are getting injunctions and Ministry of Health orders as the lumpy ordering pattern we're seeing, but it is there we are getting orders that it's growing over time. What we're talking about today is getting formal approval of the organization within Brazil that actually determines government reimbursement. With that it would help get more regular reimbursement for Brazil. So that is near the final stages. And once that's completed, we'd expect that would help boost Brazil further. So we wouldn't have as much of the logistical challenges of what you're doing with the injunction approach. Is that answer to your question?

Yeah, it's helpful. I was just wondering, is there any way to quantify how much the current system has been holding back sales? Or how much could you get a boost from?

Yeah, we've done a good job of identifying patients and many of those patients have sought injunctions. And as stated, many have received injunctions and are receiving reimbursed therapy. I would say to the magnitude of about two to threefold patients that have been identified and are seeking reimbursement versus those that have received injunctions. So, there's some upside once we receive formal reimbursement. One thing I want to point out, just to piggyback on what Emil stated, that in the first quarter, we did receive a positive opinion supporting reimbursement in Brazil. We're just working through that final stage, which is establishing clinical guidelines, which is the next step in the approval process, and we expect to complete that sometime in the New Year.

Very helpful. Thanks again.

Your next question is from Cory Kasimov with JP Morgan. Your line is open.

Hey, good afternoon, guys. Thanks for taking the question. On Angelman, has the FDA conveyed this concern before about retreatment? Because it seemed like that was the plan for the go-forward strategy in the U.S. until very recently. I guess I'm just wondering for something new that triggered this change in direction?

Well, we had our Type A meeting with them, and it was pretty clear that they were just concerned that the patient that had a reaction might be more sensitized and therefore, they'd have trouble determining the safety if it would have been different had they treated a patient who never had the reaction as opposed to one that did; that makes sense. So in terms of understanding what's going on, they felt it was safer to start with naive patients and they want us to hold back on that. There's no new data that helped change their mind. We have no new data regarding things that might cause them to have a more severe reaction. We think based on everything we have that they don't have something that we think would necessitate that way, but we can't prove the mechanism exactly right. And so without that proof, the agency wants to play it safe with regard to who they expose in the beginning. So, that's the story. There isn't anything new that came out, for example, that would have made that new change; it's just something they finally disclosed to us at the Type A meeting.

Okay. Makes sense. And then I just wanted to try to clear up the dosing you're expecting to use in the U.S.; you said it's going to be different than Canada and the UK. Is it that you're going to start with lower doses and work your way up? Or will it be higher doses here, given you've treated some patients?

No, we're going to start a little bit lower. We think that it's still in a range that will load the patients sufficiently over four doses to get a treatment effect. But I think the FDA wants to be more cautious. And so, we went along with what you have to do to get going.

Your next question is from Yigal Nochomovitz with Citi. Your line is open.

Hi, this is Carly on for Yigal. Thanks for taking our questions. We had a couple on Wilson disease. As far as the target patient profile for the Phase 1/2/3 trial, will you be focused on recruiting patients with established disease? Or is the focus on treating newly diagnosed patients? Just curious if you think there could be an advantage in terms of the magnitude of benefit with UX701 if you're able to capture patients earlier versus later in their course of the disease? And then secondly, what is your expectation at this point for when we could potentially see some initial data from this program from the dose escalation part of the study? Thank you.

Yes, thank you. So the patients will be the patients who have been or established patients who have already had a key letter. The problem doing naive is it would be very few patients, and it would take a long time. I don't disagree with the thesis that treating patients early before they've progressed would allow a cleaner result. But we do believe that since the key letters remove copper by bringing it into the urine, and what we're doing will bring copper into the bile, then we will be able to look at urinary copper and show that the copper is no longer ending up in the urine or being accumulated in the liver. It's going to be routed into the bile, right? Does that make sense? So, even though they're on the drug, we can determine if the copper pathway is changing in the body. And if the rule of plasma has gone up, so it won't really matter if they are not established and whether we can see difference happening. And the truth is there are so many more patients on established therapy, it would take us a long time to do it the other way. In the long run, though, using naive patients, I think would give a cleaner result. I think taking patients earlier in their course might change people's view on what's happening; everyone believes it's just the excess copper. But it's also possible that it's copper not being properly distributed as well. That's part of the symptomatic problems that you're seeing in Wilson. We think the gene therapy can fix both. So, that's our focus based on the ability to conduct the study and the way we can measure them. Now regarding when data, we expect to be able to get the patients enrolled in the dosing relatively quickly. I can't say specifically when that data will come out, but we will put out data, could be by the end of 2022. But I'm not 100% certain. It depends a little bit on Delta variant site execution, but we're up and running, products ready, sites are getting set up. We have I think, a very convenient protocol that will be easy on patients, so I think it will help make recruiting easier.

Okay, great. That's very helpful. Thank you so much.

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

Thanks very much for taking the question. Just on Angelman, you've commented in the past on the potential potency differences between GTX-102 and the Roche program, and there's also another program starting from Biogen. I'm wondering if we could just take a step back, and how do you think about the key elements of differentiation in a clinical setting for all these ASL targeted strategies? Are there logical points in which two agents might differ? If this is still kind of evolving, I guess what kind of aspects should we be focusing on as the clinical trials get underway here? And then just one quick follow-up. With respect to the dosing in Angelman patients in the UK and Canada, I think in the past, you've spoken about getting them through the titration getting up to a steady state level. It isn't clear to me how many patients are actually going to be at that range, and especially if we're going to be needing more like three or four doses. I guess I'm just trying to understand how you think the response data might differ this time around versus the prior experience? Thanks.

Okay. So on the competition, we know the mechanism for this ASO is special; the patented region is different. It's at the five prime end. I think Dr. Dindo has shown that it is far more potent than antisense ASOs from other parts of the message, in terms of knocking down the production of the antisense message and in the level of induction. I think each ASO could have varying levels of potency and penetration. But I think you want to have high potency across the brain, and you want to bring the mRNA down; I mean, the antisense RNA down far enough to get significant induction of the message. We have shown that we can do that with a relatively small amount of drug, and that effect goes across the whole brain to all regions. So, I think the difficulty will be how well the ASOs are distributing and how well they are able to knock down? Because all ASOs have toxicities; it is very common, you've seen them a lot of programs; there are drugs that have a lot of potential challenges. The potency will then become an added question of the therapeutic window. I do believe if we're able to successfully dose in the single-digit range, low double-digit and achieve the efficacy we saw, that will greatly reduce the possibility of having systemic ASO side effects that you sometimes see, or other neurological effects. So certainly, that's our expectation. So on the tight dosing and titration story, in the first set of patients, we're treating two in each group, and then we're going to add four and four. So it'll be 12 patients total. We'll have 12 patients and from the 12, we'll get a read on where they seem to be getting the efficacy and what dose they are at. Once we get that information, we're going to try to look at it and try to make sense of how it's the optimal way to dose going forward. But we've said before, once if we see safety and we're getting good efficacy, we'll take that information and translate it into a dose that we'll use on an expanded cohort of say 30 or 40 patients. Those patients would get a starting dose based on the dose achieved during the titration and use that as their starting dose. Does that help you? And the idea is that those 30 to 40 would now have a little more standardized dosing regimen, right? That makes sense? So titrate individuals learn a little bit and then standardize it in the next group.

Got it. Okay. Thank you, Emil.

Your next question is from Dae Gon Ha with Stifel. Your line is open.

Great. Good afternoon, and thanks for squeezing me in, and congrats on all the progress. Maybe one question on Angelman and then a quick one on 401, Emil. So on Angelman a lot of my questions have been answered but just curious on clinical trials you have one site in Canada, one site in the UK, which is going back to the variability issue. Will you have a centralized reading for the CGI to make sure that there is a consistent vote in terms of the CGI benefit, as well as some of the other benefits that are included? And then on 401, just curious, given that one of your endpoints measures the glucose control using CGMs, I was wondering if the protocol entails any backups in case CGM starts malfunctioning when you validate for any significant variability that might occur during the study? Thank you.

Sure. So there's really no way to do a CGI centrally because it's an opinion of the physician there, and not everything they're doing in terms of evaluating the patient could be centralized; we can’t turn it into a video. The sites will be trained on the various endpoints. For CGI, there's a global one and then there's individual ones for individual domains, which have specific questions that they answer, and we'll try to do it. We'll do our best for our team to train the CGI team to train the sites to be able to do these tests. We also have a number of tests that are not CGI, right, that have basic scoring mechanisms and are being administered by professionally trained psychologists, for example, as well as some other objective measures. So we won't be relying on CGI to make all the calls. I think CGI will give you a holistic feeling of what the PI thinks. But as we noted, when we presented this data before, you want to look at the other endpoints to show there's an underpinning; right? If having CGI without any underpinning in the rest of the data would be suspicious. If someone's just wishful thinking hoping they're better. But if they're really better, there should be something else happening. So we feel confident we can manage the question of objectivity by using the supporting data. Now, with regard to 401 CGM controls, while we will have them continuously monitored, we're actually going to take windows of sample time and do the calculations for how they're doing. So if, for example, they had a probe that fell off and stopped working, we would see the defect, we could take the period of time when they sampled effectively and calibrate it. So they're going to put them on calibrate measure for a period, and we'll use the sampled periods; that makes sense. Because if you expected to be able to use all the data continuously for months and months, yes, stuff is going to happen during that period. But we'll have periods of assessment that are in intervals of time, we're going to watch it more closely. And we'll take windows of sampling that will be verified as operating correctly, calibrated correctly, and receiving results. So that should help protect us against the kind of digital disaster you're talking about. And we've been thinking about that, too. I'd also point out the devices collect locally, and then they collect in the cloud too. So it's actually double-collected. If anything, we could actually shift the device and do it. But that doesn't stop a patient from having a probe malfunction or something. So you have to include all levels of the problem, not just digitally, but on the physical parts that connect to the patient, which are probably the bigger source of questions. But we've had good experience so far. We're getting a lot of good data from the patients, so we feel pretty comfortable we can get this to work without having a lot of trouble.

Your last question is from Liisa Bayko with Evercore ISI. Your line is open.

Hi. Thanks for taking my question. Just to clarify, so in the U.S., we're just back to the Angelman program. Even though you're starting lower, can you still escalate up to the 14-milligram level?

We'll start lower and see how we do, and then we'll treat the several doses at a lower dose, which, as I said, should still give us enough drug to show an effect. And then if we establish safety there, we have safety elsewhere, we’ll then apply to the FDA to kind of titrate them up. But, we're kind of taking baby steps forward in the U.S. to get them tested, get some data, and get comfort. Whatever happens in the U.S. will not control the future; we will have UK and U.S. sites more than one site doing with all that data together, and we'll come up with a plan. I think the agency is being very conservative; it's fairly typical for them. And we are just working our way to get going. But I don't think it's going to affect anything. It will delay our ability to titrate those patients. But we will still have enough drug on board to know that it's safe and to determine if it is doing something for them.

Thank you for the clarification. So, the maximum dose hasn't really been determined, or is it set at 14 like it was for the other?

For ex-U.S., we agreed at 14 based on the other authorities, but in the U.S., we haven't set a max because we're not titrating and we're starting in a low dose. We're going to repeat that multiple times. And the FDA has agreed to that. So we'll get started and start getting some data.

And that concludes the Q&A session for this conference call. I will now turn the call back to Joshua Higa for additional or closing remarks.

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.

Ladies and gentlemen, this concludes today's conference call. You may now disconnect. Stay safe and well. Have a good day.