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 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 related to our business, see our periodic reports filed with the SEC. I will 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 have made great progress toward the initiation of four pivotal clinical studies with novel therapies for rare genetic diseases and a broad portfolio of six clinical stage programs. The clinical progress is complemented by continued advances in our three commercial franchises, marking 2021 as an important inflection point in our growth as a company. Starting with gene therapy, we made significant regulatory and operational advances 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 3 study. We have also completed all the regulatory discussions for the DTX401 Phase 3 and are working with sites to get the study started soon.

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 will start with Crysvita. Our leading indicators, including patient times, start forms, and reimbursements 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. 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 from our patient support services team. At this point, three years into launch, we have established strong relationships with all of the major endocrinology and metabolic bone centers. Solid growth will come from our patient filing efforts in the community clinics where the majority of our new adult start forms originate. We are increasing investments and successful tactics that we piloted during the pandemic and 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 ultra-rare 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 are granted injunctions and gain access to name patient sales. It 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.

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 at $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 two 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 by 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 who are able to get reimbursement through the injunction process in Brazil. As is the case with Brazil’s Ministry of Health, we expect continued uneven ordering patterns for this territory.

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, growth and fine motor dysfunction, sleep dysfunction, and seizures. Late in the year, we reported positive efficacy data from the first five patients treated in the Phase 1/2 study that indicated substantial improvements in multiple domains in all patients. We also reported all five patients had a grade one or two serious adverse event of lower extremity weakness that has now 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 non-clinical data showing the effects of DTX-102 in non-human primate models at single and repeat doses at levels far exceeding an equivalent dose that would be expected to be used in our clinical program. The delayed onset weakness we saw in the Phase 1/2 was not observed in the non-human primates with single doses as high as 10 milligrams or a 110-milligram human equivalent dose, nor was it observed with seven monthly doses of 4 milligrams or an equivalent cumulative dose in humans of 314 milligrams. 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 strong effect at 0.5 milligrams dosed monthly. We recently requested a meeting with the FDA following multiple submissions of substantial non-clinical and clinical data, including data confirming that the serious adverse event in the previously treated patients has fully reversed. This meeting has been granted for later this quarter. Following the meeting, we hope to have fully satisfied the FDA’s questions around the serious adverse events 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 non-clinical information about GTX-102. The authorities agreed in principle on the expansion of the trial to Europe using a proposed modified study design, dosing, and administration strategy pending review of the application. The application to enroll clinical studies in this country was recently submitted. Separately, we also recently submitted an amended dataset and protocol to the Canadian authority in order to begin enrolling patients there. This submission is currently being reviewed by Health Canada. Our modification to the study protocol included an amended administration and dose titration plan. Trendelenburg and an artificial CSF flush should help reduce the local contact time and help the antisense oligonucleotide reach the cisterna magna as it is diluted and circulation distributed to the brain. Patients will be divided into two starting dose cohorts based on age. Those under eight years old will receive a starting dose of 3.3 milligrams while those eight 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 non-clinical activity, but below the doses associated with serious adverse events. With this three-pronged approach, we feel confident we will be able to resume this important study and share additional clinical data before the end of this year. Turning now to DTX401, our gene therapy for the treatment of glycogen storage disease Type 1A or GSD1A. We previously completed the scientific advice process with the European Medicines Agency and held the end of Phase 2 meeting with the FDA. Following these regulatory discussions, we submitted the study protocol two months ago to the FDA. As of this call, the FDA has not provided any objections to starting the study. While we await some informal feedback from the agency, we simultaneously are moving forward with steady startup. As we finalize the 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.

Thanks, Camille. After completing four approvals in our first ten years, we built out our pipeline of Ultragenyx in the last few years to put us in a position to have both a full pipeline of late-stage assets and multiple products in launch mode. Result varies one of the broadest and most diverse portfolios in the rare disease space. A clinical pipeline now includes six programs. It is well-balanced across modes, encompassing gene therapies, antibody and antisense oligonucleotide, and mRNA. It includes smaller rare diseases where we are essentially the only drug development, but also includes more competitive and much larger opportunities. Over the long term, we will continue the strategy of using our insights in relationships in rare disease defined to advance a diverse set of compelling opportunities. We will focus more 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 instructions for asking questions.

Thank you. Your first question comes from the line of Joseph Schwartz from SVB Leerink. Your line is now open.

Hi. Dialing in for Joe. Thank you for taking our questions. My question is on DTX301 for OTC deficiency. Typically, you have a co-primary endpoint. It can be analyzed several different ways. Usually you have to hit both endpoints, but sometimes you can just hit one of the two, or the hurdle can be higher for one over the other endpoint. So I was just wondering if you could discuss the statistics for your Phase 3 study.

Yeah. So we are expecting to hit both endpoints. The ammonia control is easy. But I think the question with the responder is also about the clinical meaningfulness of the results. We think that the clinical maintenance is quite dependent on being able to get off of existing therapies. So if we control ammonia, but can’t get people off their other treatments, it doesn’t mean much. However, we feel confident in putting both endpoints forward based on everything we have seen so far that if we control ammonia and maintain it below a certain level, we will be able to reduce their diet and the drugs.

Okay. Great. Thank you. And then, how are you defining responder? I know that in your opening remarks you mentioned a 50% plus reduction in the baseline disease management. But I guess I am curious about the ammonia component. Are you trying to get the patients down to the normal range or is there a threshold you have to meet?

No, the ammonia analysis indicates a continuous reduction in ammonia levels. It is not determined by whether a patient is a responder. As we relax the entry criteria for ammonia, we have observed significant decreases in ammonia levels. We anticipate a variety of ammonia levels among patients and expect that variation to narrow among those receiving treatment. This is a continuous measurement rather than a binary responder assessment. Regarding the reduction in care, we can think about thresholds; for instance, if there’s a 50% reduction, it means if a patient stops their scavenger drugs but does not adjust their diet, they achieve a 50% reduction in care needs. If they eliminate both, that results in a 100% reduction, and stopping one leads to a 50% reduction. We will recognize a 50% reduction as a response.

Okay. Great. Thank you so much.

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

Thank you for taking my questions. I have two regarding Angelman. One is for the U.S. and one is for the ex-U.S. For the U.S., since the FDA didn’t ask you for additional animal data and you submitted additional clinical data, just wondering what could hold the FDA back at your second quarter meeting? And then for the ex-U.S. both Europe and Canada, will you be able to start dosing in the first half of this year? And I think you mentioned that we will have some patient data by the end of this year? Can you elaborate a little bit on what kind of data will be shared by the end of this year?

Very good. I will go ahead and answer that. So, on the first part regarding Angelman, the FDA asked for more data on the individual patients that were treated and had the event mainly to assess their complete reversal, and we have done some additional work and shown they are completely reversed. The question is what can hold them up. We think we have given them enough to move forward. I am not sure what else would hold them up, but we think we are responding to their requests and we hope to move forward. However, that said, we also know that sometimes you can’t predict what regulatory authorities will do and we have initiated work to also start the study outside the U.S. What we said today is that one outside the U.S. authority agreed with the plan given the knowledge about the serious adverse event, the efficacy, and everything, and agreed with our plan to move forward, which is the same plan we submitted to the FDA. Canadian authorities have seen that; we are waiting for their response. The timing of those responses from the authorities will determine how quickly we can get going. If they happen within a shorter period, we could start dosing, but if they take their full period, we may not dose in the first half. It’s hard to predict. As for the type of data, we will be talking about the first patients redosing again at month since they are dosing once a month; we expect to have several months of dosing on a set of patients. Initially, our plan is that re-dosing will be for patients aged six and below or six and above. We have been looking for some fraction of patients to be treated at least a few times. Based on the response we have seen before, we think within three or four doses we will have the opportunity to see if we are observing the clinical effect and whether we are getting the adverse effect.

Next question comes from the line of Tazeen Ahmad from Bank of America. Your line is now open.

Hi. Good afternoon. Thanks for taking my question. As it relates to Angelman, when would you need to restart 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 a make-or-break situation based on any discussions you have had with the agency? The reason I am asking is that Angelman is an area of unmet need. If you are showing efficacy in these patients, what do you think the tolerance at the agency and/or physicians would have for a safety profile that might not be 100% clean? Thank you.

Sure. Regarding the timeline for starting up, we expect to need to get started either late this half or early next half in order to have a few doses on a number of patients before the end of the year. In terms of the safety profile, we believe that having lower extremity weakness wouldn’t be a favorable outcome for a chronic treatment like this. However, we’re confident we can overcome this issue because it’s not a drug pharmacologic effect, it’s more of a local irritation and inflammation effect, which should be manageable. So we believe we can get past that. Even in the event that we could not, we still might have other avenues for patients to pursue. So now that we are in this space, we have this ability to potentially change the clinical future of engagement, it’s something worth pursuing for a drug that provides important efficacy and an appropriate safety profile. I don’t think having lower extremity weakness is acceptable as a long-term safety outcome. Additionally, concerning Wilson, we are expected to start our study in the second half of this year. The Phase 3 study we are pursuing is a seamless Phase 1 through Phase 3 study.

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

Thank you for taking my question. I have two questions if that's alright. First, do you have an understanding of whether they require demonstrations of the weakness in animal models and its resolution before proceeding, or is that not a necessary factor since it’s challenging to replicate? I'm trying to gauge what would give them the confidence to move forward.

Yeah. The FDA has not asked us to recreate anything in animals and they have not requested any further work. They recognize we have used higher doses in animals and for many repeated doses with a high load and not seen it. So it is clearly not a toxicity issue with this oligonucleotide. This oligonucleotide has not shown toxicity in non-human primates given repeated doses. That is an important point. I think what I can add regarding the chemistry is that LNAs can have toxicities, but this particular oligonucleotide does not show toxicities in non-human primates with repeated doses. So we feel comfortable with the chemistry. Of course, the ability of ASOs to cause irritation or injury is known, but I believe the therapeutic index is crucial, and we think this particular drug achieves efficacy at 3-10 mg range. So we think we can avoid any secondary toxicity issues based on the potency.

With them, which is the long-term follow clinically and how do you control the risk mitigation? Is that what it is?

No, they just want more definitive proof that the patients didn’t suffer any residual neurological effects. This is a benefit-risk question. They are trying to assess if they are putting more patients at risk. We have said no and they wanted further information to confirm that is true. We have taken those measures, including MRIs and lumbar punctures and special neurophysiological tests, and it has been found that the patients are normal.

Next question comes from the line of Dae Gon Ha from Stifel. Your line is now open.

Good afternoon. Thanks for taking the question. Emil, maybe I will just touch on one more Angelman question. So recognizing you have three 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 three regulatory discussions. I mean do you see a lot of concordance between the three or do you see quite a bit of disparity in terms of what they are requesting? And then second question is more commercial; I was wondering perhaps it’s for Erik. Given that the U.S. has been easing up, you talked about the irregular ordering patterns in LatAm. But now COVID also seems to be somewhat more rampant in the ex-U.S. site. So I was wondering what you guys are currently seeing on that development front? Thanks.

Very good. Thanks for the question Dae Gon. I will let Eric answer. Regarding the first part on regulatory matters, we utilize the differences between regulatory authorities to move ahead with our programs, so it is common. We don’t look for concordance, we have proposed the same study and plan. The Canadian authorities seem to be aligned with what we submitted to the other European regions. We have continuing focus on the five patients we currently treat to manage our outcome effectively. Erik, you can now address Easing COVID as it relates to South America.

Yeah. A couple of things I want to point out first. When you consider 2020, we put out our guidance in advance of the COVID pandemic, and we ended up at the upper end because the team adapted and maintained engagement with both physicians and patients through digital means. We have learned a lot in 2020 and will continue to leverage those successful tactics as we move into 2021, which is why we accounted for our abilities to operate during this pandemic, as well as the potential for easing restrictions across the globe. However, the situation varies region by region, and in some instances, country by country, and the LatAm team has adapted just as well. So we’re confident in our projections moving forward.

We are receiving orders and have received orders from Brazil despite the pandemic. I know Brazil has been hard hit. There is 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 are pleased to see some ordering continuing.

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

Hi, Emil and team. Thank you for taking the questions. Could you expand a bit on why you opted for a single seamless protocol for Wilson’s disease, expanding the Phase 1 to Phase 2? Is there something specific about Wilson disease that’s better suited to doing a seamless protocol versus separate protocols?

Well, yes, there are distinct differences with Wilson. Firstly, it has been well-studied, well-treated, and there are established endpoints, which we could define and choose up front. Any regulatory agreement on urinary copper excretion is a relatively good measure. Our experience in doing liver gene therapy now gives us confidence we can hit the right dosing range. Furthermore, that allows the study to commence and to be smooth and efficient.

That makes a lot of sense. 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 am understanding that correctly and if so, that this study of triheptanoin has actually been running for almost two decades?

Camille, do you want to answer that?

Yeah. Sure. Thank you. Yes, you are correct. Prior to Ultragenyx taking on the development program for triheptanoin, the program was studied by academics for about a dozen years or so before that.

Next question comes from the line of Cory Kasimov from JPMorgan. Your line is now open.

Hey. Good afternoon, guys. Thanks for taking the question. Two from me as well. First one on DTX301, just wanted to ask again about the rationale of going from 48 to 64 weeks for the endpoint so patients can wean off of prior therapies. Was there anything you saw in the Phase 1/2 data that led you to think this additional time could be beneficial?

The debate with the regulators has been whether to study these diseases for up to two years, right? We didn’t feel that necessary. We agreed to add another quarter or 12 weeks to the plan, understanding that some patients might react at different times; thus, we believe that providing additional safety and time for the patients to titrate their medications would be worthwhile.

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 would enroll one patient, treat them, and then watch and wait before enrolling another or will it happen at a faster pace than that?

There’s a staging strategy proposed. There are two younger patients, two older ones that would get a few doses first and if they are okay, then we would enroll the rest of the two cohorts. So there’s some staging for two and two and then the total number would be expanded. We believe we could treat four patients reasonably quickly and then expand that to 12. If the initial patients are well treated, we may have room in our protocol to expand to another 40 patients, which will give us a lot more information.

Next question comes from the line of Maury Raycroft from Jefferies. Your line is now open.

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

Yes, patients have lost a significant amount of benefit. Some may have retained minor effects, but overall the efficacy has substantially reversed. This has been a factor in our discussion with the agency as the effects were markedly life-changing. We hope to make that a part of the overall benefit-risk assessment. If we can show them the risk of reversal is not an issue, the efficacy story could become more relevant.

Got it. That’s helpful. And then, one quick one. You mentioned potential for an Angelman publication from Scott Dindot’s lab; I’m wondering if you have a status update on that?

I don’t have immediate updates, but it was submitted. It’s a significant piece of research, and it’s a large paper, requiring a special journal. So I believe it’s still under review and I don’t have an update, but it’s exciting and informative.

Next question comes from the line of Joon Lee from Truist Securities. Your line is now open.

Hi. Thanks for taking my questions and congrats on the progress. For GSDIII, why have we decided on mRNA as opposed to DNA DTX301 and DTX401?

For GSDIII, which is a debrancher deficiency, the enzyme is complex and too large for a AVV vector. Additionally, if gene therapy fails to hit all liver cells, the toxicity may accumulate, making mRNA the better option here. We can include a larger protein and have shown very good delivery. With mRNA we should be able to clear toxic effects quicker, giving us a potential improvement for patient outcomes. Additionally, with GTX-102 and Angelman, there are several other players following your strategy and there’s also Roche with additional doses. Does this impact the FDA’s decision? I don’t believe the FDA makes decisions based on other programs’ early data; they assess each program based on its own efficacy and risk. Our program is potent and innovative, and based on the non-clinical data, we think we’re in a very good position.

Next question comes from the line of Jeff Hung from Morgan Stanley. Your line is now open.

Hi, guys. This is Hannah on for Jeff. What is the particular profile of OI patients within the pediatric population that you think would best respond? And then what do you see as likely the key differences between potential pivotal studies within pediatrics and adults and perhaps beyond the primary endpoint? Thanks.

Currently, the pediatric pivotal study is our core focus since they have the highest unmet need. We will be looking at patients who experience multiple fractures. This is crucial since we need to address the urgent care requirements and strengthen bones significantly. Our aim is to enhance both bone density and reduce fractures in these patients.

Next question is from Laura Chico from Wedbush. Your line is now open.

Hi. Good afternoon. Thanks for taking my question. I have one on UX701. I’m just wondering if you could comment a bit on the appropriate candidates for gene therapies in the context of your observational study on Wilson’s disease, and the impact of AstraZeneca and Alexion expanding enrollment in their studies.

Certainly, there are a lot of patients in the space of Wilson disease. Our study aims at stable patients but will include individuals with some significant illness. We are looking to patients showing enough severity of symptoms to measure efficacy effectively, but gently navigating the risk to their liver health.

Next question comes from Salveen Richter from Goldman Sachs. Your line is now open.

Good afternoon. Thanks for taking my questions. On Angelman, you mentioned potential variations to the program. What are those, and what are your updated thoughts on the age factor? Also, could you provide an update on the Duchenne therapy?

Regarding Angelman, we aim to treat naïve patients in Canada and ex-U.S. While in the U.S., we are focusing on retrialing the existing patients first. The age factor is important; we have seen effects across a range of ages from children to teens. Older patients may respond differently and we shouldn’t prejudge that without detailed studies.

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

Hi. This is Nicole Gabreski on for Chris. Can you discuss the process of getting UX053 into the clinic? Was there something specific that was a barrier for that program?

2020 was challenging, and running some of the non-clinical and preparatory studies was difficult. We managed to maintain our key clinical programs despite the challenges. We’ve learned how to optimize mRNA to minimize immune reaction significantly, reducing costs and improving yields going forward for this program and others.

Next question comes from Liisa Bayko from Evercore ISI. Your line is now open.

Hi. Just two quick questions. First on Angelman; does the FDA, excuse me, would they be waiting for any additional clinical data generated from other regions before allowing the process to restart in the U.S.?

The FDA would not say they are waiting for data from foreigners. They look at our data directly. The risk of reversal is their main concern, and we need to demonstrate we are managing that effectively to continue.

Okay.

Additionally, as for DMD and gene therapy, we believe there’s ample opportunity with our partners in the space, and we expect to find advantages in our product profile given our proprietary technology.

Thank you. This concludes today’s call. For additional questions please contact us by phone or at [email protected]. Thank you for joining us.

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