Ultragenyx Pharmaceutical Inc. Q2 FY2020 Earnings Call

Ladies and gentlemen, thank you for standing by. And welcome to the Ultragenyx Second Quarter of 2020 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. [Operator Instructions] And without further ado, I would like to hand the conference over to Mr. Joshua Higa. Thank you. Please go ahead, sir.

Good afternoon and welcome to the Ultragenyx financial results and corporate update conference call for the second quarter 2020. We have issued a press release detailing our financial results, which you can find on our website at ultragenyx.com. I’m Joshua Higa, Director of Investor Relations. Joining me on this call are Emil Kakkis, Chief Executive Officer and President; Shalini Sharp, Chief Financial Officer; Camille Bedrosian, Chief Medical Officer; and Erik Harris, Chief Commercial 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 2019 annual report on Form 10-K that was filed on February 14, 2020, 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 on our website in the Investors section. 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.

Good afternoon and thank you, everyone, for joining us on today’s call. I’ll start our call with a general update on our progress, then turn it over to Erik, Shalini, and Camille to provide more detailed updates on their respective areas. The second quarter was highly productive for Ultragenyx. In the span of just 2 weeks in June, we received our third and fourth FDA approval in our first 10 years of the company: the first with Crysvita for Tumor-Induced Osteomalacia or TIO, which is now the second indication with the product after its approval for XLH in 2018; the second was Dojolvi for Long-Chain Fatty Acid Oxidation Defect or LC-FAOD, a group of 6 distinct inborn errors of metabolism. These are the first approved treatments for either of these debilitating diseases. In both cases, we were able to secure full FDA approval based on our Phase 2 study, supplemented by data from expanded access programs. This significantly reduced the time to development for these therapies, for patients with no other FDA options. Our established and approved products continue to perform well. Crysvita, XLH, and Mepsevii continue to grow as we enter the third year post-approval. We’ve developed a great team and strong relationships in both medical genetics and in endocrinology fields with these early launches. This will enable efficient launches in both TIO and LC-FAOD despite some expected impact from COVID-19. Moving to our gene therapy platform and program, there have been significant recent clinical data updates for all 3 programs. At ASGCT, we presented data on both our GSDIa and OTC deficiency program. For GSDIa, all patients across all 3 cohorts in the Phase 1/2 study have responded to DTX401 gene therapy, with the patients in the latest cohort aptly tapering their use of cornstarch in oral glucose replacement therapy that is enabled now by the expression of the transgene in our vector. For OTC, we now confirm that 6 out of 9 patients in the study are responders to DTX301 gene therapy, including all 3 of the patients in the highest dose cohort. These updates further solidify our confidence in both programs as Phase 3 planning continues. The third gene therapy update was for the Hemophilia A program led by our partner Bayer. The PA on the ongoing Phase 1/2 presented data at ISTH on the 3rd cohort study. As with prior cohorts, these latest data show sustained and clinically meaningful Factor VIII increases competitive with other HemA programs and a near-complete reduction of spontaneous bleeds. As a reminder, the Bayer program is our first partnered gene therapy program and first to use material from our large-scale HeLa producer cell line system. In the first quarter of this year, we initiated a gene therapy platform partnership with Daiichi Sankyo, in which they have non-exclusive access to our HeLa, a HEK293 manufacturing system. Technology transfer related to our license has since been initiated and we will receive $25 million in milestone payments when it is complete. So with multiple collaborations in place, 3 products demonstrating positive clinical results, our gene therapy platform is on very solid footing as a source of multiple potential treatments. I’ll now turn the call over to Erik, to go into more detail regarding the launch of Dojolvi and LC-FAOD, and Crysvita in TIO, as well as progress with our other commercial programs.

Thank you, Emil. I will start by recapping our launch plans for Dojolvi and cover Crysvita. As you saw last week, Dojolvi is now commercially available to U.S. patients with LC-FAOD. Dojolvi is the first approved therapy for LC-FAOD, which is a severe, lifelong, and life-threatening disease. We have initiated the process of working with commercial and government payers to ensure that Dojolvi is accessible to all LC-FAOD patients indicated in the broad FDA label. In the first week of launch, we received start forms from multiple doctors, centers of excellence. We have shipped commercial therapy to our first patients. Just this week, the first reimbursements were approved for patients. We also had one newborn already prescribed to Dojolvi, whose older sibling had died at a very young age with FAOD. It is important to recognize that the reimbursement process does take time as various payers establish their new market policies. As a result, we expect the Dojolvi launch to build gradually over time, and most of our 2020 revenue for the product will come from EU patient sales. In the early stages of the U.S. launch, we are focused on transitioning the approximately 80 patients currently on clinical drug in the U.S. to reimbursed commercial therapy. Our team has started conversations with these physicians at our clinical sites to provide information about these transitions, which we expect to complete in the upcoming months dependent on payers’ new-to-market coverage policies. Overall, we estimate that there are approximately 2,000 to 3,500 patients with LC-FAOD. The vast majority of these patients are seen at approximately 160 metabolic genetic centers. We are very familiar with these centers and their physicians based on our experiences with Mepsevii, Crysvita, and our OTC and GSDIa programs. As a result, our incremental commercial investment will be minimal for this new launch. And while launching in the midst of the COVID-19 pandemic is not ideal, the work that we have done to adapt to the current situation for Mepsevii and Crysvita will be extremely helpful as we launch Dojolvi. These adaptations coupled with patients’ ability to take Dojolvi at home, since it's an oral therapy, along with a high unmet need, give us confidence that we will be able to have a successful launch. Turning now to Crysvita, which we have also launched in the U.S. for Tumor-Induced Osteomalacia or TIO. We have begun to treat our first commercial TIO patients. Many of the potential prescribers have the same group of endocrinology specialists who have become familiar with Crysvita for XLH over the last couple of years, so we are able to leverage our current commercial infrastructure. TIO, however, is much less common than XLH, affecting about 500 to 1,000 Americans, and it can take a long time to diagnose. Our initial focus is on the conversion of clinical trials and compassionate use patients. Similar to Dojolvi, we expect payers to update their policies for Crysvita to add the TIO indication over time. The good news is that the J-code for Crysvita remains the same for both XLH and TIO indications, which will simplify the buy and build process for payers. Today, we have had multiple starts and patient reimbursements for Crysvita and TIO. We expect the gradual and steady revenue build in this new approved indication. Crysvita for XLH continues to do well in spite of COVID-19 related challenges. Our patient support services team has reached out proactively to all of our existing patients individually to ensure continuity of care. Since the COVID-19 pandemic, we continue to receive new start forms and increase the number of patients on reimbursed therapy. Our field teams have done a noteworthy job in adjusting to this environment with our ATPs and have started to effectively use virtual platforms to engage with them. We expect to further build momentum as the country begins to reopen. Across Latin America, there’s a strong patient community that has driven a lot of awareness and demand for Crysvita. In Brazil, the region’s largest market, this has seen steadily growing numbers of injunctions that are being granted and funded by both state and federal governments. Similarly, in Colombia and Argentina, the number of patients on reimbursed named patient treatment increases. Over time, we expect Latin America to provide a more meaningful contribution to revenue as the launch in this region progresses. Because of the team’s efforts to maintain continuity of care while also finding new and creative ways to reach patients, Crysvita’s performance for the second quarter of 2020 has been strong. We’re maintaining our revenue guidance of $125 million to $140 million for Crysvita revenue in the Ultragenyx territories. As a reminder, this range includes Crysvita, XLH, and TIO and covers both profit share revenue in North America, as well as product sales in other regions. With that, I’ll turn the call over to Shalini, who will walk through our financial results.

Thank you, Erik, and good afternoon, everyone. We issued a press release earlier today that included a financial update, which I will briefly summarize. Total revenue for the 3 months ending June 30, 2020, was $61.7 million. For the quarter ended June 30, 2020, Crysvita revenue in the Ultragenyx territories was $32.4 million. This includes $29.8 million in collaboration revenue in the North American profit share territory and net product sales in other regions of $2.5 million. Total royalty revenue related to the sales of Crysvita in the European territory was $5 million, which includes $1.5 million for sales in the region prior to January 1, 2020, from a change in estimate and release of reserves by our collaboration partner. Mepsevii products revenue for the second quarter of 2020 was $4.2 million, and UX007 named patient revenue was $1.3 million. We also recognized $18.9 million of revenue related to the collaboration and license agreement with Daiichi Sankyo that was executed in March of 2020. Our total operating expenses were $124.8 million for the second quarter of 2020, which includes research and development expenses of $80.7 million and SG&A expenses of $42.3 million. We expect our R&D costs to continue increasing over time as we advance additional product candidates from preclinical development into early and pivotal clinical studies. We also expect SG&A to modestly increase over the coming quarters as we support the expansion of our existing commercial programs and the launch of Dojolvi for LC-FAOD and Crysvita for TIO. We expect the split of R&D versus SG&A expense to remain fairly consistent. In 2020, to date approximately 17% of our operating expenses are non-cash. In the second quarter of 2020, we reported net income of $25.3 million, or $0.42 per basic share, and $0.41 per diluted share. This compares to a net loss of $93.7 million, or $1.59 per share basic and diluted for the second quarter of 2019. The net income for the second quarter of 2020 includes a $95.2 million unrealized gain from the fair value adjustment on the investment in the Arcturus equity, and $18.9 million of collaboration revenue related to our agreement with Daiichi Sankyo. These were partially offset by $8.4 million in non-cash interest expense on the liability related to the sale of future royalties. Recall in the second quarter, we exercised our option to purchase 600,000 shares of Arcturus common stock at $16 per share. Upon completion of the additional equity purchase, Ultragenyx owned 3 million shares and continues to be Arcturus’ largest shareholder. For the first half of 2020, cash used in operations was $7.8 million, which includes $134.9 million of operating cash received from Daiichi Sankyo related to the collaboration and license agreements. We ended the second quarter of 2020 with $817.5 million in cash, cash equivalents, and available-for-sale investments. Moving to our guidance for 2020, we are currently maintaining the guidance range that we shared at the beginning of the year and affirmed in our first quarter earnings call. We anticipate Crysvita revenue to Ultragenyx in our territory to be between $125 million and $140 million. Both territories include North America, Latin America, and Turkey and exclude the European royalty, as this was monetized in the transaction that was completed with Royalty Pharma, which was announced in December of 2019. We continue to monitor the situation as the COVID pandemic persists. I would now like to turn the call to Camille, who will provide an update on our clinical programs.

Thank you, Shalini, and good afternoon, everyone. I will review our 2 new FDA approvals and progress with our Angelman Syndrome program before handing back to Emil to provide more detail on our recent gene therapy clinical updates. Starting with Dojolvi for Long-Chain Fatty Acid Oxidation Disorders or LC-FAOD, a devastating disease with significant morbidities, despite newborn screening and use of available management options. On June 30, we received the first-ever FDA approval of a treatment for patients with LC-FAOD. The approval stands for all 6 types of LC-FAODs and applies to both pediatric and adult patients. As Erik’s team works to make Dojolvi broadly available to patients living with this debilitating and dangerous disorder, the clinical and regulatory teams will be focused on 2 areas of next steps for the program. First, we are seeking approval for Dojolvi in other regions around the world. We had previously submitted a marketing application to ANVISA in Brazil and more recently made a new drug submission in Canada, where we have been granted priority review. Our discussions with the European Medicines Agency are ongoing. In the meantime, we will continue to make the product available to more than 70 patients with LC-FAOD, who are receiving it based on requests from physicians seeking the product for reimbursed named patient treatment in France and Italy. The development teams' other area focus going forward for Dojolvi is the implementation of our Disease Monitoring Program or DMP. As a reminder, the DMP is a long-term fully sponsored observational study of Dojolvi and LC-FAOD, and at least 300 patients for a target of 10 years. The DMP will encompass all post-marketing requirements from the FDA in a single study. Disease monitoring programs are just one developmental innovation we are employing at Ultragenyx. For example, the DMP we initiated for XLH in 2018 has enrolled very rapidly. As a reminder, patients in the LC-FAOD DMP may or may not be receiving Dojolvi. Those patients who receive therapy in our DMPs all received commercial reimbursed drug. This enables us to minimize post-marketing requirement costs while generating robust high-quality data from these very large and long-term studies. Moving on to Crysvita for Tumor-Induced Osteomalacia or TIO, a rare debilitating disease for which approximately half of patients have tumors that cannot be surgically removed, leaving them with no other current treatment options. We’ve received FDA approval of the Crysvita supplemental BLA less than 2 weeks before the Dojolvi approval. The FDA approval for both pediatric and adult patients was based on data from 2 single-arm Phase 2 studies that followed 27 patients with TIO for up to 144 weeks. In these studies, Crysvita was associated with increases in serum phosphorus and improvements in osteomalacia and healing of bone lesions. Similar to our other approved therapies, we will be implementing a long-term fully sponsored observational DMP that will enroll at least 20 patients and who will be followed for over a 10-year period. Shifting to Crysvita for X-linked hypophosphatemia or XLH, which is approved by the U.S. FDA and Health Canada for the treatment of adult and pediatric patients 6 months of age and older with this rare bone disease. Recall also that Crysvita is approved in Brazil with a slightly different indication. Our partner, Kyowa Kirin, recently announced a positive opinion from the committee for Medicinal Products for Human Use or CHMP in Europe to expand the XLH European approval to now include adults and therefore it is labeled for all patients at least one year of age. The initial EU approval only covered pediatric and adolescent patients who are still growing. Kyowa Kirin expects a final European Commission decision in the second half of this year. Our first approved therapy, Mepsevii, which is approved for the treatment of Mucopolysaccharidosis Type VII, or Sly syndrome occurring in approximately 200 pediatric and adult patients around the world recently received a positive opinion from the CHMP on a Type II variation. This variation would expand the EMA approval information to include long-term effects in that study on the reduction of urinary glycosaminoglycans or uGAGs, and improvements in the multi-domain clinical responder index, as well as the 6-minute walk test. We anticipate a formal decision from the European Commission in the second half of 2020. I will now turn to our program with GeneTx Biotherapeutics to advance GTX-102, an antisense oligonucleotide for the treatment of Angelman Syndrome. Angelman Syndrome, as you know, affects approximately 60,000 patients worldwide and is a devastating neurogenetic disorder with a broad spectrum of disease manifestations, including speech and cognitive impairment, ataxia or balance issues, sleep dysfunction, and seizures. There are no approved treatment options. This disease is a neurodevelopmental disorder and not neurodegenerative, so there is the possibility to reverse some of the manifestations. Our partners GeneTx initiated the Phase 1, 2 study of GTX-102 earlier this year, marking the first ASO to move into the clinic for Angelman Syndrome. The first 2 cohorts have been fully enrolled, and patients have received multiple doses. Safety and efficacy data from the first 2 dose escalating cohorts are currently being evaluated, and enrollment and dosing at the next dose level are expected to resume shortly. We are proud of all we have achieved so far in 2020 and will drive continued progress of the programs going forward. I want to commend our internal teams for successfully pushing through 2 concurrent FDA reviews, as well as the joint team with genetics for its impressive progress with the potential therapy for Angelman Syndrome. And importantly, I want to again thank the patients, families, caregivers, and physicians who participated in the clinical program in LC-FAOD and TIO, and those currently participating in the Angelman program, particularly in light of COVID-19. I will now turn it back to Emil, who will provide more detail on our gene therapies in development.

Thank you, Camille. As mentioned in my opening remarks, we had important data readouts from all 3 clinical gene therapy programs during Q2. Starting with DTX401 for Glycogen Storage Disease Type Ia. GSDIa is a life-threatening disease that requires patients to take cornstarch every 3 to 4 hours to avoid severe hypoglycemia and the risk of that, as well as long-term complications. We presented at ASGCT the first data from the confirmatory cohort 3 of 6e12 dose as well as longer-term data premiering in the cohort. All cohort 3 patients responded to DTX401 as we saw in the earlier cohorts. Cohort 3 patients, however, reduced their cornstarch usage at a faster rate by an average of 57% at week 12 compared to 38% and 14% at the same time point for the other 2 cohorts. Looking at the longer-term data from cohorts 1 and 2, these patients reduced cornstarch used by an average of 83%, with 4 of 6 patients discontinuing daytime cornstarch use altogether. 2 patients have completely terminated all cornstarch use. These results suggest that DTX401 is dramatically changing lives for these patients who, prior to gene therapy, would have been at risk for death with such significant reductions in cornstarch use. We continue to follow all patients in the study and expect to put out additional data on Cohort 3 in the second half of this year. We plan to have an end of Phase 2 meeting with the FDA in the same timeframe, as we gear up for a Phase 3 study in early 2021, depending on the impact of COVID-19. Moving on to DTX301 gene therapy for the treatment of Ornithine Transcarbamylase Deficiency or OTC. OTC is the most common of urea cycle disorders caused by an inability to detoxify ammonia into urea. OTC patients can experience metabolic crises that could result in neurologic issues, hospitalizations, and coma. It sometimes results in death. The ASGCT data was an update to the initial Cohort 3 data from January. ASGCT included 3 major updates. First, patient 9 is now confirmed as a responder to DTX301 following multiple sustained ureagenesis increases, meaning ammonia levels remained stable within the normal range during that time. 6 out of 9 patients in the study are now confirmed responders, including all 3 patients in the higher dose Cohort 3. Second, patient A, the previous responder, is now on the path to becoming a complete responder after discontinuing scavenger therapy and starting a relaxed diet. All 3 of the previously disclosed complete responders remained stable through up to 2 years of follow-up and remained well despite discontinuation of alternative therapies and the restricted diet for more than 1 year now. The next step of this program is to treat 3 more patients at the Cohort 3 dose with prophylactic steroids. Due to COVID-19, we’ve not yet dosed the patients in the prophylactic steroid cohort, but we are aiming to have data by the end of 2020. We intend to hold an end-of-Phase-2 meeting with the FDA and aim to start the Phase 3 in the first half of 2021. In addition to these ASGCT updates, data was presented at the recent ISTH meeting on the Hemophilia A gene therapy developed by our partner Bayer. The new data covered the third dose cohort of 2e13 GC/kg in 2 patients in the Phase 1/2 study. DTX201 led to Factor VIII expression levels of 72% and 12.9% of normal at weeks 28 and 26. Notably, there were no spontaneous bleeds after reaching peak expression, including discontinuation of prophylaxis. One of the patients experienced dramatic improvement without the need for Factor VIII replacement therapy. An update on the first 4 patients treated in the lower dose cohort showed stable Factor VIII expression after up to 16 months of follow-up. This provides further validation of our team’s affiliate program, including a relatively low dosage with Ultragenyx’s HeLa production system. The safety and efficacy results are competitive with other HemA programs with good safety observed so far. To close out my prepared remarks, as you can see, we made substantial progress so far in 2020 and expect the same for the second half of the year. I’m proud that the company has made all this progress amidst the ongoing COVID-19 pandemic. The team has adapted and found creative ways to continue working with and supporting patients, their families, and their healthcare providers. With 4 approved programs, a strong balance sheet, and one of the most experienced rare disease-focused organizations and exceptional commercial teams globally, Ultragenyx is poised for substantial progress in our development and commercial goals as a next-generation rare disease company. While we have accomplished a great deal in our first decade, we will continue to pursue smart, efficient, and effective goals that set the bar for effective rare disease development and commercialization. We aim to do so with great urgency and dynamic development and commercialization as required to overcome the inevitable challenges, especially in the first-ever treatments for rare diseases. Thank you for joining us today, and let’s move on to your questions.

Ladies and gentlemen, we will now begin the question-and-answer session. [Operator Instructions] Our first question is from Tazeen Ahmad of Bank of America. Your line is open.

Hi, good afternoon. Thanks so much for taking my questions. Emil, just a little bit of color on Crysvita for the quarter. I think you have provided some commentary about COVID, it had some effect on new patient additions that might have even had some interruptions for continuing patients. Can you give us a little bit of color on the level of impacts that we’re seeing in Q2? And then, as it relates to TIO, how are you thinking about the initial ramp? How should we be thinking about expectations, as it would still be launching into the COVID environment? Thanks.

Okay, good. On Crysvita in the U.S., I think we’ve been managing it very well. We talked a little about the proactive effort. I’ll let Erik finish with that in a moment and add a little bit about the impact. We are probably not seeing the same impact they’re seeing, but our characteristics are different. It has to be a factor in thinking through. TIO is a relatively small indication that’s slowly diagnosed. We expect it’s going to take time to develop slowly as we continue to add patients. Erik, maybe you can add a little bit on the Crysvita impact and our management of it in the second quarter.

Yeah, so the majority of the Crysvita patients in the U.S. are receiving care at home. We’ve been able to ensure the continuity of that care by working closely with the patients and the providers, where there was concern with having a home-health nurse enter due to the COVID concerns. We were able to arrange for self-administration, and that’s been the exception in that role. So continuity of care has continued. Where there were concerns about sites of care where patients had to go into the clinic, we’ve been able to arrange for at-home administration and working with the payer as well as the provider. With regards to the impact on new patient starts, there has been a ramp that has dampened a little bit as it takes longer to identify, diagnose, and initiate treatment, as healthcare providers are seeing lower volumes of patients, and certainly even less in their clinics. The way I would think of this is it’s not a demand issue; it’s really more of a capacity issue, which is why we’re confident that as the country begins to open up, we will see a rebound.

Thanks, Erik. Next question.

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

Thank you for taking my questions. First, I want to say congratulations on a very strong quarter despite COVID-19. I have 2 questions. The first one is regarding Dojolvi. I’m not sure if I missed it. Did you mention start forms? And if so, were these across all different genetic backgrounds? The second question is regarding the Angelman Syndrome. How is the safety so far from the first 2 cohorts, and how would you decide the third dose?

I’ll start with the Angelman part and then I’ll let Erik talk about the Dojolvi launch question. First of all, on Angelman, the program is managed by GeneTx. We’re encouraged by the result so far, but we’re not disclosing information yet on the conduct of the study. We do want to maintain the study’s integrity, so we’re not discussing efficacy and safety since it is open label. But as I’ve said, we’re encouraged by the results so far and we expect to resume dosing shortly. Erik, I think the question about Dojolvi related to stocking? Is that what you said, Gena?

I think you were asking about start forms, is that the one?

Uh-huh.

Yeah, we didn’t provide any specifics with regards to start forms. As we did with our other products, we’ll begin to provide specific launch metrics most likely in the next quarter. It will probably be similar to what we did for Crysvita. But regarding the performance in the early days, we’re very pleased with the interest that we received from healthcare providers and their patients. Shortly after approval, we started receiving start forms from multiple centers and prescribers. That number continues to grow, and it includes a mix of patients that were in our clinical trials receiving clinical drugs for compassionate use, as well as naive patients that are new to Dojolvi.

We’ll get to start forms – yeah, go ahead.

Regarding the genetic background?

Yeah, I don’t think we would have provided that normally. I don’t think we would normally provide that breakdown. Obviously, VLCAD is by far the most common, and CPV2 and ELP are 2 others. Those really encompass most of the patients, and TFP and CACT are much less common. So it will be those 3, the majority of them, but I don’t know that we’ll break up start forms by type. I don’t think there would be that much enlightenment there based on the clinical trial data, which I think showed effect across all patient types.

Okay. Thank you very much.

Our next question is from Yaron Werber of Cowen. Your line is open.

Yes. Can you hear me okay?

Now I can. Yes.

Okay, excellent. So I have a question on also on GTX-102. The study, I think, is entitled to enroll 20 patients in 5 cohorts. Is it magic math, and it’s sort of 4 patients per cohort? Secondly, I think you mentioned that some patients got multiple doses, and I think they’re supposed to get those sort of 4 doses or so every 28 days. I just want to confirm that you can dose them sequentially. That way each patient can get those doses, and it’s sequential that everybody has to go through one dose, look at safety, and then go to the next dose. Thanks so much.

Yes, good. The dosing is even more magical than what you propose. It’s actually 2 in the first cohort, 2 in the second cohort. Then, it goes to 4. And then the larger amounts in the last cohorts, right? So the first cohort started at a much lower dose and titrated each dose up, but we’re reaching therapeutic doses. By the time they got to the third or fourth dose, we would expect to see therapeutic dosing range, at least from our expectation projecting from animal models. So the two cohorts have been receiving multiple doses, and that’s what we’ve said. We’re always managing safety and efficacy because it’s dose cohort where each dose stepping up. There is continuous monitoring, and there are DMC reviews that occur also during the process. That’s the basic design of the 2 cohorts, that 2 patients each have received multiple doses so far. We’re only so encouraged, but we haven’t said any more. We’re trying to protect the integrity of the study.

Got it. So when you say the 2 cohorts are fully enrolled, is it fully enrolled, so there are 4 patients each. So there really were 2 patients each so far?

2 patients in cohort 1 and 2 in cohort 2. Go ahead. Camille, am I incorrect?

Yeah, that’s correct. You’re correct.

Right, and they’ll continue to enroll each cohort to up to 4 patients thereafter?

Yes, the next cohorts get bigger, 3, 4... We want to have the cohorts that were for the early safety, where very low doses were smaller because they were starting at a very low dose. But once you know the low dose is fine, then you can start the next cohort with a slightly higher level instead of a very low one. I think it’s a great thing that the clinical trial has proceeded particularly at the one center, despite COVID. Kudos go to the doctor fighting for patients there and keeping this thing going. Next question.

The next question is from Maury Raycroft of Jeffries. Your line is open.

Hi, thanks for taking my question. This is Swapnil on for Maury. Can you provide going into Dojolvi launch a little bit more perspective in terms of dynamics related to adult versus pediatric ratio reimbursement? And then what metrics will you be providing going forward? And then I have a follow-up.

Sure, so I’ll touch on the adult versus pediatric dynamics. Then, Erik, perhaps you can talk about the work metrics going forward. One of the things you have to understand about the dosing of Dojolvi is that it’s based on a percent of calories. What that means is that by the time you get to around 7 or 8 years old, you reach the peak level. The cost per patient, from late school age to adult, is actually the same. So I’m making that point to you that the number of adults or the number of 10-year-olds doesn’t really matter. The actual revenue per patient is almost the same. Is that clear? It’s not like other drugs that are weight-based; it’s a little bit different. It’s a much flatter top-curve on revenue for the patient, if that’s what your question is. We expect to see an adult-pediatric mix involved, and there are different patterns of disease that you see in adults and pediatric patients. Patients have different manifestations as pediatric patients, and later patients have different types of problems than adults. Overall, I would say, probably there are more kids with it, mainly because many of the kids are dying. Naturally, the number of patients being younger is going to be more than because of the loss of patients over time. Any other dynamics on the work metrics, I think you asked about the metrics going forward. Erik, could you touch on what we will do for metrics in Dojolvi for the coming quarters?

Yeah, most likely in the upcoming quarter, we plan to provide some launch metrics to help characterize the strength and momentum of the launch. We haven’t determined exactly what those metrics will be. But for Crysvita, we provided a number of prescribers, patient start forms, and patients on reimbursed therapy. We think we will do something similar to that. Did you have a question regarding the payer landscape? Is that what you were asking, and was there anything else?

No. I think this is good. I just had a follow-up question. This is regarding a clinical trial website. I just saw that there is an expansion for the number of patients for 401 from 9 to 18. And also for 301, there is a slight amendment in the protocol in steroid use. Can you provide some thoughts on the changes to the protocol?

For DTX301, we have said we’re going to treat 3 more patients in a prophylactic steroid cohort. So that would have already been 9 treated, and we’d have 3 more. For GSD1, we may do another cohort with earlier steroid treatment, but patients would not be limiting our progression to Phase 3; that would be the other 3 patients.

Okay. Got it. Got it. Thanks.

Our next question is from Chris Raymond of Piper Sandler. Your line is open.

Hi, this is Alli Bratzel on for Chris. Thanks for taking the question. So one on DTX301 and 401, I know you’ve been talking about holding on the Phase 2 meetings with the FDA in the second half to discuss data for those programs for a while now. So I’m just wondering, are those meetings officially on the calendar yet? Or is that something that could be pushed back due to COVID or maybe other gating factors? Any color on the status of those discussions and just your confidence in the ability to start Phase 3 on the expected timeline first half of 2021 would be helpful? Thanks.

We normally don’t talk about when meetings are scheduled, which is not something we normally disclose. We don’t anticipate having a problem having meetings for the end of Phase 2 between now and the second half if we close and get started in 2021. At this point, I don’t see a problem. I think the FDA may have more of a burden with how many gene therapy programs they are dealing with due to a lot of applications and questions. There is putting a strain on them, but at this point, we don’t see a problem getting the Phase 2 done. We’ll certainly provide updates when we’ve had meetings and decisions have been made on what is the plan moving forward with Phase 3.

Okay. Thank you.

[Operator Instructions] Your next question is from Cory Kasimov of JPMorgan. Your line is open.

Hi. This is Gavin on for Cory. We just had a quick one on the Wilson’s program, wondering what gating factors remain for the IND submission later this year.

Sure. We have already run tests. I’ve noted this before, the GMP production run, and we need to get through the testing we're running from the non-clinical work. The labs doing non-clinical work have maintained. Good question; both manufacturing and non-clinical had some impact from COVID, particularly workers getting sick and having to stay home. So far, we look like those key activities are moving ahead. We have been discussing the program with the agency and coming up with our plan for developing it. So far, we’re moving along well, but there’s clearly some impact going on with the vendors. We don’t see an obvious impact yet, and if something becomes clear, we will let people know. Next question?

The next question is from Laura Chico of Wedbush. Your line is open.

Hey, good afternoon guys. Thanks for taking the question. I wonder if we could go back to the Crysvita revenue guidance and I apologize if I missed it. How should we be thinking about the impact of any Latin America, South American countries for Crysvita and what assumptions are embedded in the guidance at this point, and maybe just longer term? Does this still remain a viable region for you to pursue orphan treatments? Any color there?

I’ll answer the first part first but – I mean, the last part first. We strongly believe in the Latin American region for rare disease treatments. We know there will always be political and economic challenges with time there. However, we think there are many patients and a willingness to support treatment in Latin America. We believe that the reimbursement plans will be reasonable. In the past, we haven’t broken out by country, and I don’t know where we’ll disclose those specific numbers yet.

To reinforce that, we see significant potential and increasing demand across multiple countries in the region. Our revenue is steadily growing as we work through the named patient sales process, which takes some time as we continue positive discussions with health authorities for formal reimbursement across multiple countries.

Great. Thanks, Erik.

Thanks. The next question is from Yigal Nochomovitz from Citi. Your line is open.

Hi, this is Carly on for Yigal. Thanks for taking our questions. Just on DTX401 and 301, finalizing the endpoints for the planned Phase 3 will clearly be a key topic of the upcoming end of Phase 2 meeting. Just wanted to get your thoughts on what you would view as kind of the best-case scenario in terms of Phase 3 endpoints heading into those meetings for these programs.

One of the reasons we like these 2 disease areas is that they are biochemical genetic disorders. Therefore, the biochemical endpoints are effect measures of the disease. OTC is a disorder of ureagenesis where ammonia accumulates if you don’t have it, which is well described in literature. So we expect ammonia to be a part of it. We will look to try to supplement the biochemical primary endpoints with secondary endpoints that give some measure of clinical efficacy, but we expect to have a biomarker primary endpoint for ammonia in some form. For GSDIa, good color is a well-accepted biomarker from the FDA. The implications of its level are well accepted and well known. Cornstarch, in this case, is used as a treatment for oral glucose replacement therapy. What we see is that the amount of cornstarch required is highly dependent on how much the gene therapy is able to release glucose on its own, thus obviating the need for oral glucose replacement. We think anything that manages glucose, such as removal of cornstarch or monitoring glucose, using continuous glucose monitoring strategies would be win for us, as all of those biomarkers are easily determined. We will, of course, also look at cognitive and other types of outcomes, but we will look at those as secondary and tertiary outcomes, not part of the primary.

Okay, great. That’s helpful. Thank you. And then just a quick follow-up, could you talk a little bit more specifically about CGM and how that could be utilized as a potential primary or secondary endpoint with 401?

Sure. The challenge with glucose monitoring is very good for diabetes. Until the Dexcom 6, it wasn’t the best for GSD1 specifically due to some particular challenges with lactate. Lactate is very high in glucose and GSDIa, which can interfere and create problems. The Dexcom 6 now provides very accurate glucose readings even in the presence of lactate, and therefore that’s a step forward in GSDIa. Continuous monitoring allows us to monitor in real-world settings, tracking what patients are doing at home. Looking at patients over multiple nights has shown that their glucose levels are being managed properly without starch at night. This allows us to capture much more data in a real-world environment. It’s far, I think, more powerful than in-hospital assessments trying to lead from a patient to the very artificial setting. It results in more data that allows us to demonstrate improved efficacy and safety in better management of highs and lows, which are important measures of glucose control. We think this is a powerful part of the story and will help us demonstrate the improved efficacy of using gene therapy versus oral cornstarch.

Great. That’s helpful. Thanks for all the detail.

The next question is from Jeff Hung of Morgan Stanley. Your line is open.

Thanks for taking the questions. For Crysvita and TIO, you indicated there are 500 to 1,000 Americans. Can you remind us how many patients in the U.S. have already been identified and what kinds of efforts you’re planning to identify additional patients? And then I have a follow-up.

We haven’t really put out any identified patient numbers, so we are not disclosing that. We are continuing to identify patients, but some patients are definitely more challenging to find because they’re often new-onset problems that can take several years to diagnose. We need to work on helping people diagnose it quicker, but we’re not disclosing patient numbers at this point. We haven’t for other programs either. Your follow-up question?

Yeah. For Dojolvi, you mentioned that there are some naive patients with the start forms. Can you comment on how the proportion of start forms from naive patients compares to your expectations?

I don’t think that that proportion of naive patients is going to be all that striking; obviously, the doctors with our trials are watching, waiting, and ready to go. It’ll take a little time to set out how many naive patients there are or even how many start forms there are. I don’t think it’ll be that striking, but as Erik has already said, there were many naive patients, and there was one newborn diagnosed and treated quickly, which I think is an important part of the future of the product. It’s having newborns diagnosed and put on it early in life instead of waiting and then transitioning treatment. That’s an important part of the story for naive patients, but it’d be pretty early to detail about ratios and make any conclusions.

Okay. Thank you.

Sure.

And this concludes our question-and-answer session. I would now like to turn the call back to Mr. Higa for closing remarks.

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

Ladies and gentlemen, this concludes today’s teleconference. You may now disconnect. Thank you for your participation.