Ultragenyx Pharmaceutical Inc. (NASDAQ:RARE) Q3 2020 Earnings Conference Call - Final Transcript

Ultragenyx Pharmaceutical Inc. (NASDAQ:RARE) Q3 2020 Earnings Conference Call - Final Transcript 2020-10-27T21:00:00+0000 Executives Joshua Higa - Ultragenyx Pharmaceutical Inc., Emil D. Kakkis - Ultragenyx Pharmaceutical Inc., Shalini Sharp - Ultragenyx Pharmaceutical Inc., Mardi Dier - Ultragenyx Pharmaceutical Inc., Erik Harris - Ultragenyx Pharmaceutical Inc., Camille Bedrosian - Ultragenyx Pharmaceutical Inc., Analysts Brendan Smith - Cowen and Company, Christopher Raymond - Piper Sandler, Maury Raycroft - Jefferies LLC, Gena Huidong Wang - Barclays Capital, Inc., Tazeen Ahmad - Bank of America Merrill Lynch, Samantha Semenkow - Citigroup, Inc., Cory Kasimov - JPMorgan Chase & Co., Salveen Richter - Goldman Sachs & Co., Kenneth Shields - Wedbush Securities, Jeffrey Hung - Morgan Stanley, Joon Lee - Truist Securities, Arlinda Lee - Canaccord Genuity Group Inc., Vincent Chen - Sanford C. Bernstein & Company LLC, Operator - Ladies and gentlemen, thank you for standing by and welcome to the Ultragenyx's Third Quarter 2020 Financial Results and Corporate Update. At this time, all participants are in a listen-only mode. After the speaker presentation, there will be a question-and-answer session. [Operator Instructions] Please be advised that today's conference may be recorded. [Operator Instructions] I would now like to hand the conference over to your host, Joshua Higa. Sir, please go ahead. Joshua Higa - Ultragenyx Pharmaceutical Inc. Good afternoon and welcome to the Ultragenyx financial results and corporate conference call for the third 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; Camille Bedrosian, Chief Medical Officer; Erik Harris, Chief Commercial Officer and Mardi Dier, our Chief Financial Officer, who joined the company a couple of weeks ago. Shalini Sharp, Executive Vice President for Finance is also on and will be available if needed for Q&A at the end of the scripted portion of this 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 2019 Annual Report on Form 10-K that was filed on February 14, 2020, our quarterly report on Form 10-Q that we filed today and our subsequent periodic reports filed with the SEC, which will all be available on our website in the Investor's 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 that 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. Emil D. Kakkis - Ultragenyx Pharmaceutical Inc. Good afternoon and thank you everyone for joining us on today's call. It's been a busy week, quarter and year for Ultragenyx. This matches the fundamental part of my philosophy for the company, which is a relentless focus on execution. I'm proud of how productive the company has been throughout the year across all facets of our diverse business. Regular [Phonetic] team and development teams have got to new approvals in two weeks in June. Commercial team and all the people supporting the products have rapidly and successfully launched those products to patients in need while still growing Crysvita and XLH and improving our annual guidance despite the global impact of COVID. The clinical team are internally and jointly working with our partner, GeneTx, has delivered a series of positive updates on our gene therapy programs and now the Angelman program and the business development team brought in a new gene therapy program for Duchenne on top of the gene therapy technology partnership announced with Daiichi Sankyo in March. We've been firing on all cylinders and will provide updates on all of this progress on the call today. Starting with our commercial programs which provide a stable source of growth underpins the rest of our development. Crysvita continues to perform strongly and is now bolstered by the additional tumor-induced osteomalacia indication. In the first quarter of launch, Dojolvi is off to a strong start in its first quarter, which is encouraging. We received start-forms from a large number of prescribers for patients in our trials, but also those naive to Dojolvi. This speaks to the unmet need for those living with LC-FAOD and to the strong relationships that we have with physicians and the major treatment centers. Moving to our strategic collaboration with Solid Biosciences. Last week, we announced that we've been developing a new gene therapy for the treatment of Duchenne Muscular Dystrophy or DMD. While there are other Duchenne programs that are far more advanced, this was an unique opportunity to combine Solid's technology with our technology and two like-minded companies to create a next-generation gene therapy for this disease. We will combine Solid's best-in-class microdystrophin with its potential ability to enhance blood flow to working muscles with our novel capsid which has an excellent immune profile and is produced by high-quality 2000 liter HeLa cell -- producer cell manufacturing process. We believe this could be a differentiated therapy for Duchenne that we will seek to achieve global accessibility. We look forward to collaborating with Solid to bring a new treatment forward rapidly and we'll continue to update you on the progress coming out of the collaboration in the coming quarters. Moving to Angelman. Yesterday, we announced positive interim data from the ongoing Phase 1/2 study of the investigational product GTX-102 in Angelman syndrome, which is a part of the collaboration with GeneTx Biotherapeutics. GTX-102 is the first antisense oligonucleotide program for Angelman to reach the clinic and is based on the extraordinary science from Dr. Scott Dindot supported by GeneTx. In our update, all five patients of the first patients treated in the study have shown substantial improvements in the Clinical Global Impression scale or CGI tailored for some of the key domains of Angelman with a mean change score of 2.4. The positive clinical effects were supported by other endpoints and remarkable reports of change is provided by the caregivers of patients treated with GTX-102. These include two patients going from being non-verbal their entire lives with difficulty communicating to now using multiple words, while others are beginning to use sign, gestures, and augmentative communication devices for the first time. Some patients adopted independent capabilities such as using a fork to feed themselves for the first time. Others are learning to swim on their own and other reports includes ability to follow commands, focus on tasks, respond by name and sleep through the night. Not only were these changes profound, but they begin rapidly often after just a few weeks to a few months of treatment and in some patients after the lowest dose, in part is due to these reportedly unprecedented changes, all families didn't indicate desire to continue in the study. Turning to safety. All five patients at the highest doses had a serious adverse event or SAE of lower extremity weakness with an elevation of protein in the CSF and which have now completely resolved. We believe the SAE is related to local inflammation in the region of intrathecal administration of GTX-102. This lower extremity weakness was not observed at the lower doses in the study where we also saw clinically meaningful responses. We believe the impact of GTX-102 is manageable with changes in dose administration strategy and so we expect to resume enrollment and dosing once we get an amendment filed and agreed to with the FDA. We are very excited about what we are seeing as are the patients families who are hearing about these results for the first time yesterday. We plan to provide additional data on these patients at the FAST Summit in December and additional safety and efficacy data on the program in 2021. Looking at these two recent developments, both Duchenne and Angelman are very significant disease both in terms of unmet need and prevalence. They're aligned with our company's strategy of developing therapies for rare disease where there is a great -- greatest need and we'll leverage our various modalities and platform to create the best treatment options for patients. Now before I turn the call over to Mardi, I'd like to start first by thanking Shalini Sharp for joining us on one last conference call, all the way from New Zealand. Shalini Sharp has been with me from the early days of the company and has been a greatly valued friend, colleague and a superb CFO. She has been instrumental in building RARE to where it is today and we could not be here without her contribution throughout the time, ups and downs in all the financings and all the work with many of you on the phone call. We certainly wish her the best going forward, but I just want her to know that her legacy and contribution to the company will remain with us at RARE forever. And with that, I will hand the call over to Shalini. Shalini Sharp - Ultragenyx Pharmaceutical Inc. Well, thank you so much, Emil, and good afternoon to everybody. I am delighted to join you all for our last quarterly conference call. I'd like to take this opportunity to thank Emil, the executive team, the finance team, the IT team and the rest of the Ultragenyx team for the extraordinary experience that I have had working here. I could not be more proud of this company, its mission to serve patients above all and its ability to effectively execute on its mission every day. I'd also like to thank you all, our analysts and our investors for your support of Ultragenyx over these past years. And with that, I'm very pleased to introduce you to our new CFO, Mardi Dier. You will be in excellent hands with Mardi and I'll now turn the call over to her to walk you through the financials for the quarter. Mardi Dier - Ultragenyx Pharmaceutical Inc. Well, thank you, Shalini and I am very excited to be joining Ultragenyx during its next stage of growth in helping patients with rare diseases. Shalini has been a critical part of building a fantastic team, one that I know already will make this a very smooth transition. So, thank you, Shalini. So, today we issued a press release that included a financial update, which I will briefly summarize. Total company revenue for the first nine months of 2020 totaled $179.5 million, representing a 163% growth over the same period in 2019. This includes revenue from Crysvita and Ultragenyx territories of $98.5 million and 91% growth over 2019 and combined revenue from Mepsevii and Dojolvi totaling $18.3 million or 78% increase compared to 2019. Total revenue for the three months ending September 30th, 2020 was $81.5 million. For the quarter ended September 30th, 2020, Crysvita revenue in the Ultragenyx territory was $37.3 million. This included $34.1 million in collaboration revenue in the North America profit share territory and net product sales in other regions of $3.3 million. Total royalty revenue related to the sales of Crysvita in the European territory was $3.3 million. Mepsevii product revenue for the third quarter of 2020 was $4.1 million. We expect these revenues may modestly increase over-time, but we do not expect there to be significant growth. In the initial quarter after receiving US FDA approval, worldwide revenue from Dojolvi was $3.9 million. This includes named patient sales and US product sales. We also recognized $32.9 million of revenue related to the collaboration and license agreement with Daiichi Sankyo that was executed in March 2020. The majority of revenue from this agreement will be recognized as work is performed on the technology transfer to Daiichi. It'll be recognized based on progress towards completion, not straight line and we expect the majority of this work to be completed by the end of 2021. Our total operating expenses were $131.8 million for the third quarter 2020 which includes research and development expenses of $87.3 million and SG&A expense of $42.1 million. We expect our R&D costs to continue increasing over-time as we advance additional product candidates from pre-clinical development into early and pivotal clinical studies. We also expect SG&A to modestly increase over the coming quarters as we support the expense of our existing commercial programs and the launch of Dojolvi for LC-FAOD and Crysvita for TIO. We expect a split of R&D versus SG&A expense to remain fairly consistent. In the third quarter of 2020, we reported a net loss of $68.8 million or $1.13 per share basic and diluted. This compares to a net loss of $113 million or $1.96 per share basic and diluted for the third quarter of 2019. The net loss for the third quarter of 2020 includes $11.5 million unrealized loss from the fair value adjustment on the investment in the Arcturus equity. This also include $8.6 million in non-cash interest expense on the liability related to the sale of future royalties. For the first nine months of 2020, net cash used in operations were $69.8 million compared to $273.3 million for the same period in 2019. We ended the third quarter 2020 with $765.5 million in cash, cash equivalents and available for sale investments. I would now like to turn the call to Erik, who will provide an update on our commercial performance for the quarter and an update on our guidance range for Crysvita. Erik Harris - Ultragenyx Pharmaceutical Inc. Thank you, Mardi. In the third quarter, Crysvita continued to deliver meaningful revenue growth. The team also launched Dojolvi for patients with long-chain fatty acid oxidation disorders and Crysvita for tumor-induced osteomalacia. Our third product, Mepsevii continues to provide a meaningful therapy to patients with MPS 7, an ultra-rare diseases. I would like to begin by providing an update on Dojolvi launch which is going very well. Dojolvi was approved in June by the USFDA and was launched on July 22nd for the treatment of all forms of LC-FAOD or for molecularly confirmed diagnosis across the 2,500 to 3,000 pediatric and adult patients in the US. As of the end of the third quarter, we have received approximately 120 start-forms from approximately 60 unique prescribers. All 80 of the clinical trials and compassionate use patients have been converted to commercial therapy with many successfully navigating reimbursement. And approximately 30% of all start-forms are for patients who are naive to prior Dojolvi therapy. The team has made significant progress on the reimbursement front in the first few months after being approved. This has led to more than 60 patients on reimbursed commercial therapy. The payer mix is approximately 70% commercial and 30% government, compares with formal policies in place but most are approving Dojolvi on an exception basis during a new-to-market coverage guidelines. We continue to work closely with commercial and government payers to ensure that Dojolvi is accessible to all LC-FAOD patients as indicated by the broad FDA label. Dojolvi as a pharmacy benefit and it is importance in [Technical Issues] does take time as various payers establish their coverage policies. Looking forward, we will continue leveraging our established commercial infrastructure along with the fewer than 10 incremental hires we added to support the Dojolvi launch. Over-time, we expect revenue from the Dojolvi in the US to gradually build as the launch gained even more traction. Outside of the United States, Dojolvi has been submitted for approval with ANVISA in Brazil and has been submitted to Health Canada after being granted priority review. The discussions with EU regulators are ongoing and with the US approval, patients in other European and Latin American countries are now able to access to Dojolvi through named-patient programs. These programs have been meaningful -- that have been a meaningful way for patients in France and Italy to gain access to this important therapy. I would like to reiterate our commitment to broad access. During these regulatory discussions and review phases, request for named-patient access will continue to be supported in all relevant countries. We continue to expect named-patient sales to make up the bulk of Dojolvi sales in 2020. Moving next to Crysvita, which was approved last quarter by the FDA for its second indication, the treatment of FGF23 related hypophosphatemia and tumor-induced osteomalacia or TIO. We estimate there to be between 500 to 1,000 TIO patients in the US with 50% having unresectable tumors. The launch for this indication has gone well as we have been able to successfully leverage our existing infrastructure and relationships with physicians to ensure the small patient population who is able to receive this important therapy. Now turning more broadly to Crysvita for XLH. We have been able to maintain continuity of care for just about all patients on treatment. We continue to adapt to the COVID situation by shifting more resources to digital initiatives along with virtual personal promotions and limited in-person meetings more recently. We are also starting to see increasing success with finding more patients, leading to growth in new start forms and reimburse patients. In Latin America, a strong patient community and KOL support continued to drive the live awareness and demand for Crysvita. In Brazil, the region's largest market we are seeing a steadily growing number of injunctions that are being granted and funded by both the state and federal governments. Similarly in Colombia and Argentina, the number of patients on reimbursed name patient treatment have increased. Over-time, we expect Latin America to provide a more meaningful contribution to revenue as the launch in this region progresses. Recall, at the beginning of the year, pre-COVID, we established a range of $125 million to $140 million for Crysvita revenues in Ultragenyx territories. On our second quarter call, we maintained this range as we continued to evaluate the impact of the pandemic and our team's ability to execute. Based on recent trends, we are raising the lower-end of our guidance to $130 million, bringing the revised range to $130 million to $140 million. While there is still some uncertainty related to COVID as we enter the winter season and this long-term impact on Crysvita revenue, we are confident the strategies and tactics we have put in place will allow us to close out the year within this range. At peak, we continue to believe Crysvita has a potential to be a blockbuster as we move into a significant rare disease treatment for patients with XLH and TIO around the world. With that, I will turn the call over to Camille, who will provide an update on the gene therapy clinical programs. Camille Bedrosian - Ultragenyx Pharmaceutical Inc. Thank you, Erik, and good afternoon everyone. Emil provided the encouraging update on our Angelman Syndrome program and I will review progress with our other clinical stage programs. Starting with DTX301, our gene therapy program for the treatment of ornithine transcarbamylase deficiency or OTC. OTC is a most common of urea cycle disorders caused by inability to detoxify ammonia into urea and patients with OTC can experience metabolic crisis that could result in neurological complications, hospitalizations and coma. It also sometimes results in death. Data from our ongoing Phase 1/2 study demonstrate durable and clinically meaningful responses to DTX301. Importantly, these improvements have continued after patients discontinued their previous alternative pathway medications and liberalize their diets. For DTX301, a fourth cohort of three patients at the 1 times 10th to the 13th genome copies per kilogram dose is ongoing using prophylactic steroids. We expect data by the end of 2020. We are also continuing Phase 3 planning and discussions with the FDA and plan to start the Phase 3 study in 2021. Moving to DTX401 for glycogen storage disease type 1a. GSD1a is a life-threatening disease that requires patients to take corn starch every three to four hours to avoid severe hypoglycemia, long-term complications and potentially death. Results from the Phase 1/2 study so far show that DTX401 is changing the lives of these patients who are showing improved glucose metabolism with significant reduction in and less reliance on corn starch. Prior to gene therapy, these levels of corn starch reduction would have put these patients at risk for death. Safety has been acceptable to-date with any transaminase elevations managed by reactive steroids. In addition to following the first three cohorts for longer-term data, we also are enrolling a fourth cohort of three patients using our prophylactic steroid regimen at the same 6 times 10th to the 12th genome copies per kilogram dose level. This decision is based on the value of preventing standardized use of steroids rather than reactive monitoring and treatment present in the commercial setting. The timing of this cohort will not impact the initiation of the Phase 3 study. We are moving forward with planning our Phase 3 study for DTX401. Following meetings with the FDA and finalization of the study design, we plan to initiate this study in the first half of 2021. With these updates, I will now turn the call back to Emil. Thank you very much. Emil D. Kakkis - Ultragenyx Pharmaceutical Inc. Thank you Camille. Adding to Erik's summary on our commercial programs, have been very strong through 2020 and we are in an unique position with this robust commercial business that has three product simultaneously in the growth phase of launch. On top of that, we have a gene therapy platform that has delivered positive clinical results in 2020 across three diseases, but also continues to be a source of new pipeline opportunities and new partnerships. Next up, will be Wilson disease gene therapy, which is a larger rare disease and will be the first program internally to leverage the scalability of our HeLa manufacturing platform that is vital for larger patient populations. And behind that, we have other large indications moving ahead. This includes the newly announced Duchenne program, which is a competitive space, one that we believe we are uniquely able to bring forward. And beyond the gene therapy space, we have the exciting Angelman data from yesterday that supports that we have a potent molecule in that disease and we have a plan in place to work through the safety issue to advance this product forward for this large and severe disease. Over the last couple of years, we've gone from a clinical stage biotech to a diversified commercial rare disease leader with a number of large opportunities ahead of us. We will continue executing across all facets of our business with our dedicated employees across the globe and a strong balance sheet and growing revenue. Let's move on to your questions. Operator, please provide the instructions for the Q&A portion of the call. Q & A Operator - Yes, sir. [Operator Instructions] Our first question comes from the line of Yaron Werber of Cowen. Your line is open. Brendan Smith - Cowen and Company Hi guys, this is Brendan on for Yaron. Thanks very much for taking the question and congrats again on the progress. Just a couple of quick ones from us. I guess first on DMD, as you mentioned there are obviously a few players already in motion here and I totally understand it very early in the process. But can you just give us maybe a little bit of a sense of how you kind of plan to be differentiated in your approach maybe mechanistically or if it's really a matter of your capsid versus other ones out there. And then just really quickly on the data from the gene therapy, prophylactic steroid cohorts. I know you mentioned we could potentially get data from the OTC by year-end. I'm just kind of wondering about timing for the GSD1a patients. Thanks very much. Emil D. Kakkis - Ultragenyx Pharmaceutical Inc. Very good. When I look at the Duchenne program, there are several aspects of differentiation. One is the nNOS-binding microdystrophin from Solid. The second is the capsid we view, which has very excellent immune profile. The third is ability to produce sys [Phonetic] AAV in a mammalian large-scale system, which we've been using now for two programs very successfully and produce a high quality AAV. High quality many features, which are achievable with the producer cell line approach is more difficult to do with transaction approach. We think with those three areas, we are differentiated. Combined that with skills both companies have in this space, I think we have an opportunity to do something special for Duchenne patients and to bring program forward that can become accessible globally, not just in the US. So that's I think how I would answer that question. On the prophylactic steroid timing, we are dosing patients in both groups. We will have some data on them this year, but neither program does a steroid cohort interfere with the initiation of Phase 3. Both programs were planned to have the prophylactic steroid approach built into the program, but it is helpful to us before we start Phase 3 to have done some tracings and shown how it looks good. So the Phase 3 planning continues for both and prophylactic steroid data, we'll provide some data this year on those patients. Brendan Smith - Cowen and Company All right, great. Thanks very much. Operator - Thank you. Our next question comes from Chris Raymond of Piper Sandler. Your question please. Christopher Raymond - Piper Sandler Thanks. Also on the DMD program. Emil, there is a hypothesis surrounding gene therapy in DMD where muscles are able to be transfused maybe as efficiently as they would normally because of the damage that's caused by actual disease. I guess -- I'm sure you've looked at this closely, is there a way to address that clinically or do you have any thoughts on that. And then also maybe sort of a question on just execution on the program you have specifically. Can you remind us how long it takes to establish a HeLa producer cell line. Thanks. Emil D. Kakkis - Ultragenyx Pharmaceutical Inc. Sure. So on Duchenne and really we're filled with lot of different muscle diseases. Muscle, even without injury by the way is very difficult to deliver particulates of large molecules in general. They have very tight fenestrated capillaries, it's difficult with delivery of products, it's designed that way, so you don't create big swollen muscles when you exercise. It is designed to control fluid flow and that creates challenges while delivering. We are highly aware of the issue and we have ways that we're approaching on how to improve it. The issue being damaged or not, I think that the -- there is certainly another part of the story, but we are looking at ways to help improve that and I won't say any more of it at this point in time, but we're aware of the challenge and the challenge in muscle in general. With regard to producer cell lines, using the automated approaches we have created at the company and processes that we've established generally we can identify a high quality stable clone within or usually about six months of time. That would be a clone that can survive growth at 2,000 liters and maintain stable incorporation and can produce high titers of AAV vector. The process of the automation allows us to actually screen a large number of clones and help identify a stable and high producing clone. The combination of those approaches gives us the power than the creator, manufacturing platform has hyper-reproducibility, high quality and to do it in a way that's from a long-term commercial standpoint reproducible at the 2000 liter scale. Christopher Raymond - Piper Sandler Okay. Thank you Operator - Thank you. Our next question comes from the line of Maury Raycroft of Jefferies. Your line is open. Maury Raycroft - Jefferies LLC Hi, thanks for taking my questions. For Dojolvi, just wondering for the 30% naive patients, if you can talk more about those patients and their demographics, including age, and can you comment if the naive patients represent a bolus or more of a natural uptake of getting patients on treatment. Erik Harris - Ultragenyx Pharmaceutical Inc. Well, we haven't really described in detail with the exact ages of the patients. I think they are across the spectrum and there have been newborns, of course identified and put on drug as well. But in general, it is the spectrum of patients and obviously it's early launch and I don't think we can say if it's a bolus or steady yet because we just talking about a quarter of work, but we believe from the response we're getting from physicians out there and the number of prescribers, which is now already 60 has clearly brought interest in the product and we would expect this to continue seeing start forms generated exactly [Technical Issues] bolus that I think we will to have to watch and wait how it moves forward. Maury Raycroft - Jefferies LLC Got it, okay. And then for Angelman, I guess besides the natural history data out there, is there good existing efficacy data to contextualize what you're seeing in Angelman based on the time points and the age range and along these lines, is it possible to reconcile or convert data on the CGI-I-AS versus the more general CGI-I scale. Emil D. Kakkis - Ultragenyx Pharmaceutical Inc. Well, certainly I can try to provide some help for you. When you look at natural history data in Angelman patients, they generally gained some ground until I think around two or three years of age. And from there on, they're relatively flat and they don't really change much over-time, they're pretty flat. So the changes we're seeing are not something with same people, ages are non-verbal and by the way all deletion patients are non-verbal, they never become verbal and so to have patients becoming verbal and using words is highly unusual and regardless of what CGI or any other score you could make up, the fact that patients are talking, learning their names, responding to instructions and using other forms of communication are -- it is something unique and different and valuable in of itself because communication problems are the number one family reported need that affect them and their life with the patient. With regard to CGI, the global score is involved, looking at all the domains and just creating a summation of the physician view but each domain has particular areas that they look at in making the score pre-CGI. It's not really that different from any other CGI, it's just that it is based on particular problems of patients with Angelman have inside each domain. I would say to you in general, people do not see change in Angelman on any score including CGI and there is some data on what the placebo effect might be in CGI. But I think the kind of magnitude, we're seeing which was a mean change score of 2.4 which means basically half way between much improved to very much improved is a very strong score that has passed anything possible with natural history by far and for families with the disease, absolutely unique and compelling. So we're comfortable with the potency and we'll put out more data at the December FAST meeting on the details of information that support the CGI data. Maury Raycroft - Jefferies LLC Got it. That's really helpful, Thanks for taking my questions. Operator - Thank you. Our next question comes from Gena Wang of Barclays. Your question please. Gena Huidong Wang - Barclays Capital, Inc. Thank you for taking my questions. First, I wanted to say to Shalini, it has been great working with you for the past five to six years and my best wishes to your next journey. And Mardi, we are looking forward to working with you. And so I have two sets of questions. First one is the Dojolvi. So is it fair to assume majority of the patients right now on drug is teen and adults, let's say 70% to 80% are teen and adult and also how many ex-US patients right now are on a named-patient access program. And my second question is in regarding the DMD gene therapy. And you mentioned that you could file R&D within one year. So what additional cooperation -- can you give additional color on all the capabilities reaching the need to do R&D, including such as CMC potency assay and also do you need FDA inspection in order for you to start. Emil D. Kakkis - Ultragenyx Pharmaceutical Inc. Thanks Gena, that's quite a few questions. I don't know if you want to say anything Shalini. Shalini Sharp - Ultragenyx Pharmaceutical Inc. Okay. I will just thank you, Gena, to you and your team and I really enjoyed working with you all as well. Emil D. Kakkis - Ultragenyx Pharmaceutical Inc. Good. With Dojolvi, thing to understand about dosing is that the patients in the first four or five years of life have increasing amount of drug usage. But once you get about five, six, seven, or eight years old, then it's a very flat curve and so patients from school age to adults are getting very similar amounts of drug, which we estimate is after adjustment for gross to net and compliance, around 130,000 a year. So what might matter is how many very young patients we have, but we're probably not going to be putting out that much delineation at this point in time. I don't know if you want to add anything else Erik, on this issue of patients on Dojolvi. Erik Harris - Ultragenyx Pharmaceutical Inc. Nothing else there to that. Emil D. Kakkis - Ultragenyx Pharmaceutical Inc. All right. I think the other question you asked was how many patients were named-patient ex-US. Yes, on the French-HU program [Phonetic], it's a little less than 50 patients I think are on the FAOD in France. In Italy, it's a handful of patients, but because of the approval in the US, we are able to respond to name patient requests in more countries now. So we expect that potentially to grow, although not dramatically. The US revenue is certainly going to grow we think significantly as we move forward in the launch. Last question was on IND for Wilson. So far, the program has gotten -- DMD, did you say. I am sorry. Gena Huidong Wang - Barclays Capital, Inc. Yeah. It is for both Wilson and DMD. Emil D. Kakkis - Ultragenyx Pharmaceutical Inc. Okay. Well, for Wilson -- we'll start with Wilson. And I guess you are out of that. For Wilson, we have completed making the drug substance at scale and it runs well in the HeLa platform and we made a lot of product and we're in the test release phase of that program and that requires a lot of analytical methods and so forth that's ongoing. There is some non-clinical work going and those pieces are coming together and we should be on track to hit two files at the end of the year, the IND and our expectation is as long as there is no more COVID related shutdowns of labs or other things going on, then we should. If there are some problems with that, then we could find ourselves somewhat delayed, but overall, the process has gone well and we've been working and have clinical development plan put together for the program. So on Duchenne with the other program, it's at a beginning stage. We are in the process of making the production system, which is the HeLa producer cell line system more often can be testing a number of other factors in the design. So it will take some months to get through that process. Then we have to just scale-up and so forth, which will take some time. We haven't said [Indecipherable] timeframe but I wanted to be clear, it's certainly well more than a year for us to be able to get the manufacturing and non-clinical work put together, so it's not an immediate -- it's not an immediate event. We want to get it right. If we're coming in at this point after other parties already in the clinic, we want to come in and nail it with a very high quality system and quality production as well as a good strategy administration that will optimize the treatment effect. Gena Huidong Wang - Barclays Capital, Inc. Thank you. Operator - Thank you. Our next question comes from the line of Tazeen Ahmad of Bank of America. Your line is open. Tazeen Ahmad - Bank of America Merrill Lynch Hi, good afternoon. Thanks for taking my questions. Emil, I just wanted to get your thoughts on where you are in reaching commercial supple scale for both DTX401 and DTX301 programs and more specifically, have you completed any necessary potency assays for the FDA. And then I have a follow-up. Emil D. Kakkis - Ultragenyx Pharmaceutical Inc. Yes. Well, we've been dealing with potency assay across the program -- across all the programs and have an understanding with the agency how we're managing that for all the programs. They have been talking to us about this for a while. So it's not a new thing and I think it's pretty clear to them that in entering Phase 3, they want to see a potency assay as part of each manufacturing process and on lot release and their point is they want to make absolutely sure that we're getting potent vector. We have a number of -- the guidance allows for a matrix of multiple assays with multiple, but they don't really want one that looks at the active protein story and we will have those in place for those programs. Tazeen Ahmad - Bank of America Merrill Lynch Okay. And then can you just give us a little bit more background on what led to the decision to add a prophylactic steroid cohort to the DTX401 program. Emil D. Kakkis - Ultragenyx Pharmaceutical Inc. Well, it was actually -- the DTX401 plan was sort of there and it has been talked about as much. In cohort three, we use steroids a little earlier, we set the trigger for initiation of steroids a little bit earlier. It look like we got a better effect at controlling the -- any plan for a response from liver and the sense was that with the safety apparent of doing that we decided we would look at moving the steroids up even a little bit earlier on in the process and we think that we're just practically speaking become a lot easier in the commercial setting and would help us get ahead of any inflammation that might get going. So it's basically learnings from cohort three, but it was actually in the plan and with the data, the way it looks from our third cohort it seem prudent to do that as well. It doesn't affect us. We have soft product available and we could treat another three. I will tell you the other benefit of course for having 12 patients here and 12 patients in the other program is that while the number of patients that we treat that are successfully treated certainly can help us with the long-term durability argument that they will be on treatment far ahead of the Phase 3 program in that as you know is going to become an important piece at getting or moving forward in a filing approval process is to show that we have enough durability and so having a few extra is probably helpful in that. So we'll be exploring that we are already enrolling patients in it and I think it just adds to the story for how to treat in an efficient way when you're in the commercial setting. Tazeen Ahmad - Bank of America Merrill Lynch Okay, thank you. Operator - Thank you. Our next question comes from the line of Yigal Nochomovitz of Citi. Your line is open. Samantha Semenkow - Citigroup, Inc. This is Samantha on for Yigal. Thank you very much for taking our questions. Just first on the Crysvita guidance revision. Is that incremental $5 million on the lower end related to the expectations for the TIO launch or is that related to the increase and the identification of new XLH patients that you mentioned in your prepared remarks? Emil D. Kakkis - Ultragenyx Pharmaceutical Inc. Well, the guidance we put out in the beginning of the year did assume that TIO would get approved launch. The guidance we put out was for all Crysvita sales for the year. And so we've moved up the lower-end of the guidance, because our revenue is actually guiding into the higher part of the guidance. So that was simply tightening up the predictions for the street. I don't know, Erik, if you had any other thoughts on the guidance that you want to provide? Erik Harris - Ultragenyx Pharmaceutical Inc. Yeah. I would just say just to build on my remarks earlier, so far less than 1% of the existing patients have been impacted as a result of the COVID pandemic. And while we are seeing growth rates that are trending back toward pre-COVID levels there, but not there yet, but are trending in the right direction. I think that's as a result of the team is continuing to find innovative ways as [Indecipherable] providers and patients to virtual meetings and in live meetings were allowed according to safety protocols and more offices are opening up and seeing more patients in clinic. So we are encouraged by the rebound that we're seeing. Emil D. Kakkis - Ultragenyx Pharmaceutical Inc. Great. Thanks, Erik. So I don't -- and at the end, the bottom line not TIO really the maintenance of the base off of COVID has kept us in game and the launch has continued and to tighten up our focus and remove the bottom end of the guidance range. I think that's good news for the Crysvita franchise. Samantha Semenkow - Citigroup, Inc. Okay, great. Thank you. And then just a follow-up on the DMD question. Once you get this construct into the clinic, how quickly do you think you can advance into a pivotal trial. Do you think you'll be able to use the safety data that you've generated for DTX401 and DTX301 to sort of advance it a little bit faster maybe some of your other gene therapy program? Emil D. Kakkis - Ultragenyx Pharmaceutical Inc. Well, I think we would be able to understand from those programs, the safety profile, but more importantly the dosing range of affect, but I think the truth is in Duchenne the dosing is quite different. The safety will be quite different. So there's a little bit less than we can leverage upon. I think the manufacturing might be helpful particularly the HemA program which is HeLa produced would give us some -- would provide us some advantage. So I don't think I would say it's -- let's say those programs alone, I think the biggest advantage would come through in understanding of likely dose range we need to achieve and being able to design and the biomarker endpoints involved as well as clinical endpoints and being able to design a seamless design trial, which would take us through the dosing phase as well as the randomized phase more rapidly, which is the approach we're going to take with Wilson. And I think that type design, which has been promoted by CBER and Peter Marks. I think, it is possible when you know enough about the disease to know the endpoints and the measures you want to make, then you can kind of predict the plan and just settle the dosing and move right into Phase 3 without having a gap. That would be one of the ways we can shorten the timeline after we get to the clinic. Samantha Semenkow - Citigroup, Inc. Okay, great. Thanks for taking our questions. Operator - Thank you. Our next question comes from the line of Cory Kasimov of JPMorgan. Your question please. Cory Kasimov - JPMorgan Chase & Co. Hey, good afternoon. First of all, it's great to hear from Shalini, so hope you're enjoying your time in New Zealand. Two questions from me as well. First on UX701 in Wilson. Can you just give some insight into how you're thinking about initial clinical studies and what the duration of follow-up might look like there. And then my second question is just to follow up on DTX401 for GSDIa. And with your comment that the new prophylactic steroid cohort that you're evaluating now won't impact the timing of Phase 3, does that mean you would start Phase 3 and amend the protocol if necessary just taking early look and build up a prophylactic steroid kind of regimen into that? Emil D. Kakkis - Ultragenyx Pharmaceutical Inc. Okay. So the first question is around UX701, which is the gene therapy for Wilson disease. The clinical studies -- our plan in the clinical studies is to do a significantly larger study than we did in the others, but it will be three cohort groups that will be exploring dose and then with that dose information will essentially go straight into the Phase 3 design and one seamless design. So we're getting -- we're going to seeking its approval on doing a single seamless design where you go through dosing and go right to the pivotal design. The reason that's possible is that the agreement on primary endpoint is on a biomarker based primary endpoint is doable, because of the history of approvals in Duchenne and therefore we think we can set-up and operate a program straight through in one shot, so that will help it. The study length, look, I think the FDA is very clear that they want to make sure there's sufficient durability in the program. The patients from the early dose cohorts would probably end up having close to a year or more time on drug than the Phase 3 component patients, but we haven't fully nailed down what exactly the amount length of time is, but our expectation based on design, they have a 48-week blinded study, how much extension data we'll need to discuss with the agency at some point in time, but our plan is to have 48-week plan to study for the core efficacy and safety determination. So with the DTX401 prophylactic steroid question, we're primarily looking to see that we can keep the inflammation down in the first few weeks and that effect is sufficient to allow us to get the good corn starch reductions. We only need a few weeks of data in order to know how steroids are working for us. So that's we're looking for. Last time in the third cohort, what we did with steroids that were, as soon as they changed from baseline, which really meant it was only like a couple of weeks in from the treatment and so now we're to starting a little bit earlier. So it's really not that fundamentally different from where we are, it's just a little bit earlier and we'll have to see that, its safe and doesn't have any issues with the GSD1a patients and as long as that happens first week, we will know. Our plan though is to submit the profile with the new proposed [Phonetic] additions that way. If we had an issue in the [Indecipherable], yes, we could then amend the protocol back away from that, but I doubt that we will and I think it's probably the best way forward. Cory Kasimov - JPMorgan Chase & Co. Okay. Thanks Emil. Operator - Thank you. Our next question comes from the line of Salveen Richter of Goldman Sachs. Your question please. Salveen Richter - Goldman Sachs & Co. Good afternoon. Shalini, it's been great working with you and enjoy the break and Mardi congratulations on joining Ultragenyx. Emil, I was just wondering if you could update us with where you stand with regard to optimizing the HeLa platform to create this third generation process and how you intend to layer this HeLa manufacturing into your pipeline, particularly with Wilson? Emil D. Kakkis - Ultragenyx Pharmaceutical Inc. Right. So the Wilson program is produced with the HeLa we call 2.0 version of the process. However, we've already created HeLa 3.0 version from that version and we don't have at this point time or need to crossover to it, but we could at some point in time. But right now, we will head to the clinic with the 2.0 version, which is already very productive and certainly providing more than enough product. The HeLa 3.0 level of productivity improvements, which are some patented additional changes we're making, which were presented at the ASGCT. Those change I think will particularly be valuable for the Duchenne program because where you really need that much higher productivity therefore is a real big win for that. And with those changes, we can get the productivity up several fold even higher and reach levels that will really enable the ability at 2,000 liter scale to produce enough product to treat many patients for every run. So we're looking at HeLa 3.0 point is really coming into play there. The process though making that 3.0 version can be done with any existing HeLa producer cell line. We can actually take existing line and turn it into the 3.0 version. So we could certainly go back. We haven't done it for Wilson with HeLa three other programs and do that as well. Going forward, we look to see the HeLa 3.0 version as being the right version. But we're still finishing the development of that and the Duchenne will give us a chance to optimize it for human use. Salveen Richter - Goldman Sachs & Co. Great. Thank you. Operator - Thank you. Our next question comes from Laura Chico of Wedbush Securities. Please go ahead. Kenneth Shields - Wedbush Securities Hi, this is Ken Shields on for Laura Chico. Thanks for taking my question. So one for Mardi. What created the opportunity and how should we think about capital allocation and financing strategy. And Ultragenyx has benefited from recent transaction, so what should we anticipate as we are looking at? Mardi Dier - Ultragenyx Pharmaceutical Inc. Yeah, great. Great. Thanks for the question and it is pretty easy decision to join Ultragenyx and I think you heard a lot about it on the call. I think the team has guided the company in such a great way to get to this point, but they certainly plan for their next phase of growth and I'm pretty honored to be part of the team now and to help them achieve that. In terms of capital allocation, I think the company has done a fantastic job, frankly to be here. If you look at our cash balance at the end of last year and the cash balance today, it's pretty darn close to the same number and particularly the last two deals that brought in capital non-equity dilutive in nature where the Royalty Pharma, Royalty deal last December and then of course the Daiichi deal, which we've talked about today together bringing in well over $500 million into the company. So that's fantastic. So the company is in a really strong cash position. We did announce, of course, the Solid deal recently. But with that deal and sort of our base business going forward, we have cash that takes us into 2023, but I want to highlight that we're on a growth path. So we like deals that look like Solid and I want to highlight the GeneTx purchase option as well for the Angelman program, which we have the option to purchase that company for $125 million after some period of time after Phase 2 data. So we're in great position, but we are very active as well and we look forward to the next steps. Kenneth Shields - Wedbush Securities Thank you. And maybe just one more. So on Angelman syndrome, how do you think about the competitive landscape and the potential for a CRISPR based therapy versus an ASO strategy. I think there is a recent publication that came out and then might have your interim data. I was just wondering if you could opine on the potential for gene editing disease? Emil D. Kakkis - Ultragenyx Pharmaceutical Inc. Thank you. Well, for Angelman disease, fortunately for Angelman patients, there is a lot of people working on strategies right now. And there are a lot of very interesting strategies out there. So they certainly all have potential. We picked ASO by the way particularly because we felt it was more likely be superior than gene therapy or even a CRISPR type approach. The ASO can just -- particularly in the areas it distributes well to the whole brain and induces the expression in a wide variety of neurons across the brain which we think is really important in this disease state whereas gene therapy now, even in the non-human primate or in humans is still getting a small fraction to neurons. So while that can work in something like SMA, it may not work in disease that has very complex neuronal communications. I think, gene editing is going to be extremely challenging, the brain getting an adequate and an effective expression in the neurons to actually have the impact you desire. And keep in mind it's only the neurons that are imprinted, the other cells are not imprinted. So if you gene correct non-neuronal cells here that's actually may not be what you want to do. So while this is complicated, I would say having looked it all, our view is ASO is with the best strategy, it turned on the paternal chromosome which was there, it allows that expression occur in a regulated fashion and it does it in a wide variety of neurons and I think that's still going to be hard to beat even so there are more ASOs out there than us, so with Roche, Biogen, [Indecipherable] both very capable firms with a lot of expertise. We picked the GeneTx program to get involved because we felt they had a superior understanding of the R&D regulation and the science which was we think superior and it's basically more evolved and understanding regarding how to knock-down the RNA and their oligo I think is substantially more potent than others that were tried in the laboratory. So we're excited about that oligo and I actually think it's still going to be the best strategy and it will be hard to match I think with other strategies. Kenneth Shields - Wedbush Securities Okay. Thank you very much. Operator - Thank you. Our next question comes from Jeff Hung of Morgan Stanley. Please go ahead. Jeffrey Hung - Morgan Stanley Thanks for taking the question and best wishes to Shalini. Just to clarify the guidance if I'm looking at this right, the midpoint of the range in size approximately flat sequential growth in the fourth quarter Crysvita sales in Ultragenyx territories. You mentioned outstanding uncertainty due to COVID, so is that the main driver or is it conservatism. Are there any other potential factors that we should be thinking about for the fourth quarter. Thanks. Emil D. Kakkis - Ultragenyx Pharmaceutical Inc. Well, I think there are probably a lot of factors like how about the widely discussed COVID surge ongoing out there. Erik, do you want to touch on the question, which is really how the guidance relates to what's happening, what are the risks to the guidance, maybe going forward and what the changes were. Is that about right, Jeff? Jeffrey Hung - Morgan Stanley Yeah. Erik Harris - Ultragenyx Pharmaceutical Inc. Yeah. We are encouraged by the rebound that we're seeing, but there is still a great deal of uncertainty as to when the market will fully open to pre-COVID level. So it creates some challenges with forecasting as you think about as we move in, close out the year and move into 2021. Jeffrey Hung - Morgan Stanley Thank you. Emil D. Kakkis - Ultragenyx Pharmaceutical Inc. Yes. Thank you. Operator - Thank you. Our next question comes from Joon Lee of Truist Securities. Your line is open. Joon Lee - Truist Securities Hi, congrats on the strong quarter and thanks for taking my questions as well. Our GTX-102 for Angelman use IVIG to treat some of the patients which implies IgG response, yet you said on the call yesterday, I believe that IgG [Indecipherable] ratio were not altered, so can you tell us a little bit more about what the nature of the new response was. And then second question is based on the MRI, did we actually -- as you described, appear to be very localized. But my question is, what was the greatest extent of the spread of the information in the patients -- in any patient actually just trying to assess the potential to spread to other spinal cord levels maybe little bit more about functions. Thank you. Emil D. Kakkis - Ultragenyx Pharmaceutical Inc. Sure. So the use of IVIG areas we've done more reactively as the patient's symptoms, that was not actually based on a known immunological situation that we've thought IVIG would work. It was just looking parallel from other conditions not because there's any rational basis it was used. It is not clear the IVIG steroids are actually having impact. In fact, we were just including them for completeness, but it does not indicate that there is an immunoglobulin based and we have no evidence for that at this point. Regard to localized [Phonetic], we said lumbosacral but actually lumbosacral was the largest extent and that was in the smallest patients that's where it extended to the lumbar region. But in the bigger patients it was really almost in the sacral region only, so it was actually smaller. The biggest region was up to the lumbar and it did not include thoracic levels or higher levels. So we don't think it would spread, we think it appears to be region where the drug sits immediately after administration. Without trendelenburg if a small patient it would fill up a little more than a big patient where it will only fill up the bottom part. So we think that the trendelenburg which hopefully tips the cup over and have all the stuff pour to top which is what we think would change things and we're adding a flush additional to CSF after the dosing to help wash-out the drug from the lumbosacral region, which we think would both produce a local effect and help promote the movement. The thing once the drug moves north and flows, it will mix now with CSF up in the spinal cord mix and dilute and when it reaches the cisterna magna there is almost of pumping mixing action that goes on with it. So if you sit there long enough, the drug should move farther up and mix more efficiently and not sit in any one place, so it's why we believe we can alter the distribution. It's not a new thing. Trendelenburg and these actions are commonly used in other intrathecal drugs and I've been personally doing intrathecal therapy for 20 years, so it's there, I'm quite familiar with them. These are very simple things you can do to alter and this is why we're very confident we can manage this and it will not become an issue. Joon Lee - Truist Securities And just a follow-up question. But there are other ASO therapies that led to some localized inflammation or reactions that will result with trendelenburg? Emil D. Kakkis - Ultragenyx Pharmaceutical Inc. Well, there are other ASO therapies that clearly cause meningeal irritation and elevated CSF protein, multiple ones in the clinic have shown that. So that's definitely true. So the trendelenburg can be used in any situation. I don't know, but I can't speak to the clinical judgment of other people what they do or don't do but trendelenburg is widely used in intrathecal therapies as a way to take the heavier drug solution and move it toward the brain where it needs to work. Joon Lee - Truist Securities All right. Thank you. Operator - Thank you. Our next question comes from Arlinda Lee of Canaccord. Your question please. Arlinda Lee - Canaccord Genuity Group Inc. Hi, thank you for taking my questions. Maybe a quick one on Dojolvi. Can you provide an update on what's going on in the discussions with the regulatory agencies and then maybe more involved. On the HeLa efficiencies, you've mentioned that you're now in version 3.0. I'm wondering if you're looking to further enhance improvements there. And can you talk about how you think about the HeLa programs and your appetite for additional collaborations and additional indications you're interested in going into. Thank you. Emil D. Kakkis - Ultragenyx Pharmaceutical Inc. Thank you. So on Dojolvi regulatory we have -- just to update, we have filed in Canada under priority review, we filed in Brazil in addition and for those are the two there in play. In Europe, we're having discussions because we need to get a pediatric investigational plan and we're having ongoing discussions and no filing plan yet for Europe. So that's where we are in the [Indecipherable]. With the US approval though we can do named-patient sales in many places where the request come to us and we can fulfill those requests. With regard to HeLa 3.0, the new version has some alterations which help generate more productivity in our really substantial and very important then, so the team led by Sam Wadsworth is of course continually looking on what's next and are continuing adding to the platform and building its value and I think these changes, the kind of things that happened in the early days of monoclonal antibodies that whoever controlled the creation of large-scale, cost efficient system for monoclonal antibodies started kind of owning the field and ending up partnering and gaining a lot of ground. Now we believe there are additional collaborations are possible whether for indications we would develop or ones for which we would provide the technology and an agreement as we did with Daiichi Sankyo. We are looking at those kind of arrangements, we would -- the deal with Daiichi Sankyo also involves a lot of tech transfer and a lot of effort, but on the spectrum we could do another deal as extensive as that or other deals in which the technologies license for particular indications and we're open to a variety of avenues and we've created the largest mammalian system and high quality system for AVV manufacturers, coming to us to make it available and work with the companies and putting more products in play. Duchenne story just became one that we could take advantage ourselves, it's an area of muscle that we're pretty knowledgeable about and for which Solid as a partner was available to help bring their Duchenne particular knowledge to the floor especially their microdystrophin. We certainly would look at other deals of a similar type where we would supply our technology and pick up another product where the unique scalable and large-scale production and high titre productivity of the HeLa platform, it could be a distinct advantage particularly then in high dose indications. So we are looking at those and Sam will continually ask for investment in further versions of the platform, I guarantee it. Arlinda Lee - Canaccord Genuity Group Inc. Great. Thank you very much. Operator - Thank you. Our next question comes from Vincent Chen of Bernstein. Your question please. Vincent Chen - Sanford C. Bernstein & Company LLC Thank you so much for putting me in. I have a couple of a science questions on Angelman and DMD. Starting with Angelman I was wondering if you could provide some more color on what you think the mechanism is for the potential inflammation seeing and what findings or observation support this hypothesis. Is this something that you think it's likely to be come in effect come into simply RNA dose intrathecally or bolus [Indecipherable] or is it something that maybe related to certain RNA molecules or certain RNA modifications. And then for DMD and the Solid collaboration, I'd be curious what is your thinking around what causes the complement-related side effects that Solid has seen previously. Are these likely to be related to the use of a longer half-life vector like AAV9 and do you think a program using your capsid would be potentially less susceptible. Emil D. Kakkis - Ultragenyx Pharmaceutical Inc. Sure. So in the Angelman story, the mechanism of the inflammation, we think is probably a very distinct from the mechanism of the action of the drug. All ASOs can have toxicity applied to cells in culture and [Indecipherable] published in very elegant paper showing that -- showing how ASOs of various types combine certain proteins that lead to toxicity. This is the ideal ASO with positive toxicity as a class is pretty well established in many different oligo, so it's not something very new. The issue of meningeal inflammation protein in CSF is also widely observed. We don't think the mechanism has anything to do with mechanism of oligo and RNA, it has really to do with a local cell toxicity relating to too much oligo present and being taken up. That is why we believe it is primarily an issue of getting the concentration and the contact time down locally. But we know and the data supports this is that we have looked at non-human primates and we know that in those non-primates without trendelenburg have done the same ways we're doing in human. We do see very high concentrations in the local tissues. They hadn't been associated with a problem in non-human primate. The concentration of the brain are lower than what you see locally applied drug. But now in humans, that isn't a problem and so therefore we're having to take action, but it hadn't caused this problem in non-human primates. So we know the concentration is higher there. We know from in-vitro work with a number of laboratories that oligo at high concentration can cause localized toxicity. So we think it's a simple matter of just lowering the exposure level in the local and trying to reduce that inflammation. I think it's something that's completely manageable and not a fundamental type toxicity that's related to the actual drug action, it is related to a local toxicity of just too much drug in the locally applied space. So we feel that's something very differentiated from what the drug does and therefore very manageable and I feel confident we'll get it managed. Now with regard to Duchenne, both Pfizer and the Pfizer program and Solids program have had common activation -- appears to be antibody related common activation. This could be due to longer exposure time with AAV9 which lasts longer. The Sarepta program to the extent they've disclosed and this appears to have -- not have this particular problem. We know that AAV8 related vector is clearly bit quicker and that may be a factor. We have an AAV8 variant that is has a very good immune profile and which we think has a good potential of being an optimum product. We know it delivers to muscle and therefore we feel confident. It's a good choice from its immune profile standpoint, it's faster clearance from the circulation to be a good option to combine with the really best-in-class microdystrophin that Solid has and for Solid this gives them another way to win. They've got their current product it could do well and it could be fine and figure out the issues they've had. This also gives them another way to work with us and another upside potential for Duchenne patients. I like deals that get two winners put together, something that will create a common goal and combine the best technology there is out there and they've done that type of deal in the past and I think it was kind of deal that can work. Duchenne is a very big indication, there is a lot of room here and I think there's a lot of room for doing better, and we think the platform we have in the dystrophin combined with some learnings and intelligent approach could provide a very good option for treating Duchenne. We're behind everyone else but I think we can be -- we can be better. Vincent Chen - Sanford C. Bernstein & Company LLC Great. Thanks for taking the question. Congrats on the progress. Emil D. Kakkis - Ultragenyx Pharmaceutical Inc. Thank you. Operator - Thank you. At this time, I'd like to turn the call back over to Joshua Higa for closing remarks. Sir? Joshua Higa - Ultragenyx Pharmaceutical Inc. Thank you. This concludes today's call. If there are any additional questions, please contact us by phone or at ir.ultragenyx.com. Thank you for joining us. Operator - [Operator Closing Remarks]

Ultragenyx Pharmaceutical Inc. (NASDAQ:RARE) Q3 2020 Earnings Conference Call - Final Transcript

Oct 27, 2020 • 05:00 pm ET

Ultragenyx Pharmaceutical Inc. (NASDAQ:RARE) Q3 2020 Earnings Conference Call - Final Transcript

Emil D. Kakkis