Ultragenyx Pharmaceutical Inc

NASDAQ:RARE

Earnings Call Transcript 2020-Q4

[Operator]

Good afternoon, ladies and gentlemen, and welcome to the Fourth Quarter and Full Year 2020 Financial Results and Corporate Update Conference Call. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session, and instructions will follow at that time. [Operator Instructions]

I would now like to turn the conference over to your host, Mr. Joshua Higa. Sir, you may begin.

[Joshua Higa, Director, Investor Relations]

Good afternoon, and welcome to the Ultragenyx Financial Results and Corporate Update Conference Call for the fourth quarter and full year 2020. We have issued a press release detailing our financial results, which you can find on our website at ultragenyx.com.

I am Joshua Higa, Director of Investor Relations. And joining me on this call today 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.

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 Quarterly Report on Form 10-Q that was filed on October 27, 2020, our Annual Report on Form 10-K 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 that, 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'll now turn the call over to Emil.

[Emil Kakkis, Chief Executive Officer and President]

Good afternoon, and thank you, everyone, for joining us today. 2020 was a transformative year for Ultragenyx as we executed on many of our strategic priorities. We now completed the fourth approval from our portfolio, we had at IPO. And over the last couple of years have now refilled our portfolio with substantial opportunities in six clinical stage programs, four of which are entering pivotal studies.

We also have 14 pre-clinical programs that are advancing our first mRNA program to the clinic this year. The efficient conversion of our pipeline to our next opportunities will allow us to accelerate our value creation and treat more rare disease patients with the first-ever specific treatment.

From a commercials perspective, we achieved the upper end of Crysvita revenue guidance despite a global pandemic and received two US approvals and launch treatments for two more diseases with no other approved treatments.

From our clinical programs, we released important data updates from our gene therapy programs in GSDIa and OTC deficiency, as well as the first glimpse of results for the antisense oligonucleotide GTX-102 in Angelman syndrome. Those initial Angelman results suggest promising activity in this relatively large rare disease, with no approved therapies, but certainly much more to do to realize the potential.

On the gene therapy side, we initiated one of the largest ever gene therapy licensing deals by providing non-exclusive rises to Daiichi Sankyo to utilize our manufacturing platform, including our HeLa producer selling technology.

Later in the year, we partnered with solid biosciences in Duchenne Muscular Dystrophy to pair their differentiated microdystrophin construct with our AAV8 variants in our productive HeLa PCL system.

Most recently, we broke ground and began construction on our gene therapy manufacturing facility in Bedford, Massachusetts that will initially provide 30 manufacturing runs per year at the 2,000-liter manufacturing scale.

Ultragenyx now has one of the broadest gene therapy franchises, which originated from our acquisition of Dimension Therapeutics in 2017. Our portfolio now includes three in-house pivotal clinical stage program, one additional clinical program partnered with Bayer and two publicly disclosed in-house preclinical programs. Our robust HeLa PCL manufacturing platforms enable us to make AAV vectors at large scale, the highly efficient robust process that will enable the next generation of larger clinical programs.

But that is just the gene therapy side of the business, our development strategy is to choose the right modality for each disease, and we have a variety of other therapeutic modes in our portfolio. For genetic disease of bone, monoclonal antibodies can be the most effective way for effecting change in their biology.

In December, we added a new late-stage monoclonal antibody program by collaboration with Mereo BioPharma, setrusumab or UX143 has completed a Phase 2b study in adult patients with multiple types of osteogenesis imperfecta, or OI, which is one of the largest rare genetic bone diseases and significantly more common than XLH.

Camille will provide more detail on this program later. But I will note that OI and the UX143 program are a perfect complement for our bone franchise and the expertise we have built with Crysvita. The learnings from our Crysvita development program will be very helpful in the future development of UX143, and there is significant overlap between the physicians who treat OI, XLH and TIO.

Importantly, this collaboration provides us with commercial rights of the product throughout the world with the exception of Europe, where we receive a royalty. While 2020 was a year full of unforeseen challenges, Ultragenyx was able to make substantial progress executing our strategic plan across our preclinical and commercial programs with great success this past year.

I'll hand it over to Erik to provide more detail on our commercial performance for the year.

[Erik Harris, Chief Commercial Officer]

Thank you, Emil, and good afternoon, everyone. I'm truly proud of how the commercial team executed in 2020 in the face of never before seeing challenges. 12 months ago, pre-COVID, we issued guidance for Crysvita revenue in our territories of $125 million to $140 million. Despite the stay-at-home orders, many doctors' offices temporarily closing to non-essential in-person visits and all the uncertainty of a global pandemic, we were able to finish the year at approximately $139 million, right at the top end of our guidance range.

For 2021, we have issued guidance of $180 million to $190 million for Crysvita revenue in Ultragenyx territories. This represents between 30% and 37% year-over-year growth as we ended the fourth year of Crysvita's launch. This steady growth is enabled by the many digital strategies to educate physicians in finding XLH patients and getting these patients on Crysvita, while ensuring that existing patients stay on Crysvita during this pandemic.

We believe we will continue to see the mix of XLH patients on Crysvita shift towards a greater portion of adult patients. This will be driven by our increasing efforts on finding adult patients by expanding our reach out to more endocrinologists, nephrologists and other specialties in the community setting. To support these efforts, we will expand both our commercial and medical field teams who will be focused on these harder-to-find adult XLH patients.

In the middle of last year, we launched a TIO indication for Crysvita. The launch is going very well. We have converted the majority of clinical trial patients to reimburse drug and are receiving Start Forms for TIO patients from the major metabolic bone centers. Reimbursement for TIO is progressing well and is consistent with XLH reimbursement at the same stage of launch. We will not be providing specific patient numbers for TIO, as sales in that indication are included in our overall Crysvita revenue guidance.

Outside of the US, we are making steady progress in our discussions with health and reimbursement efficient. Demand remained strong across Latin America, as we continue to see more and more patients being granted injunctions required to gain access to name patient sales.

The ordering patterns from the health authorities in this region tend to be inconsistent, leading to some revenue lumpiness, which is consistent with other rare disease products in that region. We will keep you updated as we look forward to receiving full reimbursement in other Ultragenyx territories.

Moving now to Dojolvi, which was also launched in the middle of last year for the treatment of long-chain fatty acid oxidation disorders in the United States. At the end of December, we received approximately 190 completed Start Forms from approximately 90 unique prescribers of Dojolvi, which speaks to the breadth and interest we are seeing for this product launch from the physician community.

This led to approximately 130 patients on reimbursed commercial therapy, which also includes all 80 patients who participated in our clinical studies. We are also seeing strong support from payers. As of the end of January 2021, over 100 million lives in the US have Dojolvi coverage from over 40 policies, which includes some of the largest national payers.

In these first quarters of the Dojolvi launch, we will now be providing revenue guidance and believe the Start Forms and prescriber metrics provide a better sense of the strength of the launch.

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

[Mardi Dier, Chief Financial Officer]

Thanks, Eric. Good afternoon, everyone, and thank you for joining today's call. We issued a press release earlier today that included a financial update, which I will briefly summarize. Company revenue for the year ending December 31, 2020, totaled $271 million. Crysvita revenue in Ultragenyx territories was $138.9 million, including $128.6 million from the North American profit share territory and net product sales of $10.4 million in other regions. Total royalty revenue related to the sale of Crysvita in the European territory was $14.5 million.

Mepsevii revenue for 2020 was $15.3 million. We expect these revenues may increase modestly over time. Dojolvi revenue for the year was $13 million. This includes approximately five months of revenue after the US launch of Dojolvi toward the end of July and 12 months of named patient sales in other regions.

2020 total revenue also included – includes $89.2 million of non-cash revenue related to the tech transfer services provided to Daiichi Sankyo as part of our strategic manufacturing partnership around the HeLa PCL and HEK293 technology. Our total operating expenses for the year were $601.1 million, which includes research and development expenses of $412.1 million and SG&A expenses of $182.9 million.

In 2021, we expect our R&D cost to increase as we support three pivotal gene therapy clinical studies, the cetuximab Phase 2/3 clinical study in OI. UX053 our first mRNA Phase 1/2 clinical study in GSD III and a number of other IND-enabling activities as we get ready to advance the next programs into the clinic.

We expect SG&A to modestly increase in 2021, as we continue to support the expansion and launches of Crysvita, Ajovy and Mepsevii. For the year ended December 31st, 2020, net loss was $186.6 million or $3.07 per share, this compares to a net loss for the same period in 2019 of $402.7 million or $7.12 per share.

Net loss for the year ended December 31st, 2020, includes $170.4 million increase in the fair value of investments in equity securities. Net cash used in operations for the year was $132.2 million, compared to $345.4 million for the same period in 2019.

We ended 2020 with $1.2 billion in cash, cash equivalents and marketable securities. This puts us in an excellent position to be able to support the execution of and achieve key milestones in our late-stage clinical pipeline and commercial expansion.

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

[Camille Bedrosian, Chief Medical Officer]

Thanks, Mardi, and good afternoon, everyone. On January 8, we issued a comprehensive press release, that detailed the latest data, regulatory progress and Phase 3 plans for our gene therapy programs. Therefore, today, I will briefly summarize our current status and next steps for our three pivotal stage gene therapy program.

DTX401 for glycogen storage disease, Type 1a, has completed the scientific advice process with the European Medicines Agency, or EMA, as well as held an end of Phase 2 meeting with the FDA. Out of these meetings, we have aligned on the Phase 3 study design and endpoints.

We currently are on track to initiate this pivotal study, in the first half of 2021. Shifting now to DTX301 for Ornithine transcarbamylase or OTC deficiency, we have received feedback from our initial scientific advice discussions with the EMA. And we'll have an end of Phase 2 meeting with the FDA, barring any unforeseen delays, by the end of this quarter.

Based on the initial discussions, we feel confident about where we will end up with regards to the design and endpoints for this Phase 3 study. We currently are on track to initiate this study, in the second half of 2021.

Moving now to, UX701 for Wilson disease our third pivotal gene therapy program to enter the clinic in 2021. Earlier this year, we announced that the seamless, single protocol Phase 1/2/3 IND application has cleared FDA review.

The program also recently received fast track designation, which will enable additional dialogue and feedback from the FDA. This study currently is on track to initiate in the first half of 2021.

Now I'll touch on, GTX-102, and antisense oligonucleotide, which is being developed with our partner, GeneTx for the treatment of Angelman syndrome. Angelman syndrome is a devastating neurogenetic disorder, with a broad spectrum of disease manifestations, including speech and cognitive impairment, ataxia or balance issues, sleep dysfunction and seizures. GTX-102 is the first antisense oligonucleotide program for Angelman to reach the clinic.

Late last year, we announced positive interim data from the ongoing Phase 1/2 study of GTX-102. All five patients who were treated, demonstrated improvements in at least three disease domains and scores of much improved or very much improved in two disease domains as measured by the Clinical Global Impression of Improvement scale for Angelman Syndrome. These improvements were also supported by other increases in measures, including Observed Reported Communication Ability or ORCA and Bayley-4 communication scale, as well as by preliminary EEG readings. All five patients also had a grade one or two serious adverse events of lower extremity weakness associated with local inflammation in the region of administration in the lower back at the higher doses of GTX-102.

Dosing was paused after the first SAE onset was observed and the study is currently on clinical hold. The SAE has fully resolved in all five patients and clinical improvements have been sustained beyond the resolution of the SAE.

GeneTx, our partner, has submitted to the FDA a substantial information amendment including follow-up safety information for the five patient’s dosed and nonclinical data in nonhuman primates. We have proposed an amended dosing and administration plan to the FDA. These changes are expected to reduce the local contact time and concentration of the ASO.

Furthermore, the new dosing plan is within the observed range of the clinical activity but well-below doses associated with SAE. GeneTx received some questions from the FDA and responses were provided. We currently expect the study to resume enrollment and dosing in the first half of 2021, following resolution of FDA requests and approval to proceed.

Once we started, we expect additional interim data from the study that are expected in the second half of 2021. We are also in the process of expanding the study to other countries, including Canada, where our clinical trial application was previously filed. A protocol and information amendment similar to that proposed to FDA will be submitted.

Our fourth pivotal program to enter the clinic in 2021 will be the UX143 or setrusumab, a monoclonal antibody for the treatment of osteogenesis in Perfecta or OI through our partnership with Mereo. OI is an extremely serious bone disease, where a defect in collagen results in significant bone fragility leading to stiffness, pain, fractures and deformities. Oftentimes, OI is believed to be a result of weak collagen. But based on our sponsor preclinical work and others research, we now understand that the major cause of bone weakness in OI is due to excess bone absorption triggered by the abnormal collagen and the inadequate production of new bone leading to low bone mass. These data show that if you could simply increase bone formation and reduce the excessive bone absorption, you can increase bone density and improve bone strength, even with the abnormal collagen and achieve improved fracture prevention. We believe this is the insight that could change the future for patients with OI.

Mereo has released Phase 2 data in 90 adult patients with OI, randomized among three different dose levels. The patients were dosed monthly for 12 months. Study results indicated substantial improvements in bone mineral density in OI types 1, 3 and 4, the three types included in the study. This response was dose-dependent and observed across different anatomical sites.

The study also showed an ability to create a significant amount of bone, which we believe is a very important factor in improving bone strength. The safety profile for cetuximab was favorable for patients with OI.

Pending discussions with regulatory agencies, we are planning to enroll a Phase 2/3 study in pediatric patients. The first will identify the optimal dose based on increases in the serum bone formation marker, P1NP, and their role into a randomized control period, looking at fracture rate reduction and bone mineral density over an estimated 15 to 24 months.

While a separate pivotal study also is being planned for adults with OI, we believe the pediatric population will give us the fastest avenue for approval for the product. We currently expect to initiate the pediatric Phase 2/3 in the second half of 2021.

The last program I will briefly summarize is UX053 for glycogen storage disease type 3 and or GSDIII. GSDIII is an inborn error of metabolism caused by mutations in the AGL gene, which is responsible for the production of the glycogen debrancher enzyme.

A deficiency of the debrancher enzyme impairs the breakdown of glycogen in the liver and leads to a toxic residual carbohydrate. Through our license from Arcturus, we have developed an mRNA with a lipid nanoparticle product that is intended to restore the parenteral enzyme function, thereby clearing the accumulated toxic residual carbohydrate and normalizing glycogen metabolism in the liver.

We are currently on track for an IND in the first half of 2021 and to initiate a Phase 1/2 study in the second half of the year.

I'll now turn the call back to Emil to wrap up.

[Emil Kakkis, Chief Executive Officer and President]

Thanks, Camille, Mardi and Erik. 2021 is going to be a full year with lots of important progress across our commercial and clinical programs. The active work in BD has refilled the pipeline with multiple late-stage catalysts with one of the best rare disease portfolios in the business.

In the commercial portfolio, we're looking forward to continue expanding Crysvita in the adult market through greater efforts to find patients and outlying clinics and through pedigree analysis. We're also continuing to expand Crysvita use outside of the US, Latin America, Canada and Turkey.

Dojolvi is off to a strong start, and I know the team will continue to execute launch for patients with LC-FAOD, who are in great and urgent need for a new treatment option. Our commercial Med Affairs teams have adapted very well to launching three products and four diseases in the COVID environment.

Within our gene therapy business, we've broken ground in the manufacturing facility in Bedford, Massachusetts, a three programs going to late-stage clinical trials. We continue to advance our early-stage work in neuromuscular disease of CDKL5 deficiency and Duchenne Muscular Dystrophy.

We're also continuing to improve on the Hela manufacturing technology with the new 3.0 system that will have even higher productivity and reduced COGs, making gene therapy a bio-modality for these larger higher dose indications on a global basis.

Our nucleic acid therapeutics pipeline will also advance. We're making progress in resuming the SOP Phase 1/2 study in Angelman. We plan to initiate clinical enrollment for the mRNA UX053 and Glycogen Storage Disease type 3 or Debrancher deficiency.

With our first mRNA program to come out of our lives with our cures that license also provides rights for up to 12 mRNA and other nucleic acid therapy targets. The GSDIII program is also a great complement to our efforts in GSDIa and builds on our broader portfolio of therapies aimed at inborn errors of metabolism that have not been treated by more traditional means.

The addition of setrusumab gives us a de-risk late-stage -- will leverage our expertise in creating clinical loan pathways for rare genetic bone diseases. As you can see, we're in a great moment in our evolution of the company with multiple late-stage assets across therapeutic areas and modalities, all enabled by continued strong financial performance from our approved programs, strategic investing, and diligence.

Now, let's move on to your questions. Operator, please provide the instructions for the Q&A portion of the call.

[Operator]

Thank you sir. [Operator Instructions] Your first question comes from the line of Maury Raycroft from Jefferies. Your line is open.

[Emil Kakkis, Chief Executive Officer and President]

Hello Maury. Are you there Maury? Well, that’s a very good question. We are doing great and thank you for asking. Maury, you may on mute. Operator, why don’t we go onto the next caller until Maury gets his communications fixed.

[Operator]

Yes sir. Your next question comes from the line of Yaron Werber from Cowen. Your line is open.

[Yaron Werber, Cowen]

Hey good afternoon. Thanks for taking my question. So, Emil, I got maybe the first question, the pipeline is now -- looks really good, right? I mean you've essentially two drugs going into pivotal, another one potentially into a Phase II/III. I mean it's fairly full. Do you have more room for BD? Are you still looking? Or you're sort of good for the next year?

And then, Mardi, I don't know if you can give us any sense. How do we model the Daiichi-related revenues? Do you have visibility that you could share with us? Thank you.

[Emil Kakkis, Chief Executive Officer and President]

Great. Yaron, I think -- if you look at our portfolio, we tend to target having five to seven clinical stage programs. And right now, we would have six with what we're doing. So, we're in a relatively full state in terms of development stage programs.

We are still continuing to be because we always continue to look. If there were something amazing, we wouldn't want to walk past it. We would look for that opportunity. But we are -- potentially, have ability to leverage our commercial organization with a later stage opportunity. But I do believe from an earlier development stage opportunities, we're very full and we've been at loss and we've got a lot of work to do, and I'm excited about the portfolio. I don't think you can imagine being in a better place than what we've been able to put together over the last couple of years.

So, Mardi, maybe you can answer the other question.

[Mardi Dier, Chief Financial Officer]

Yes. Real simply, Yaron with Daiichi, of course, the deal that we completed back in March was for $200 million upfront. From an accounting purpose, we have this non-cash revenue recognition that we believe is associated with the tech transfer of the deal. So, there's about $60 million plus left on that recognition of revenue and that should be completed in 2021. So that should be a pretty specific way to model it in 2021.

[Yaron Werber, Cowen]

Great. Thank you.

[Operator]

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

[Gena Wang, Barclays]

Thank you for taking my questions. I have two questions. One is regarding the Angelman syndrome. It seems that, if they already give you feedback, and Emil, just wondering if you can give a little bit more color regarding the amendment to the protocol. Is there any additional change versus your original submission regarding the protocol amendment?

And my second question is regarding the dosing change. You used ddPCR for the GSDI pivotal study and it changed the dose from 6e12 to 1e13. Just wondering, do you need to do similar change for the OTC program? And will you use ddPCR across all the future programs so that the dosing will be more accurate going forward?

[Emil Kakkis, Chief Executive Officer and President]

Sure. Great. So, on the Angelman, we gave them this very large substantial amendment. They provided them a response with some specific questions, additional information, inquiry that they were interested in. They -- those questions did not change the plan we had proposed. We listened to what they put together and provided now an amendment to the protocol and IV et cetera, and all the things required in order to proceed ahead. So we'll wait and see their response to that. But the questions didn't really change our plan. They were basically in line.

I think, our plan is pretty well thought out. I don't think that there is -- I think there's not much you could do to change it, but we'll wait and see for their feedback or maybe settle ways to manage it. And they want to assure safety just like we do and we're happy to work with them to get that done. But we feel comfortable, we're going to get back into treating these patients and the patients have been inquiry, they really want to get back to treatment. So we're -- we want to get back to it. I think we're in good shape for that, and we'll see what they say.

On the GSDI story, we're not really changing the dose. What we're doing is changing how we're measuring the dose. So, what -- it's a real important the total dose effect we're giving the same as it was before. It's just what we're calling it has changed. And what's happened is the original acute PCR methods have some limitations and variability in them. They're not as good, and we've been working on the digital drop method, which is higher more reproducible, more validatable and therefore, a more accurate representation.

And what it turned out for GSD1a is that, we were really the amount of vector we're giving, which we considered 6e12 before was actually closer to e13 when you use a more accurate digital drop method. And it just relates to the techniques and the biases of certain techniques.

For the OTC program, there is also a difference, and we are using the digital drop. But would it be clear to everyone is that, the dose is the same as it was. It's just what we're labeling the dose as based on a more accurate method. And this is one of the things I think the FDA has been on and we all want is to continue to improve the quality of the methods, to give us accurate representations of how many of these particles are alive and well in the vector product that we can use for gene therapy. So practically speaking, it doesn't change anything. But from a standpoint of the quality of the process, it helps give the FDA and ourselves confidence on what we're administering every lot.

[Gena Wang, Barclays]

Great. Thank you.

[Operator]

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

[Cory Kasimov, JPMorgan]

Hey, good afternoon guys. Thanks for taking the questions. First one on Angelman, assuming you do, in fact, get that study up and running in the first half of the year as you're expecting. How quickly do you think, you'll know whether the amended dosing and administration plan is working and avoiding the SAEs you saw originally? And then I have one follow-up on Wilsons.

[Emil Kakkis, Chief Executive Officer and President]

Well, the way the protocol is proposed that we will redose the existing patients, the five patients, and we'll also enroll another 12 patients in a staged manner and look at basically 4 doses and then they'll go into a maintenance every 3 months. So by the time we get through 4 months of dosing with these patients in the both 5 and the additional 12, that will give us a sense of are we getting efficacy we thought after accumulating the effect over multiple doses at a lower level? And are we seeing safety?

So we'd expect to get to that story later in the year because it takes about 4 months for each patient enrolled to get through the dosing. So we can get through 4 doses and show the same substantial efficacy we saw before and not have the safety then that helps improve it.

Once they go on to maintenance where they're going every 3-month dosing, I think we feel a little more comfortable that the safety will be better. The problem we had was only during the monthly phase. So if we can get through the monthly phase, go on to maintenance dosing and are good through the monthly phase and get the efficacy we're hoping for, then I think we'll know and it should happen later this year.

[Cory Kasimov, JPMorgan]

Okay. That's very helpful. And then for your seamless Phase I/II/III for Wilsons, what's the process in terms of making go/no-go decisions here to move to the next stage in this particular type of design? Is it -- should we think of it just as a truncated study across all three typical phases? Or is there something else that goes into it?

[Emil Kakkis, Chief Executive Officer and President]

Well, there's 2 stages. In Stage 1, we're going to dose a placebo and drug in three cohorts, a first dose cohort, 5e12, e13, 2e13, all right? So it's going to be a sequence of patients through three cohorts. During this period, there will be an interim assessment, a blinded interim assessment to show whether the -- what the dose is looking like and what's happening, and we'll make a decision on dose after those three cohorts.

At that point, we would know in a blinded fashion in group that we are seeing in efficacy on safety that's appropriate, and we'll pick the dose to move forward. So we'd expect somewhere in there to have some data that we would put out that would not -- but we want to make sure not to harm the conduct of the study, but we'll put out some information about where we stand and that we've crossed from the dosing stage into the pivotal stage. Is that helpful?

[Cory Kasimov, JPMorgan]

Yes, definitely. Thanks Emil. Appreciate it.

[Operator]

Your next question comes from the line of Joon Lee from Truist Securities. You may ask your question.

[Joon Lee, Truist Securities]

Hi, thanks for taking my question. So Emil, can you affirm that the FDA was generally in agreement that trendelenburg and lower dosing would be sufficient to avoid the SAEs? Or did they want something entirely different? And then secondly, what if any lease is there from the failure of OV101 and Angelman? Is placebo effect possibly an issue when using CTI IS? Just curious if there's anything that could be learned from that study to apply to your study? Thank you.

[Emil Kakkis, Chief Executive Officer and President]

Sure. Well, The FDA did not question trendelenburg and flush the procedures because actually they've been used widely. And I think we provided the justification of that because it's been done by the way in chemotherapy for years, years, not like we made this up. It's been well established to reduce local toxicity in chemotherapy drugs. So it's not like we're -- something that's never been done before.

So there wasn't really a question about that. It was more about what the event is and what's going on kind of thing. Just -- they just want confidence around that we can make the right interpretation of what's happening and our interpretation of it being a local inflammatory event. And those required, let's just more detailed information about the MRIs and other things so they can kind of understand what we understand.

So there was no question about the strategy on lower dosing, capping and the other changes at this point. So we feel pretty good about where we're at. I do think we're making the right choices, and I think there's a good basis for our changes to be beneficial.

Now with regard to OV101, I don't think it has too much read through it. If it was, of course, an approved product during our Phase 3, it would probably create more complexity for how we're managing patients on it or not on it. With regard to CGI and its value, I appreciate the fact that our five patients were open label. The magnitude of the effect that we're seeing is not 0.7 points, remember the average for the five patient was 2.4 points. So the degree of efficacy changes far larger than you might see from placebo, if that was placebo effect.

So in addition to that, there were multiple other evaluations in the trial that supported the communication changes and other changes observed, including sleep and other things, including mobility. So it wasn't just CGI. It was actually a whole host of secondary, the valuations also supporting the change. So that's why we know this is real, and we know it's profound. And we were -- we think it's something could be quite important for these patients.

We know, by the way, that with the time is passing, of course, the patients have effect lasted maybe four, five months in many of the symptoms. But as the time it's passed, of course, patients have lost some ground and are anxious to get started again. So in our case, I'm 100% confident this is not placebo effect. We have too much data to support it. And, of course, the magnitude effects just beyond what you would assume to be part of a placebo effect.

[Joon Lee, Truist Securities]

And just quickly following up on the Angelman's. You know, you have not created a target for yourself. There's companies pursuing the exact same approach, start to stop. What kind of node do you have around your product that could protect -- keep your franchise [ph] well better?

[Emil Kakkis, Chief Executive Officer and President]

Well, I think you've got a target make, the first thing you've got to run fast. So they're hard to hit. But that's, sort of, the -- but truthful too. I think our ability to execute is going to be real important. The truth is if you want to -- as a company, we will work on some larger rare disease areas. But when we do, it's not going to be all alone like some other ones, like OTC, GSDI, GSDIII, it's more comfortable. We're really pretty much the only clinical play.

It will be there, but here's the thing about the whole program. The reason we picked this Angelman program, the work GeneTx had done is that we have the data that we were looking at, that they produced in vitro and others, all the works done day to day. We said, what they're doing and the region they're targeting is far more potent, able to knockdown all the antisense transcripts than what other people are doing. And we felt there was a distinct intellectual property, scientific insight improvement.

The other methods trying to do, what we're doing is actually very hard. I do think the ASO method will be better and that gene therapy will be hard to replicate because you cannot deliver every neuron evenly, and you can't have variations of expression of this thing. They're too high.

So it's going to be a lot trickier to deal with this on a gene therapy basis than an ASO basis because with ASO, we enabled the gene to be expressed, but we don't force it to be expressed. It allows an endogenous regulatory maxes than to even out amount of this EB-3A protein.

So maybe a little bit of scientific detail. What I'm saying to you, there is a very strong basis for why this is going to allow you to get more neurons active and allow them to be regulated properly. And I think that's why we believe ASO was the best method among those. And among the ASO methods, we have the best targeted region, and that's our confidence in what we're doing. At the same time, we're going to run fast.

[Joon Lee, Truist Securities]

Thank you.

[Operator]

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

[Yigal Nochomovitz, Citigroup]

Hi, Erik. Hi, Emil. Thank you for taking the question. So could you provide a bit of perspective on Ultragenyx strategy to differentiate cetuximab profile from burosumab given, as you know, both antibodies target Sclerostin. And in light of the fact that Amgen is also pursuing osteogenesis imperfecta with romo in a Phase I that was recently posted on clinical trials?

And then secondarily, if you could comment on the advantages of targeting Sclerostin as opposed to RANKL or TGF-beta for osteogenesis imperfecta. Given as you know that Amgen is pursuing OI Phase III and OI with Prolia and Sanofi is pursuing OI with LENUMAB in Phase I. Thanks.

[Emil Kakkis, Chief Executive Officer and President]

Good. Thank you. This sounds like another variation of target on our back question. But -- so look, we're very familiar with romo. And in fact, Michael Minsky that works with us, worked for Amgen for 10 years on romo and has a lot of knowledge. It's a good anti-flu antibody. Its main commercial potential for Amgen has been around osteoporosis.

As part of their development program, they are required to do a pediatric investigational plan for Europe, which requires them to run the study. So they are running a study. What they will do with that in the long run is unclear. But the idea that the PIP is just they have to try to test their products in that population, but they're not focused on that population.

We're going to look at the dosing and dose regimen uniquely to apply to OI. And we think the dosing may need to be higher, and it's in pediatrics. And they're doing therapy for one year, whereas I think we will need to do more chronic or have at least an induction in the mines phase, which is not part of their program. So our folks on OI will allow us to adapt the dosing and regimen to optimize for the OI indication. That said, could people use romo off-label and will we have to deal with that commercially? And I say, yes, we will. We'll still have to deal with it.

But OI is a lot of patients and a lot different types that can be benefited. And we think somewhere in there with the dosing and other issues that there's a very important product that we could achieve regardless of what the pricing issues play out.

The second point you asked about is the other competing molecules, I think Sclerostin has some unique features that are particularly good. If you look at OI, the patients have too much re-absorption, but they also have inadequate bone anabolism. So you definitely want a strong anabolic agent. And we think Sclerostin appears to be a very strong anabolic agent. And in the animal model of OI is very potent at inducing good bone formation that results in strong bones that resist fracture.

So we think that the focus on anabolism with some effect on re-absorption, I think is probably valuable, especially in the context of bisphosphonate. Certainly, TGF-betas, Sanofi is working on is another strategy. It's another hormone involved in bone regulation. I don't have a lot to say right now. It could be effective. We'll have to keep our eye on what they're doing. RANK Ligand or bases of denosumab is what I assume you're talking about.

It's another approach, but it's a little different. It's related more to the re-absorption. I just think -- we think based on what we're seeing is Sclerostin is best. And I will also say Sclerostin may be the first step and maybe they would need to ultimately as a second-generation version to add another molecule like a combination to optimize.

But given the size of OI and our particular expertise in running bone development, I have confidence we can push forward a good product that will make a real big difference for OI patients.

[Yigal Nochomovitz, Citigroup]

Thank you. Super helpful. Thank you, Emil.

[Operator]

Your next question comes from the line of Salveen Richter from Goldman Sachs. Your line is open.

[Emil Kakkis, Chief Executive Officer and President]

Hello. Is that Salveen?

[Operator]

The question has been returned, sir. Your next question comes from the line of Liisa Bayko from Evercore ISI. Your line is open.

[Liisa Bayko, Evercore ISI]

Hi, there. Thanks for taking the question. For DTX401 for GSDIa, are you going to be enrolling patients in Phase 3 from all the different kind of mutation types? And should we expect similar efficacy across those? Thanks.

[Emil Kakkis, Chief Executive Officer and President]

We are not restricting to a particular mutation. But remember in GSDIa, about 80% of the patients are null. So it's probably as homogeneous phenotype of null expression as you can get. And so we feel pretty comfortable that even if there is some, let's say, lesser mutation, patients with less effect -- less -- sorry, deficiency that we would expect the effect to be as good or better because if we most of the patients we've been treating have been all nulls. So if we can treat the nulls effectively, then treating the missense one should be easier, not harder, right? So we feel pretty confident we can treat. We can treat all of them based on how many nulls we've already treated.

[Liisa Bayko, Evercore ISI]

Okay. Thanks.

[Operator]

Your next question comes from the line of Jeff Hung from Morgan Stanley. You may ask your question.

[Jeff Hung, Morgan Stanley]

Thanks for taking the questions. For UX701, you went through the plans for the single-protocol Phase 1/2/3. So going forward, do you see this as a standard way you'll be conducting studies for other gene therapies? Or was there something specific for this program that allows for the single-protocol study design?

[Emil Kakkis, Chief Executive Officer and President]

There are some factors that make single-protocol design possible. And one of the key ones, Jeff, is endpoints, like primary endpoint. In the Wilson case, because there's all these approved products, we know and the FDA has already agreed that urinary copper execution can -- 24-hour urinary copper excretion can be the primary endpoint. With the primary endpoint defined, then you can design an entire program straight through. If you don't have a primary endpoint defined, it's a little in hard to try to define a Phase 1/2/3 without having analyzed and configure the right inclusion criteria for the next stage. Does that make sense? So, it really has to do with what your level of confidence in the endpoint.

Now for Duchenne, where there is knowledge of the endpoints, then for example, that's one where a Phase 1/2/3 may be possible because those standpoints have been developed. For CDKL5 is the neurologic disorder is a little bit different. We're creating new endpoints. That's something where it may be a little harder to do a straight-through program. In any case, you could design it any way you like separate or together. The key advantage of making it one continuous one is that you don't have to go through a regulatory query step in the middle, right? That's the thing that preparing the data, submitting, getting the meeting you burn up 8 months, sometimes almost a year of time in there, and that's the savings. So wherever we can get confidence from the agency upfront on endpoints and design, then we can try to take that rapid path.

[Jeff Hung, Morgan Stanley]

Great. And then for Crysvita, you talked about the focus on finding adult patients. But what's the current proportion of treated patients that are pediatric? I think in the past, you mentioned it's about 60%. Just curious if that's changed much over time? Thanks.

[Emil Kakkis, Chief Executive Officer and President]

Yes. From the new patients, I don't know, Erik, do you want to add anything to that? But basically, it's been shifting more toward adult in terms of the fraction of current prescriptions.

[Erik Harris, Chief Commercial Officer]

The last time we reported out on this, the mix was about 55% to 45%. 55% peds versus 45% adults. We've continued to see the overall shift toward -- more heavily toward adult patients. And in the last couple of quarters, we've been finding more adult patients than pediatric patients. So we expect that to continue to shift more heavily.

[Jeff Hung, Morgan Stanley]

Great. Thank you.

[Operator]

Your next question comes from the line of Laura Chico from Wedbush Securities. You may ask your question.

[Laura Chico, Wedbush Securities]

Thank you very much, and good afternoon. So just following up on the Crysvita co-promote. So I know it's probably looking a bit ahead, but the co-promotion is set to change in 2023? And you just mentioned kind of the mix between the pediatric and the adult patients. I'm just curious as we're kind of entering the second part of this agreement. Is the focus on shifting towards adults, the theme to be thinking about as one of the key drivers to maximize the remaining trajectory? Or are there other, I guess, just strategic initiatives we should be thinking about?

And then just one quick follow-up with regards to 810 in DMD. I guess following a competitor update from a gene therapy study, I'm wondering if you could maybe opine a little bit on how you're thinking about alternative biomarkers in the DMD space? Thank you.

[Emil Kakkis, Chief Executive Officer and President]

Good, thank you Laura. So with regard to Crysvita, we still have room to penetrate both the peds and the adult market. We're not finished in that process. So -- but we have got to about 30% of the peds. So we continue to work on growing the peds market as well as the adult. It's just that the adult market, the unmet need there is probably a larger number of patients right now, right? And they're a little more lost, a little harder to find. So we are making a big effort. I don't know that it has a great deal to do with the transition. It's just mainly about optimizing the growth of the product ahead of it. So it really is more about where we see the most opportunity. I don't know if, Erik, you had anything else to add to that?

[Erik Harris, Chief Commercial Officer]

The only thing I would add to that is that it certainly is one of our top priorities in finding the adult patients. And we've shifted resources to do just that from both digital and virtual. But as well as I stated, we have plans to expand both the commercial and medical field teams to be able to target more physicians in the community setting where most of the adult patients are, so to take advantage of that opportunity.

[Emil Kakkis, Chief Executive Officer and President]

Yes. And I think one of the thing we're doing is because each pediatric patient on drug likely has three or four adults that are related to them on average, using the pedigree enough to help find relative across countries is important. The other thing that's happening in adults is that we're getting a lot more feedback of adults on treatment and how they're doing, and there's a lot more recognition with adults. There are many adults that need to be treated, and I think that's going to help. But if you look at the total number of patients that we could treat, the adult population is, I think, still an area where there's a lot more patients for us to transition. So it's all about optimizing the growth of the product but adults and peds both matter.

And we're working with our partner KHK and planning transition. But remember, after the transition, of course, we continue with the same essential revenue. If you look at the revenue post. It's just we're not doing the commercial as much, but we will be doing promotion of medical genetics after the transition. So we will have a role in promotion for the product in at least one segment of doctors.

Let's talk about the other – the biomarker story. So the question, it sounds like you were asking about is, whether any outcome data from – after others would suggest that we should – how do we look at the biomarkers for proving efficacy. And I think the challenge here is that, measuring to stroke and then doing it accurately and knowing how it means is tricky. And I think there's a lot of good methods and I do think we're going to want to look carefully at the methods, because I do think they will have an impact on the – on the impression of what you're achieving. I do think, though, that there is another factor, which is how do markers translate really into clinical benefit, which I think is partly at the question.

And what we are familiar with muscles disease will help. But the truth is that even, if you deliver the compound, engaging it into the muscle and integrating it and having an effect on clinical function takes time. And in addition, with generally in muscle, once you've lost function, have just not seen treatments that bring back function. It's almost always about maintaining and not losing. And I think that maybe a mindset we have to think about. And that's where treating early before they've lost function is probably going to be important. So we're going to look at the quality of the biomarkers and ensure that we're doing things that we think are validatable. But I guarantee is all coming in are [Technical Difficulty]

[Camille Bedrosian, Chief Medical Officer]

Emil, we’re having a little bit of audio problem coming from your phone.

[Emil Kakkis, Chief Executive Officer and President]

You can hear me now, all right?

[Camille Bedrosian, Chief Medical Officer]

Yes.

[Emil Kakkis, Chief Executive Officer and President]

Okay. I think there may be a problem my phone maybe getting hot from the sun. The company is hot too, but anyways, good questions.

[Laura Chico, Wedbush Securities]

Thank you, Emil.

[Operator]

[Operator Instructions] Your last question comes from the line of Maury Raycroft from Jefferies. Your line is open.

[Maury Raycroft, Jefferies]

Hi, everyone. Thanks for taking my questions. So I just wanted to check in on Dojolvi, it seems like it's off to a really good start. And I'm guessing, you're not going to say too much more on traction with newborn patients and naive use. But I'm wondering if you can provide any specifics around progress in screening and getting uptake in these patients?

[Emil Kakkis, Chief Executive Officer and President]

Yeah. Well, there's – we haven't – we don't have any more to report in newborns. There are some newborns that have prescribed, and we also have had some emergency cases still happening that we've had to respond to quickly without reimbursement process being a whole separate story. So we've been doing some of that already, and that continues. I don't really have any more specific about uptake in the newborn I think we need to continue to make sure that policies allow patients to newborns to be treated. But what I would say to you is that patient and once patient we treated, we will treat them, whether reimbursement comes through or not, we'll treat the babies and work for the reimbursement process whenever it can be worked. But remember, in this situation, you don't have time for – we're talking about babies, especially if they have symptoms, they got to be taken care of and you don't have time for the process. And so we're very comfortable with providing free drug acids immediately to patients and then handling the reimbursement process over time. I don't know, Erik, if there's anything else you could provide on the issue of newborns.

[Erik Harris, Chief Commercial Officer]

I would say is that our Ultragenyx hub has been very responsive with those requests for newborns, where we've been able to get product to these newborns is certainly under 24 hours, as early as six hours in some emergency cases. So we're set up to address this need for such a fatal disease, life-threatening disease for these newborns.

[Mary Raycroft]

Yes, that's helpful. And last question is just on UX053. Just wondering, if you can provide any more perspective on what the study would look like, the types of patients you plan on enrolling? And could we potentially see data from now and by the end of 2021?

[Emil Kakkis, Chief Executive Officer and President]

Yes. We would expect that we may have some data at the end of the year. Maybe, Camille, can you provide early – just a brief nugget on the study? I'm sure it'll come up with clinicaltrials.gov in more in detail.

[Camille Bedrosian, Chief Medical Officer]

Yes. It will. It will. Thank you for the question. Thank you, Emil. Yes, the study is first and foremost, the safety study, first out, also looking at and identifying the dose, dose finding followed by dose ranging and we'll have a randomized cohorts of patients, placebo and the drug. And in addition, there'll be multiple doses in the second round of cohorts for the patients. There'll be patients with GSDIII, regardless of mutation, and we'll start initially with adults, followed by pediatric patients.

[Mary Raycroft]

Got it. Very good. Thank you for taking my questions.

[Camille Bedrosian, Chief Medical Officer]

Sure. Thank you.

[Operator]

And I am showing no further question at this time. I would now like to turn the conference back to Mr. Joshua Higa.

[Joshua Higa, Director, Investor Relations]

Thank you. This concludes today's call. If there are additional questions, please contact us by phone or at [e-mail]. Thank you.

[Operator]

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation, and have a wonderful day. You may all disconnect.