Good afternoon, and welcome to the Ultragenyx Second Quarter 2024 Financial Results Conference Call. At this time, all participants are in a listen-only mode. At the end of the prepared remarks, you will have opportunity to ask questions during the question-and-answer portion of the call. [Audio Gap] Vice President of Investor Relations.

Please go ahead..

Thank you. We have issued a press release detailing our financial results, which you can find on our website at ultragenyx.com. Joining me on this call are Emil Kakkis, Chief Executive Officer and President, Erik Harris, Chief Commercial Officer; Howard Horn, Chief Financial Officer; and Eric Crombez, Chief Medical Officer.

I'd like to remind everyone that during today's call, we will be making forward-looking statements. These statements are subject to certain risks and uncertainties and our actual results may differ materially. Please refer to the risk factors discussed in our latest SEC filings. I'll now turn the call over to Emil..

Thanks Josh, and good afternoon, everyone. We've had an incredible first half of the year and look forward to sharing more with you today. On the commercial front, our strong revenue performance puts us on the trajectory to outperform our prior projections and so we're raising our total revenue guidance range.

We're happy with what this means for access to our drugs globally and Eric and Howard can share more on the revenue details. Within our clinical pipeline we have meaningfully advanced our late-stage programs through multiple positive data readouts and successful and critically important regulatory interactions.

On the data front in addition to the positive results we shared earlier this year on both UX-111 in Sanfilippo syndrome and GTX-102 in Angelman syndrome, we recently announced positive Phase III results from the DTX401 gene therapy for the treatment of patients with glycosidase Type 1a and additional long-term positive Phase II results from the UX143 antibody for the treatment of patients with Osteogenesis Imperfecta.

For GTX102 for Angelman syndrome, we announced the successful completion of an end of Phase II meeting with the FDA where we align on Phase III study design and key endpoints to be evaluated. Our teams have been working with our study sites to initiate our global Phase III study by the end of this year.

On UX-111 for Angelman syndrome Type A we also reached agreement with FDA on a path forward to seek accelerated approval. The FDA has agreed to cerebral spinal fluid heparan sulfate is a reasonable surrogate endpoint to support submission of a BLA supported by our clinical data to date.

Our next step is to finalize the details of our submission with the agency in a pre-BLA meeting and we intend to submit this BLA later this year or early next. Selectively this puts us in a position to have; multiple regulatory marketing submissions and key clinical data readouts over the next six to 18 months, which is extraordinary.

I spent my career developing therapies in rare disease and I can tell you I've never seen a rare disease company with the breadth and depth of opportunities we have ahead of us, nor with our ability to move all these things forward.

These achievements are a direct result of our excellent execution across the company from our committed employees and our best-in-class approach to rare fees drug development. It's a very exciting time for Ultragenyx.

I'll now turn the call over to our Chief Commercial Officer, Erik Harris to provide an update on the momentum across our commercial portfolio that has led us to raise our total revenue guidance for the year..

Thank you, Emil, and good afternoon, everyone. I'll start with Crysvita's performance in the United States. The demand for Crysvita in the US remained strong in Q2 2024. Approximately 60% of the stock forms came from adult patients and were prescribed by community physicians with over 40 new prescribers in the quarter.

This is encouraging, given adult penetration is in the low 20s and implies Crysvita has ample room to continue growing. We are confident in our full year U.S. revenue projections given the strength of the underlying demand.

Shifting to Crysvita in Latin America where we lead commercialization, our LatAm team delivered another successful quarter by adding approximately 60 new patients to Crysvita, totaling over 620 patients on reimbursed therapy since launch. Brazil is the largest market in Latin America and continues to drive the majority of revenue in the region.

That said, we are beginning to see more meaningful contributions from countries like Argentina and Mexico supported by the underlying patient demand.

As I mentioned on previous earnings calls, we expect quarter-to-quarter variability in LatAm revenue, due to uneven ordering patterns, but remain confident in the underlying demand growth for our products. Moving on to Dojolvi. Growth of new start forms remained strong.

In the US, we added approximately 30 start forms and 30 patients on reimbursed therapy, resulting in approximately 520 reimbursed patients since launch. The split between pediatric and adult patients continues to be approximately 65% peds and 35% adults.

The number of new prescribers continue to grow, adding approximately 10 new prescribers in Q2 2024 with half of them writing more than one prescription. For Dojolvi across Europe and the MENA region, revenue is currently driven by named patient sales request. There are approximately 215 patients treated under MPS across 12 countries in the region.

The majority of demand is from France, but we are receiving an increasing number of requests from other countries within the EMEA region, including the Middle East. As I have said before, 2024 is an important launch year for Evkeeza.

And in the EMEA region, we added approximately 60 new patients in the second quarter who are being treated through MPS and regular reimbursement processes, where we have approval. In Japan, the launch is starting, but has already gained meaningful contribution following regulatory approval in January and pricing and reimbursement approval in April.

The team there has done an excellent job to map and identify a majority of patients in the country and has processed 35 stock forms through the second quarter of 2024. In our territories, we continue to receive positive feedback from the HOFH physician and patient communities and they are all very excited to have Evkeeza as a treatment option.

We expect demand for Evkeeza to continue growing as we bring this important therapy to patients with HOFH. Overall, Q2 2024 was a strong quarter for Ultragenyx. As expected, the second quarter bounced off the first quarter seasonality leading to $147 million in total revenue.

The broad strength across the commercial portfolio through the first six months of the year put us on a trajectory that gives us confidence we will exceed the guidance range that we established at the beginning of the year.

With that, I'll turn the call to Howard to share more details on our financial results for the quarter and guidance for the year..

Thanks, Erik and good afternoon everyone. I'll start by briefly summarizing our financials that were reported in our press release earlier today. As Erik noted, we reported $147 million in total revenue for the second quarter of 2024.

Crysvita contributed $114 million, including $67 million from North America, $40 million from Latin America and Turkey and $6 million from Europe. Dojolvi revenue in the second quarter was $19 million, Evkeeza revenue in the second quarter was $8 million and Mepsevii revenue in the second quarter was $6 million.

Our total operating expenses in the second quarter were $263 million, which included R&D expenses of $162 million, SG&A expenses of $81 million and cost of sales of $21 million. Operating expenses included noncash stock-based compensation of $39 million. In the second quarter, net loss was $132 million or $1.52 per share.

As of June 30, 2024, we had $874 million in cash, cash equivalents and marketable securities, which included net proceeds of $381 million from our offering in June. Net cash used in operations was $77 million for the second quarter and was $268 million in total for the first half of the year.

As we discussed on our May call, there is seasonality in the first quarter because it includes items like the payment of annual bonuses. Our guidance for 2024 net cash used in operations remains unchanged and is expected to be less than $400 million for the year.

Shifting to revenue guidance, we are increasing our range for total revenue, which is now expected to be between $530 million and $550 million for the year. This reflects strong performance and trajectory across all of our products, including Crysvita globally and the launch of Evkeeza in our territories. Accordingly.

we are targeting Crysvita revenue to be towards the upper end of our existing range of $375 million to $400 million, which includes all regions and all forms of Crysvita revenue to Ultragenyx. Specifically, it includes Crysvita product revenue from Latin America and Turkey, and cash and non-cash royalties from North America and Europe.

We continue to expect the Dojolvi revenue to be between $75 million and $80 million. With that, I'll turn the call to our CMO, Eric Crombez..

Thank you, Howard, and good afternoon everyone. The first half of this year has seen a number of important clinical catalysts for UX-111 for the treatment of MPS IIIA. We announced data demonstrating clinically significant reductions in heparan sulfate that correlated with improved long-term cognitive function.

This was followed up with our announcement in June that we reached agreement with the FDA that CSF heparin sulfate can be used as a surge endpoint for accelerated approval. We expect to finalize details of our filing package in a pre-BLA meeting later this year with the goal of filing the BLA around the end of 2024.

For DTX401 for the treatment of GSDIa, we announced positive top line data from the Phase III study that showed that treatment with DTX401 resulted in a statistically significant reduction in daily cornstarch at week 48 with maintenance of strong glucose control.

Results from this study will be discussed with regulatory authorities in a pre-BLA meeting in the second half of 2024.

For UX143, for the treatment of Osteogenesis Imperfecta, we announced 14-month data from the Phase II portion of Orbit that showed treatment with setrusumab resulted in a sustained 67% reduction in annual in fracture rate and persistent median annualized fracture rate of zero.

There were also continued substantial improvements in bone mineral density with a mean increase from baseline of 22% and a mean improvement in Z score of 1.25.

For GTX-102 for the treatment of Angelman syndrome in April, we shared additional Phase I/II data from the expansion cohorts that showed rapid and clinically meaningful improvements across multiple domains. These improvements were consistent or exceeding those of the dose escalation cohorts data at day 170.

We also shared that additional long-term data in dose escalation cohorts showed increasing and sustained clinical benefit through day 758. There's been a lot of news flow in the space recently and we feel very good about the ability of GTX-102 to improve the lives of patients affected by this disorder.

We continue to see the patients in the Phase II portion of the study developing new skills across multiple domains with no new serious adverse events, and we believe we are in a strong position as we advance Phase III start-up activities.

Last month we completed a successful end of Phase II meeting with the FDA, where we aligned on the design for a global 48-week blinded randomized sham-controlled Phase III study. We expect to enroll approximately 120 patients between four and 17 years of age who have a full UBE3A deletion.

The primary endpoint will be improvement in cognition assessed by Bayley-4 cognition raw score. The study will also include a key secondary endpoint of a multi-domain responder index evaluating cognition, receptive communication, behavior, gross motor and sleep.

Individual secondary endpoints were also discussed and aligned on with the FDA for the domains of communication, behavior, motor function and sleep. Phase III study start-up activities have been ongoing for some time. And now with FDA alignment we are focused on initiating the study by year-end.

The ongoing Phase II study includes 25 phase across eight countries, which allowed us to respond to the significant global demand to participate in the study and for these types to gain experience with GTX-102.

With startup activities already in progress and alignment with FDA and design, we are on track to begin enrollment of our Phase III study by the end of this year.

While this initial Phase 3 study will focus on patients with full deletions who represent the majority of patients with Angelman syndrome, we are also planning to initiate an open-label study to evaluate GTX-102 for the treatment of patients with other genotype and in other age groups in 2025.

We expect to enroll both studies in parallel and plan to include both sets of data in a future BLA application. I'll now turn the call back to Emil to provide some closing remarks..

Thank you, Eric. In the first part of the year, we made significant progress advancing our clinical pipeline and we performed well globally on the commercialization of four products. I'll close quickly by summarizing our key clinical catalysts for the rest of the year.

For GTX-102 for Angelman syndrome, we're working to initiate the Phase 3 study by the end of the year and over time plan to share updates on how the Phase 2 patients are doing as they continue receiving maintenance doses.

Our long-term data is far superior to any other data presented on ASOs for Angelman to-date and this puts us in excellent position for the future of that program. For the Phase 3 portion of the UX143 Orbit study, there are two interim analyses planned was the first anticipated by year-end or early 2025.

The first analysis will have a stringent threshold of p value less than or equal to 0.001. If the threshold is not met, a second interim analysis will occur a few months later followed by a final Angelman study at 18 months.

The first interim analysis will not be reported to the company by the Data Monitoring Committee unless the data have met this very stringent threshold and it's important for study integrity to run these analysis very carefully and rigorously.

In the event of an interim analysis clears the threshold, we would share that outcome but top line results would not be announced immediately as the study would require patients to complete their final visits over a couple of months and then there's time to collect and prepare the data for a formal analysis.

For UX701 for Wilson disease, we expect to share Stage 1 data in the second half of the year. In the dose finding stage of data readout, we'll be prompted once the last patient with Cohort three as Angelman [ph] therapy for six months or more followed by some additional time to collect and analyze all of the data.

All of these are very exciting catalysts and while the teams are executing on these clinical programs we will also be working on two BLA submissions one for UX-111 for Sanfilippo syndrome, which is expected around the end of the year; and the other for DTX401 for glycogen storage disease type 1a which is expected in 2025.

Ultragenyx is at an incredible inflection point. Over the next 12 to 18 months we expect to have filed two BLAs provide Phase 3 data new UX143 and should be well on our way with the GTX-102 Phase 3 study, all the while we are generating meaningful revenue growth is now expected to be between $530 million and $550 million this year.

With that, let's move on to your questions. Operator, please provide the Q&A instructions..

Thank you very much, sir. [Operator Instructions] The first question that we have comes from Gena Wang of Barclays. Please go ahead..

Angelman syndrome data update. We also saw quite a few other data update from both Ionis and Roche.

Maybe what is your latest thoughts regarding the competitive landscape and the read-through to your trial design especially if we're looking at the loading dose frequency and also, the endpoints such as expressive communication for Bayley?.

Emil was your line muted? We can't hear you. All right. It looks like we're having maybe a little bit of technical difficulty and we've lost Emil's line.

Eric, are you able to help out with that question?.

Yes. Thanks and certainly we've been following along the important data updates that were released around the time of ASF. So certainly, feel very good about where we stand looking more closely at the data both from Roche and importantly from Ionis.

We – as we've mentioned, we had a very successful end of Phase II meeting with the FDA and we really have locked in our plans for Phase III as we're looking forward to first patient by end of year.

We have done some thought on loading dose and reducing from four to three loading doses, which also gives us the ability to increase our dose and drive to higher doses in a shorter period and really get to a data readout for that Phase III under one year of time.

Again, looking across all of the important domains, we've been talking about collectively in the MDRI and individually as secondary endpoints, we're seeing great movement across all of those domains.

We are moving forward with cognition raw scores for our primary endpoint but certainly looking at expressive communication as an important secondary endpoint.

Hello I'm back..

Eric took care of the call.

Gena are there any follow-up there that you had for Emil?.

Sure. Yes.

So maybe regarding the Wilson data in second half this year maybe how many more patients and what kind of data do you on biomarker you wish you with that?.

Well, there is a total of 15 patients, five in each cohort. So it will be 15 patients worth of data at each dose level. It will be primarily biochemical. There's not enough patients in there that have a lot of clinical information right that you could – so it will be focused on copper levels, distribution levels and other aspects of [indiscernible].

I think it will give us an understanding of is the gene therapy working well. We had certainly an early indication and that was very encouraging. So we're primarily focus on the biochemical part of the story at this point..

Great. Thank you..

Question we have comes from Salveen Richter of Goldman Sachs. Please go ahead..

Hey, Salveen. I am not sure your line is muted, we can’t reach..

Hi.

Can you hear me now?.

Loud and clear, Salveen. Go ahead..

So sorry about that. Thank you for taking my question.

Could you help us understand how you look on OI with regard to the Phase II data translating to Phase III here? And particularly, as the patients see improvements how that kind of impacts the rate of fractures here for the population and your assumptions around that in the Phase III trial?.

Well, I think what we've shown at the 14-month data was in fact that the bone marrow density continues to increase dramatically. And the p-value got much smaller.

So remember that's looking at all the patients not just the median, but it tells you – the p-value declining substantially tells that all of the patients are moving toward a reduction in fractures. So we feel that the effect is very large.

In terms of translating to Phase III, we know from the data we had in a few placebos that they do not see bone marrow density improvement during this period of time. So there will be no placebo effect from that. With regard to fractures, fractures are dependent on both disease severity and also environmental factors like what the patient is doing.

Our expectation is that patients when they feel better could start doing more work, but what we have seen is patients that have gotten stronger and have been on treatment for a longer period of time will have falls and not have fractures.

So we feel pretty confident that the strength of bones as such to even compensate for any change might occur because patients are more active.

But we do think that the way patients feel their activity will bode well for supportive clinical data and how the patients are doing, which I think will support the value of the product and its clinical means for this.

Did I hit on the thing you were most interested in Salveen?.

That's really helpful. Thank you..

The next question we have comes from Dae Gon Ha from Stifel. Please go ahead..

Hey, good afternoon, guys. Thanks for taking my question. Hope, I'm coming off. Okay.

Can you guys hear me?.

Loud and clear, Dae Gon.

Awesome. So maybe just revisiting or maybe rewording Gena's earlier question, Emil coming out of that ASF and we certainly have some details around the different domains and its impact by the ASOs.

I guess now that the Phase III trial design is set, is there a certain strategy you have in terms of maximizing GTX-102's, product differentiation as you feel about the other ASO coming through fairly quickly? And then, just maybe a little bit tangential here, but I was wondering if you guys ever thought about using an numayo [ph] reservoir for GTX-102, just thinking about intrathecal administration and its affiliated side effects? I mean wouldn't numayo reservoir be like life cycle management strategy, where you can get more drug a bit more safely perhaps, with greater potency? Thanks so much..

Thanks, Dae Gon. So on the first, I think the thing is to part about looking at our data is that we actually are showing long-term data and showing the Bailey four condition into the double-digit range for the majority of patients, if you look long enough. So we were showing two years plus of data. I haven't seen any of that from anyone.

So from right now, we're the only program that's showing that kind of data. Our drug is more potent than the other drugs. We're operating in the 5- to 14-milligram range far below that. That tells you the science of what we've been talking about is right. The targeted region that we have added is more potent and more effective.

So, we believe will differentiate on superior efficacy. And I'm waiting to see other data from people that will actually, match what we have. With regard to your point, I think it's a good point. I think one of our philosophies in nephrology [ph] is that we first make things work and then we make them easy.

Our goal is to get a drug approved drug for this Angelman syndrome, as soon as possible. But then we'll look at how do you make this easier for patients, or more potent. But Omya is one thing. It is certainly an invasive approach. It has its upsides and downsides.

There are also companies that make lumbar catheter-type devices, which would have catheters inside, which you can access which is a much simpler procedure than a lumber puncture, through a port a similar idea. So certainly those are things we can do, as a life cycle management. Those are things we will consider and we as a company never sit still.

If we get approved, we're still going to be constantly looking into ways to improve the patient experience improve the efficacy, and continue to drive forward with the best possible outcome. So we feel like we're in a great position. And after ASF, I haven't seen anything that tells me any different way..

Fair enough. Thank you very much and congrats on the progress..

Thank you. The next question we have comes from Tazeen Ahmad of Bank of America. Please go ahead..

Hi, good afternoon. And thanks for taking my question. On Wilson, you're talking about doing that interim Stage 1 readout. And maybe I wanted to get a sense on initially, your thought was that you would have a readout in the first half, and then it's moved a couple of times to now second half of the year. Just curious, the reason for the delay.

And then once we do see that data, what should we expect those next steps in the development of that program? Thanks..

Yes. So Tazeen, thank you for the question. I think one of the first thing is that to finish out the cohort three, took longer and we end up having patient that qualifies and something happened, we had ended up dragging out the last patient. And so that was part of one of the problems.

One thing, we saw in the Cohort one day that we did put out, is it actually took more time. It wasn't -- you took more than six months to see the effects of the drug. It's a transporter for copper. It's not going to behave like some of our enzymes. So, we're learning a little bit about it.

So our take was we need to go at least six months of data from the last patient in, and that's what the timing is. I think you have to add on to that, time to clean the data it is an international Phase II/III study for prepared in Phase and put it out. So we felt it's important to get this right and make the decisions and so that's where it is.

But we're encouraged by the early data we saw. And I think, there is a gene therapy treatment for Wilson on the horizon. And we'll continue to put that data forth and come up, with our plan for heading into Phase III..

Thanks. Operator, next question please..

Thank you, sir. The next question we have comes from Kristen Kluska of Cantor Fitzgerald. Please go ahead..

Hi, congrats on a great quarter. On setrusumab, I wanted to ask if you think that there are any benefits this drug could potentially show as it relates to the pain these patients experience.

Is there a reason to think that both reducing those fractures and putting down better bone has the potential to have an impact on pain?.

Yes. Our impression from the Phase II patients particularly with their increased activity they're feeling better. They're having less pain. And while we look -- talk about fractures all the time, OI patients have weak bones. And what that means is lots of micro fractures.

So, if they do some heavily -- strong activity, they'll feel terrible the next day because they probably have induced a bunch of micro fractures. So, it's not a single point fracture.

What we can see from the patients treated at the one-year point or beyond patients are having much more activity not needing wheelchairs, not being as afraid of physical activity. So, we have confidence that stronger bones will reduce micro fractures and we'll improve pain.

And so we are evaluating both pain quality of life and other measures in the study. And it's a large enough study that should help us power those endpoints. So, we think it's one of the ways that we'll make I think setrusumab a really important therapy for OI..

And then just on that point I know people sometimes ask if you're feeling better and you're doing more activities does that open the door for any potential fractures? But maybe on the other end of that spectrum if people are exercising and doing more activity could that help even further slowdown any type of bone loss or density loss? Thank you again..

Yes, it's a very good point. I think it certainly could increase fracture risk. We did have a patient who started doing sports again and did have a fracture, but I'm not the one to tell a patient you feel great now, now if don't do anything with that, right? It's just not rational to think that.

What I will say is these patients if you're sedentary you or I sit in our bed and we don't do enough our bones get weaker. So, the exercise they do will actually stimulate their bones to lay down the bone where their bone is weakest. It will actually enhance their bone strength further.

So, I think we'll have a beneficial effect for them to be more active and with sports or anything else. So, we're not worried about the moral risk of getting more fractures. We think it's part of a healthy pattern towards more activity stronger bone and better lives for these OI patients..

Thanks Emil..

Thank you. The next question we have comes from Anupam Rama of JPMorgan. Please go ahead..

Hi everyone. This is Priyanka on for Anupam. Just a quick question from us.

For UX-111 even though the BLA filing will be based on available data, are there any gating factors for the BLA filing later this year or into early next year?.

Well, the one thing we need to make sure is that the CMC put together with our contract manufacturer, they're doing an excellent job. This is [indiscernible]. They are derived from the nationwide children's people. They know their stuff they do good work. And so we feel we're pretty much on track to get where we need to go.

That would be one thing that has to be in line. We're having our discussion with agency about exactly what needs to be in a BLA. And agency has shown the proper flexibility on what needs to be now what can be in later. And I think right now I don't see any gating factors.

It isn't a lot of work putting a BLA together and but we're expected to get there this year. Answer.

Thanks so much for taking our question..

Operator, next question please..

Thank you. The next question we have comes from Joon Lee of Truist Securities. Please go ahead..

Hey congrats on the strong quarter and thanks for taking our question. During Biogen's conference call this morning when asked why they did not opt in to Ionis' Angelman program, Biogen and Piaget data may not have cross the preset go no-go threshold. Knowing what you know about the competing ASO from what's been publicly disclosed.

In what ways do you think GTX-102 may be a better option for patients than IONIS 582? In other words, as patients consider enrolling for GTX-102 or IONIS study what would be the selling point for your program? Thank you..

Well, I think I am sure Biogen is considering looking at all the data that are publicly available. Since we show substantially higher levels of daily condition achievement over longer periods of time and steady growth and in multiple domains in fact, I think that's a strong data set.

What we've seen from our Ionis competitor is a limited amount of data through six months. So I'm sure that Biogen has a capability to understand what the data look like and how to compare and they made their choice. It seems unlikely to me that they wouldn't have opted in, if they had a product that was equal to ours.

And at this point we don't think it is equal. And I think our data longer term is substantially stronger. And it didn't meet their criteria and might not have met ours if we were doing their product. But right now, we feel good about our product it's potency and the fact that I think it's the number one ASO for Angelman at this point..

Thank you..

Thank you. The next question we have comes from Maury Raycroft of Jefferies. Please go ahead..

Hi. Thanks for taking my question. And I'll ask one about Wilson's disease. For your upcoming update, you're assessing global copper metabolism by biomarkers.

What would be considered a win or what magnitude of change do you need to see to advance to Phase III? Or what scenarios could require further optimization?.

Thanks, Maury.

I think with Wilson to have an effective gene therapy I think it's necessary to see patients to be able to get off standard of care, right and maintain free copper levels and urinary copper accretion that indicates that they are now top copper through the proper pathway, right? So first off, we have to be able to replace chelators as a weighted detox copper.

Secondly, we'd like to see some significant improvement in the majority of patients in copper distribution that is a ceruloplasmin copper levels which are generally very low in these patients and are the source of copper to be distributed to the brain and other places.

And in many patients, we think that copper deficiency is a contributor to the Wilson phenotype. So those are the two things we're looking for a substantial improvement in copper distribution over their background baseline, particularly in those patients were it's low and the ability to remove standard of care and maintain toxicity control..

Got it. That’s helpful. Thanks for taking my question..

Thank you. The next question we have comes from Joseph Schwartz of Leerink Partners. Please go ahead..

Hi, all. This is Will on for Joe. Thanks for taking our questions. Congrats on the progress this quarter. One for us on GTX-102 outside of the study design and endpoints.

Just wondering if the FDA has provided any color on the bar success for approval? And along the same lines, can you remind us of our understanding of what a clinically meaningful benefit would be on the Bailey four endpoint? Thank you..

Well, first off, they agreed to a continues variable analysis for the Baily 4, right? So there was no set threshold established or required. They thought variable approach was the right way. So they didn't require responder analysis. We do a responder as part of the MDRI which will support the ceruloplasmin [ph] maintenance.

So that's what they've required to us. They haven't set any numbers. In our mind, if we can show what we've already seen in Phase II which is achieving a majority of patients into the double-digit range of Baily 4 that's essentially twice what is considered a statistic significant improvement in the Baily 4 I think that's quite important.

But I want to be clear about it, while we Baily 4 as a primary. The other end points are part of the story and the value of it as we see it through the MRI the eyes of the [indiscernible] is this combination of factors that is a change of life for patients. So I look at the big picture the Bayley 4 score self doesn't tell the whole story.

Knowing the patient sleeps well is not falling down as much, behavior is calmer, is understanding language spoken language instructions better these are all things that are a change of life for patients at home. And we think some of these states have multiple domains of improvement are going to tell you why this drug would be important for patients.

So if we can replicate that in Phase III what we're already showing you in Phase II I think we're in good shape..

Thank you. The next question we have comes from Yaron Werber of TD Cowen. Please go ahead..

Hi. Thanks for including us as well. Maybe I just have one and one follow-up.

Emil maybe just the -- an age the 48-week endpoint can you give us a little bit of a sense what kind of a delta in terms of powering are you kind of hoping to see and planning to see in the Phase III? And is there going to be a longer look as a secondary end point? And then just on GSDIa we're beginning to get questions kind of how to think about what's feasible in terms of the commercial opportunity here? I think you've kind of talked about price being let's say just in the mid- sort of $1 million or so.

I don't want to speak for you but how big of a market can we think here? Thank you..

Great. So the 48-week data we actually -- if you look at our April AAN terminology deck we actually put a slide on powering in there showing we're well above 90 percentile. Even if you assume the placebo group had the 3x the natural history three or four times in natural history we still had well more than 90% power.

In fact, with the typical natural history control group in fact we would be well above 95% powered. So it is very well powered to see, the effect size we're seeing right now which were into the double-digit range in -- when you talk about 48 weeks.

One of the reasons we went longer is we felt you accumulate more improvements and that made it a better story overall. So that's the powering on Angelman.

With regard to GST1a a commercial opportunity, I think the thing to recognize is for the patients the exact amount of cornstarch is less the issue than the fear of dying if they miss their doses their brittle nature of their disease.

And what we're seeing with these patients is a change in their outlook on what's happening to them, because they are no longer highly dependent of cornstarch to survive.

We think our data in the Phase III because of the blinding and the inability to call patients and doctors what their sugars were didn't get us as strong a reduction as we've seen and we are seeing an extension. But we know that number will get better and better as their physiology changes.

But the effect of feeling better and having a change of life is very much there. We think there's a high urgency in this disease. I think people hate living, would have gone to the head waiting to die. And the corn starch is just a representation of that risk that occurs for them every day.

And it's nothing like some of the other diseases with regard to the urgency that exists. So we think it will be highly desired in the patient population and we expect patients to want to get dosed. And we think that's a key to gene therapy success commercially has been what's the level of patient urgency that's been defining what's been happening.

With regard to pricing, we certainly have not put out pricing at this point. It's a bit too early. We have said in the past that pricing in the $1 million to $2 million range is possible. I think price points have gotten even higher for some programs. But we haven't set down what our plan is. We're going to look carefully at this and come at it.

But I think GSDIa is a very reasonable and important opportunity. I think it will do well. And I think it will be an important new therapy. I expect it to perform more like some of the other programs where there's high levels of urgency..

Thank you. The next question we have comes from Jeffrey Hung of Morgan Stanley. Please go ahead..

Hi. This is Michael Riad on for Jeff Hung. Going back to setrusumab and thinking about that cycle of fractures leading to bone deformation and then loss of activity.

What factors do you think play a role -- bigger on the treatment course? Is it age or OI type? I mean if you think about like the profile which is now -- do you view it as like a broadly better options for the most pediatric patients regardless of type? Whereas for adults you'd expect more OI type-dependent penetration? Thank you..

Well, I think each patient is going to have a reason to be treated. It may be different.

If you're a Type 3 patient or Type 4 with a really severe bone disease and your treated when you're one or two years old our hope and we will see with the Phase 3 data show is that we could be transformed in terms of stopping fracture stopping vertical compression and not basically destroying your skeleton before your three or four years of age and ending up in a wheelchair.

So that would be what you could do when you're treating kids that are young. However, when they're all like, even if you're in a wheelchair because you have to form bones you're still fracturing, you're still in pain all the time.

Being able to stopping and pain by stopping fracturing even if you can't change the information it's still highly valuable in an adult would Type 3 or Type s4. For Type 1, probably the sphere half of that population, we'll have enough fractures where at any age young or old, it's going to be beneficial.

They don't have as much information, but being able to be comfortable participating in sports or activities you might not have been doing before, I think will get Type 1s treated. There may be some Type 1s who are milder, don't have as many fractures and there might not be as an addressable -- as much addressable need in those patients.

So we would expect all Type 1s. What I can say from the data we've shown you though, the Type 1s do really well on the treatment as do the Type 3s and 4s. So we expect that we'd have a good penetration of all three types as well as in all ages, because we think there's a reason to treat at any point in life any of these diseases..

Great. Thank you. I appreciate that added color. And then for Angelman, I just want to circle back to something. So obviously we saw like competitor data that showed good responses up to six months and the Phase 3 is out to 48 weeks, but that makes the Phase 1/2 giving a bit of a more unique insight into those longer-term benefits.

So I was just wondering how that data like, you think it can be used for evaluating that more like durable clinical aspect and like the developmental gains that have been achieved?.

Are you asking about or data or someone else's data? I didn't quite understand it....

I'm asking about like the Phase 1/2, like how that Phase 1/2, data especially like larger-term data can..

Long-term….

Yes..

Yeah. Well, I think what's important about the long-term data is to see patients continue to gain ground. They don't like to they continue to gain ground which tells you that 48 weeks is only one point on a longer journey where these kids are going where they can go is still unclear how much better could they get.

The other point I would make is that, while you get a brain to start functioning better it does take time for kids to learn things, right? Just like growing up you had -- took time to learn them, right? So this is a developmental component particularly in receptive communication and repressive communication that we think might take more time as kids have to essentially learn something that they didn't know and they can't understand.

So there's complex, control functions that might take more time, but we feel that 48 weeks is a good time point to capture enough improvement to shift -- to demonstrate the shift from the control group gets the drug approved, but the long-term continued improvement will be why patients stay on drug and why the product will penetrate the population if successful in Phase 3..

Thanks so much for taking my question..

Thank you. The next question we have comes from Jack Allen of Baird. Please go ahead..

Hi. Thanks so much for taking my question and congratulations on the progress over the quarter. I wanted to ask on setrusumab, I guess a few little parts of this question.

The first of which I was wondering what we should expect as we look towards the second half of the year and the presentation of additional data for setrusumab? It looks like the BMD and Z scores are continuing to improve overtime.

Do you expect to provide additional color as it relates to differences in fracture rates over time with setrusumab and how that correlates with the biomarkers we're looking at there? And then I also just wanted to follow-up and ask about any comment as it related to the enrollment in the Orbit study and the types of patients you're seeing in that trial versus the Phase 2 portion of that study?.

Sure. So with regard to the second half, we haven't set a plan now a particular set of data that we might prevent or not. I mean honestly right now our goal is to crank Phase 3 and to be prepared as necessary to file a BLA, if we're able to hit in the interim.

But right now I'm not sure, if we will put out more data, but the patients clearly have continued improvement overtime. And 14 months is certainly not the end of the story. They continue -- the patient who have been on the 17 to 24 months have continued to do extremely well and are -- it's very encouraging and it's been transformative.

So we definitely think that's true. We may put it out at some point in time, but I think most people are eyes already turned toward interim analyses in 2025. So we haven't committed to other more data yet. With regard to the Orbit type of patients, we did enroll more Type 3s and 4s. We now put up the ratio.

But in the first Phase 2 study we had 17 Type 1s and seven Type 3s and 4s. And it's significantly larger Type 3s and 4s in the Orbit study, which is what we wanted. We wanted to get more severe patients that have more fractures that have more medical need. And we're able to enroll a lot number of those.

I think actually the Phase II data stimulated them to get involved because before they were apprehensive once they saw data then the doctors started putting in their most -- patients in most need. So there is a little bit of shift there, but I don't think it will be substantially different in what we see compared to our Phase II data..

Got it. Thanks so much for the context. Maybe just one brief follow-up. I know you get a lot of questions on how to think about the powering of the Orbit study.

But in that context what were your expectations for enrollment when you set out to enroll the Phase III portion of Orbit, and I guess did you enroll potentially more severe patients than expected? Any thoughts on how that may impact the power?.

Well, we originally started with 195-patient study. And then when we saw our first look of data at six months, it was pretty clear that the fracture reduction of 67% is way past what's needed. We brought that down to 150, which is not a huge difference in power frankly.

But we wanted to keep it that large, because there's -- you want to get enough Type 1s, Type 3s and 4, to look at the subset, right? And you also had peds and adults, so you have to look at the age subsets.

So the number 150 if you could look at the overall powering, but I also look at it as having enough of each group to be able to look at their data and understand the benefit in young or old or Type 3s, 4s or 1s. So that was one of the drivers in maintaining the number of 150.

I think with the fracture reduction rate and assuming a higher fraction rate in the study there was plenty of power, we could have made the study smaller. But I think when you try to cover the types and the severities and the age groups what we put, I think was a good design that will capture the amount of data across all types of Hawaii..

Got it. Thanks so much for color, and congrats on all the progress..

Thank you..

Thank you. The next question we have comes from Lisa Walter of RBC. Please go ahead..

Great. Thanks for taking our question. This is Lisa on for Luca. This question is for Emil. More of a big picture question. Wondering, if we can get your thoughts on the future of the rare pediatric disease voucher program, it sounds like this is set to expire on September 30th, unless it is reauthorized by Congress.

So if it's not reauthorized how might this affect rare disease drug development going forward? Any color there would be much appreciated. Thanks so much..

Yeah. So the sun setting of being able to get them -- being able to apply for new ones is happening later this year and through next year. For us as a company there should be two PRVs available to us or if we file for UX-111 and DTX401, we should be able to get to. So for us it doesn't affect us in the short term in our own financial planning.

In the long run, the PRV vouchers really changed the equation on what happens in some of the ultra-rare diseases. And for us, we've sold two vouchers something like $170 million, $180 million of additional cash for Ultragenyx has had a major impact on our ability to develop other rare disease drugs. We've submitted that information.

We're highly supportive of the PRV. We think those bipartisan support on the helm is rarely that for almost anything. So right now I feel that it will get done, but hasn't happened yet and the election year is a crazy time to do things, but we think it's something that rare doesn't matter with regard to what party you are if you have a rare disease.

So we hope the PRB will get to support. We are certainly providing it..

Thanks, operator. We’ll got to the next…..

Thank you..

Can go to the next question?.

The next question we have comes from Liisa Bayko of Evercore ISI. Please go ahead..

This is Jim Ming [ph] on for Liisa. Thanks so much for taking our questions. So we noticed that Amgen is running an open-label Phase III study for romosozumab in OI and they have indicated that if the Phase III study is positive they may have an opportunity to pursue approval and launch in OI.

So I'm just wondering what implications do you think it would have for setrusumab if Amgen decides to pursue approval in OI? Thank you..

Well that's news to us. They've already given us the intellectual property access. So I don't think they've had that much interest in it. They -- as a biologic for them not surprise is a huge indication. It's growing. There's a big shift toward anabolic agents in osteoporosis I really think that's their focus.

With regard to OI we've seen their Phase II data. We understand their dosing from the published comments in the clinicaltrials.gov or the European version of it. Right now they're getting substantially less bone marrow density at the dose levels they're using.

So we're a superior treatment in terms of our bone modes improvement and we will then be superior in fracture reduction. So I think you should look at this as an unclear story. What they've done in their Phase III is not optimized the drug or the presentation for OI.

And so I really don't have concerns right now because we know our data is far superior for them to get to our data they would have to change your dosing dramatically from Phase III which is not likely to happen at this point. So at this point, I think there will be inferred us and I think that will be a factor.

Now because they use a higher dose of romo potentially but then the differentiation with regard to pricing goes away if you have to give five times or eight times more drug to match our dosing level. So we feel like we're in a good position and I haven't heard anything from Amgen by this before.

I believe that the osteoporosis in their main space for us and has been listed as part of their rare disease franchise at all. So I'd be surprised if they're changing that..

That’s helpful. Thank you..

Thank you. Ladies and gentlemen, we have reached the end of our question-and-answer session. And I would like to turn the call back to Joshua Higa for closing remarks. Please go ahead sir..

Thank you. This concludes today's call. If there are additional questions please contact us by phone or at ir.ultragenyx.com. Thank you for joining us..

Thank you. Ladies and gentlemen that then concludes today's conference. Thank you for joining us. You may now disconnect your lines..