Ultragenyx Pharmaceutical Q2 2024 Earnings Call Transcript

Quartr
Provided by Quartr
August 1, 2024

There are 13 speakers on the call.

Operator

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

Speaker 1

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 Kakas, Chief Executive Officer and President Eric 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.

Speaker 1

Please refer to the risk factors discussed in our latest SEC filings. I'll now turn the call over to Emil.

Speaker 2

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 a 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 will share more on the revenue details.

Speaker 2

Within our clinical pipeline, we've meaningfully advanced our late stage program 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-one hundred and eleven in Sanfilippo syndrome and GTX-one hundred and two in Angelman syndrome, we recently announced positive Phase 3 results from the DTX-four zero one gene therapy for the treatment of patients with Glycogen Storage Disease Type 1a and additional long term positive Phase 2 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 2 meeting with the FDA where we align on Phase 3 study design and key endpoints to be evaluated. Our teams have been working with our study sites to initiate our global Phase 3 study by the end of this year. On UOX-one hundred and eleven for Sanfilippo Syndrome Type A, we also reached agreement with the agency on a path forward to seek accelerated approval.

Speaker 2

The FDA has agreed that cerebral spinal fluid heparan sulfate is a reasonable surrogate endpoint 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 delay meeting and we intend to submit this delay later this year or early next. Collectively, this puts us in a position to have multiple regulatory marketing submissions and key clinical data readouts over the next 6 to 18 months, which is extraordinary. I spent my career developing therapies in rare disease and I can tell you that 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 of these things forward. These achievements are direct result of our excellent execution across the company from our committed employees and our best in class approach to rare disease drug development.

Speaker 2

It's a very exciting time for Ultragenyx. I'll now turn the call over to our Chief Commercial Officer, Eric 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.

Speaker 3

Thank you, Emil, and good afternoon, everyone. I'll start with Crysvita's performance in the United States. The demand for Crysvita in the U. S. Remained strong in Q2 2024.

Speaker 3

Approximately 60% of the start 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.

Speaker 3

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 6 20 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 DYJOVI, growth of new start forms remains strong.

Speaker 3

In the U. S, 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 continued to grow, adding approximately 10 new prescribers in Q2 2024 with half of them writing more than one prescription. For Dajovy across Europe and the MENA region, revenue is currently driven by named patient sales request.

Speaker 3

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 Vopeeza. In the EMEA region, we added approximately 60 new patients in the second quarter who were 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.

Speaker 3

The team there has done an excellent job to map and identify a majority of patients in the country and has processed 35 start forms through the Q2 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 Efkeza as a treatment option. We expect demand for Efkeza 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 2nd quarter bounced off the 1st quarter seasonality, leading to $147,000,000 in total revenue.

Speaker 3

The broad strength across the commercial portfolio through the 1st 6 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.

Speaker 4

Thanks, Eric, and good afternoon, everyone. I'll start by briefly summarizing our financials that were reported in our press release earlier today. As Eric noted, we reported $147,000,000 in total revenue for the Q2 of 2024. Prespita contributed $114,000,000 including $67,000,000 from North America, dollars 40,000,000 from Latin America and Turkey, and $6,000,000 from Europe. Dejolby revenue in the 2nd quarter was $19,000,000 EKEZA revenue in the 2nd quarter was 8,000,000 dollars and Mepsevii revenue in the 2nd quarter was $6,000,000 Our total operating expenses in the 2nd quarter were $263,000,000 which included R and D expenses of $162,000,000 SG and A expenses of 81,000,000 dollars and cost of sales of $21,000,000 Operating expenses included non cash stock based compensation of 39,000,000 dollars In the Q2, net loss was $132,000,000 or $1.52 per share.

Speaker 4

As of June 30, 2024, we had $874,000,000 in cash, cash equivalents and marketable securities, which included net proceeds of $381,000,000 from our offering in June. Net cash used in operations was $77,000,000 for the 2nd quarter and was $268,000,000 in total for the first half of the year. As we discussed on our May call, there is seasonality in the Q1 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 $400,000,000 for the year. Shifting to revenue guidance, we are increasing our range for total revenue, which is now expected to be between $530,000,000 $550,000,000 for the year.

Speaker 4

This reflects strong performance and trajectory across all of our products, including Presquita globally and the launch of IKEZA in our territories. Accordingly, we are targeting Presquita revenue to be towards the upper end of our existing range of $375,000,000 to $400,000,000 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 JOLBI revenue to be between $75,000,000 $80,000,000 With that, I'll turn the call to our CMO, Eric Prombos.

Speaker 5

Thank you, Howard, and good afternoon, everyone. The first half of the year has seen a number of important clinical catalysts for UX-one hundred and eleven 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 pepperinsaltate can be used as a surrogate 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.

Speaker 5

For DTX401, for the treatment of GSD1a, we announced positive top line data from the Phase 3 study that show that treatment with DTX401 resulted in a statistically significant reduction in daily cornstarch intake 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 twenty twenty four. For UX-one hundred and forty three, for the treatment of osteogenesis imperfecta, we announced 14 month data from the Phase 2 portion of Orbit that showed treatment with cetuzumab resulted in a sustained 67% reduction in annualized fracture rate and persistent median annualized fracture rate of 0. There were also continued substantial improvements in bone mineral with a mean increase from baseline of 22% and a mean improvement in Z score of 1.25. For GTX-one hundred and two for the treatment of Angelman syndrome, in April we shared additional Phase onetwo data from the expansion cohorts that showed rapid and clinically meaningful improvements across multiple domains.

Speaker 5

These improvements were consistent or exceeding those of the dose escalation cohort data at day 170. We also shared that additional long term data and dose escalation cohorts showed increasing and sustained clinical benefit through day 758. There's been a lot of news flow in the space GTX-one hundred and two to improve the lives of patients affected by this disorder. We continue to see the patients in the Phase 2 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 3 start up activities. Last month we completed a successful end of Phase 2 meeting with the FDA where we aligned on the design for a global 48 week blinded randomized sham controlled Phase 3 study.

Speaker 5

We expect to enroll approximately 120 patients between 4 17 years of age who have a full UBE IIIA deletion. The primary endpoint will be improvement in cognition assessed by Bayley's 4 cognitive 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 3 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.

Speaker 5

The ongoing Phase 2 study includes 25 states across 8 countries which allowed us to respond to the significant global demand to participate in the study and for these sites to gain experience with GTX102. With start up activities already in progress and alignment with FDA and design, we are on track to begin enrollment of our Phase 3 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-one hundred and two for the treatment of patients with other genotypes 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.

Speaker 2

Thank you, Eric. In the 1st part of the year, we've made significant progress advancing our clinical pipeline and we performed well globally on the commercialization of 4 products. I'll close quickly by summarizing our key clinical catalysts for the rest of the year. For GTX102 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 3 patients are doing as they continue receiving maintenance doses. Our long term data is far superior to any other data presented on ASO's arrangement to date and this puts us in excellent position for the future of that program.

Speaker 2

For the Phase 3 portion of the UX-one hundred and forty three ORBIT study, there are 2 interim analyses planned with 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 analysis 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. It is important for steady integrity to run these analyses very carefully and rigorously.

Speaker 2

In the event of an interim analysis that 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 this dose finding stage, the data readout will be prompted once the last patient cohort 3 has been on therapy for 6 months or more followed by some additional time to collect and analyze all of the data.

Speaker 6

All of

Speaker 2

these are very exciting catalysts and while the teams are executing on these clinical programs, we will also be working on 2 BLA submissions, one for UX-one hundred and eleven for Sanfilippo syndrome, which is expected around the end of the year and the other for DTX401 for collection store 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 2 BLAs, provide Phase 3 data on UX-one hundred and forty three and should be well on our way to the GTX-one hundred and two Phase 3 study. All the while, we are generating meaningful revenue growth and is now expected to be between $530,000,000 $550,000,000 this year. With that, let's move on to your questions.

Speaker 2

Operator, please provide the Q and A instructions.

Operator

Thank you very much, sir. At this time, we will be conducting a question and answer The first question that we have comes from Gena Wang of Barclays. Please go

Speaker 7

Angelman syndrome data update, we also saw quite a few other data update from both Ionis and Roche. Maybe, Amir, 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?

Speaker 1

All right. It looks like we're having maybe a little bit of technical Eric, are you able to help out with that question?

Speaker 5

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. As we've mentioned, we had a very successful end of Phase 2 meeting with the FDA and we really have locked in plans for Phase 3 as we're looking forward to 1st patient in by end of year. We have done some thought on loading dose and reducing from 4 to 3 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 3 under 1 year of time.

Speaker 5

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.

Speaker 1

Yes. Eric took care of the call. Gina, was there any follow-up there that you had for AMOL?

Speaker 7

Sure. Yes. So maybe regarding the WIL data in second half this year, maybe how many more patients and what kind of data beyond biomarker you will share with us?

Speaker 2

Well, there's a total of 15 patients, 5 in each cohort. So it will be 15 patients' worth of data, 5 at each dose level. It will be primarily biochemical. There's not enough patients in there to have a lot of clinical information, right, that you could so it will be focused on copper levels, distribution levels and other aspects of copper metabolism, I think will give us an understanding of is the gene therapy working well. We had certainly an early indication and that was very encouraging.

Speaker 2

So we'll primarily focus on the biochemical part of the story at

Speaker 7

this point. Great. Thank you.

Speaker 2

The

Operator

next question we have from Salveen Richter of Goldman Sachs. Please go ahead.

Speaker 1

Hey, Salveen, I'm not sure if your line muted, we can't

Speaker 8

Hi, can you hear me now?

Speaker 1

Loud and clear, Salveen. Go ahead.

Speaker 8

So sorry about that. Thank you for taking my question. Could you help us understand how you look on OI with regard how you look at OI with regard to the Phase 2 data translating to Phase 3 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 3 trial?

Speaker 2

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. That tells you the P value declining substantially tells you that all the patients are moving toward a reduction in fractures. So we feel the effect is very large. In terms of translating the Phase 3, 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.

Speaker 2

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 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 is 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 mean for this.

Speaker 2

That hit on the thing you were most interested in, Salveen.

Speaker 8

That's really helpful. Thank you.

Operator

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

Speaker 9

Hey, good afternoon, guys. Thanks for taking my questions. Hope I'm coming off okay. Can you guys hear me?

Speaker 2

Loud and clear, gang. We do.

Speaker 9

Awesome. So maybe just revisiting or maybe rewording Gino'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 3 trial design is set, is there a certain strategy you have in terms of maximizing GTX-one hundred and two'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 Omaya reservoir for GTX-one hundred and two, just thinking about intrathecal administration and its affiliated side effects, I mean, would an Omia reservoir be like a life cycle management strategy where you can get more drug bit more safely perhaps with greater potency?

Speaker 9

Thanks so much.

Speaker 2

Thanks, Aegon. So on the first, I think the thing that's most important about looking at our data is that we actually are showing long term data and showing the Bayley for cognition into the double digit range for the majority of patients, if you look long enough. So we were showing 2 years plus of data. I haven't seen any of that from anyone. So for right now, we're the only program that's showing that kind of data.

Speaker 2

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 padded is more potent and more effective. So we believe we'll differentiate on superior efficacy and I'm waiting to see other data from people that will actually match what we have.

Speaker 2

With regard to your point, I think it's a good point. I think one of our philosophies in rare pearls 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. Then we'll look at how do you make this easier for patients or more potent. An OMAI is one thing.

Speaker 2

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 could access, which is a much simpler procedure than a lumbar puncture through a port, a similar idea. So certainly those are things we can do as a lifecycle management. Those are things we will consider.

Speaker 2

And we as a company never sit still. If we get approved, we're still going to be constantly looking to 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 differently.

Speaker 9

Fair enough. Thank you very much

Speaker 1

and congrats on the progress. Thanks.

Operator

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

Speaker 8

Hi, good afternoon. Thanks for taking my question. On Wilson, you're talking about doing that interim Stage 1 readout. And maybe, Emil, I wanted to get a sense on initially your thought was that you would have a readout on 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.

Speaker 8

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

Speaker 2

Yes. So Tazeen, thank you for the question. I think one of the first thing is that to finish out the Cohort 3 took longer. We end up having a patient that qualified and something happened and we had to it ended up dragging out the last patient. And so that was part of one of the problems.

Speaker 2

One thing we saw in the cohort 1 data that we did put out is that it actually took more time. It wasn't it took more than 6 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 about it.

Speaker 2

So our take was we need to go at least 6 months of data from the last patient in and that's what the timing is. And you have to add on to that time to clean the data. It is an international phase, 2, 3 study, prepared analyses and put it out. So we felt it's important to get this right and make good 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 the heading into Phase 3.

Speaker 1

Thanks. Operator, next question please.

Operator

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

Speaker 8

Hi, congrats on a great quarter. On tatruzumab, 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?

Speaker 2

Yes. Our impression from the Phase 2 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 induced a bunch of micro fractures.

Speaker 2

So it's not a single point fracture. What we can see from the patients treated at the 1 year point or beyond patients 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 will 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.

Speaker 2

So we think it's one of the ways that will make, I think, cetuzumab a really important therapy for OI.

Speaker 8

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

Speaker 2

Yes. It's a very good point. I think you 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, don't do anything with that, right?

Speaker 2

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 it will have a beneficial effect for them to be more active and with sports or anything else.

Speaker 2

So we're not worried about the moral risk of getting more fractures. We think it's part of a healthy pattern toward more activity, stronger bone and better lives for these OI patients.

Speaker 8

Thanks, Emil.

Operator

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

Speaker 10

Hi, everyone. This is Priyanka on for Anupam. Just a quick question from us. For UX-one hundred and eleven, 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?

Speaker 2

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 Andalyn. They're derived from the Nationwide Children's People. They know their stuff.

Speaker 2

They do a good work. And so we feel we're pretty much on track to get where we need to go. That would be one thing. It has to be in line. We're having our discussion with agency about exactly what needs to be in a BLA.

Speaker 2

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 is a lot of work putting a BLA together. And but we're expected to get there this year.

Speaker 10

Thanks so much for taking our question.

Speaker 1

Operator, next question please.

Operator

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

Speaker 1

Hey, congrats on the strong quarter and thanks for taking our questions. During Biogen's conference call this morning, when asked why they did not opt into Ionis' Angelman program, Biogen implied that the data may not have crossed 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 GTX102 may be a better option for patients than IONIS-five eighty 2. In other words, as patients consider enrolling for either GTX-one hundred and two or IONIS study, what would be the selling point for your program? Thank you.

Speaker 2

Well, I think I am sure Biogen is considering looking at all the data that are public available since we show substantially higher levels of Bayley Fork condition achievement over longer periods of time, 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 6 months. So I'm sure that Biogen has the 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 with this point, we don't think it is equal.

Speaker 2

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, its potency and the fact that I think it's the number one ASO for Angelman at this point.

Speaker 1

Thank

Operator

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

Speaker 1

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 3 or what scenarios could require further optimization?

Speaker 2

Thanks, Maury. I think with Wilson, to have an effective gene therapy, I think it's necessary to see patients be able to get off standard of care, right, and maintain free copper levels and urinary copper attrition that indicates that they are now detoxified copper through the proper pathway, right? So first off, we have to be able to replace chelators as a way to detox copper. Secondly, we'd like to see some significant improvement in majority of patients in copper distribution that is the ceruloplasm 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.

Speaker 2

So those are the 2 things we're looking for, a substantial improvement in copper distribution over their background baseline, particularly those patients weren't low and the ability to remove standard of care and maintain toxicity control.

Speaker 1

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

Operator

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

Speaker 11

Hi, all. This is Will on for Joe. Congrats on the progress this quarter. One for us on GTX-one hundred and two. Outside of the study design and endpoints, Just wondering if the FDA has provided any color on the bar of success for approval?

Speaker 11

And along the same lines, can you remind us of our understanding of what a clinically meaningful benefit would be on the Bayley-four endpoint? Thank you.

Speaker 2

Well, first off, they agreed to a continuous variable analysis for the VAIL-four, right? So there was no set threshold established or required. They felt that a continuous variable approach was the right way. So they didn't require responder analysis. We do responder as part of the MDRI, which will support the clinical needs of this.

Speaker 2

So that's what they've required of us. They haven't set any numbers. In our mind, if we can show what we've already seen in Phase 2, which is achieving in majority of patients into the double digit range of Bayley-four. That's essentially twice what is considered a statistically significant improvement in the Bayley score. I think that's quite important.

Speaker 2

But I want to be clear about it. While we did Baileys 4 as a primary, the other endpoints are part of the story and the value of it as we see it through the MDRI the eyes of the MDRI is this combination of factors that is a change of life for patients. So I'd look at the big picture. The Bayley-four score itself doesn't tell the whole story. Knowing the patient sleeps well, is not falling down as much, the behavior is calmer, is understanding language, spoken language instructions better.

Speaker 2

These are all things that are a change of life for patients at home. And we think some of these days have multiple veins of improvement. They're going to tell you why this drug would be important for patients. So we can replicate that in Phase 3, what we already shown you in Phase 2, I think we're in good shape.

Operator

Thank you, sir. Next question we have comes from Yaron Werba of TD Cohen. Please go ahead.

Speaker 12

All right. Thanks for including us as well. Maybe I just have one follow-up. Emil, maybe just the and Angelman, the 48 week endpoint, can you give us a little bit of a sense what kind of a delta in terms of powering that you are you kind of hoping to see and planning to see in the Phase 3? And is there going to be a longer look as a secondary endpoint?

Speaker 12

And then just on GSD1a, 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 $1,000,000 or so. I don't want to speak for you, but how big of a market can we think here? Thank you.

Speaker 2

Great. So the 48 week data, we actually if you look at our April AAN, cat immunology 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 3 times the 3 times the natural history, 3 or 4 times natural history, we still had well more 90% power. In fact, with the typical natural history control group, in fact, we would be well above 95% power. So it is very well powered to see the effect sizes we're seeing right now, which were into the double digit range in when you talk about 48 weeks.

Speaker 2

One of the reasons we've been longer is we felt you accumulate more improvements and that made it a better story overall. So that's with the powering on Angelman. With regard to GSD1a 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 on cornstarch to survive. We think our data in the Phase 3 because of the blinding and the inability to tell patients and doctors what their sugars were, didn't get us as strong of a reduction as we've seen and we are seeing an extension.

Speaker 2

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 with a gun to the head waiting to die. And the cornstarch is just a representation of that risk that occurs to them every day.

Speaker 2

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.

Speaker 2

We have said in the past that pricing in the $1,000,000 to $2,000,000 range is possible. I think price points have gotten even higher for some program. 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 GSD1a is a very reasonable and important opportunity.

Speaker 2

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.

Operator

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

Speaker 1

Hi, this is Michael Riad on for Jeff Hung. Thank you for taking our question. Going back to cetrusumab and thinking about that cycle of fractures mean, if you think about like the profile of such as NAB, do you view it as like a broadly better option for most pediatric patients regardless of type, whereas for adults, you'd expect more OI type dependent penetration? Thank you.

Speaker 2

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 you're treated when you're 1 or 2 years old, our hope and we will see what the base the Phase 3 data show is that we could be transformed within terms of stopping fractures, stopping vertical compression and not basically destroying your skeleton before you're 3 or 4 years of age and ending up in a wheelchair. So that would be what you could do when you're treating kids very young. However, when they're old, like even if you're in a wheelchair because you have deformed bones, you're still fracturing, you're still in pain all the time.

Speaker 2

Being able to stop being in pain by stopping fracturing, even if you can't change deformation is still highly valuable in an adult with Type 3 or 4. For Type 1, probably the sphere half of that population will have enough fractures where at any age, young or old, it's going to be beneficial. They don't have as much deformation, but being able to be comfortable participating in sports or activities you might not have been doing before, I think we'll get type 1 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 wouldn't expect all type 1s.

Speaker 2

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 at all ages, because we think there's a reason to treat at any point in life and with any of these diseases.

Speaker 1

Okay. Thank you. I appreciate that added color. And then for Angelman, I just want to circle back to something. So obviously, we saw a competitor data that showed good responses up to 6 months and the Phase III is out to 48 weeks, but that makes the Phase III giving a bit of a more unique insight into those longer term benefits.

Speaker 1

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?

Speaker 2

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

Speaker 1

I'm asking about like the Phase onetwo, like how that Phase onetwo data, especially like the larger term data can yes?

Speaker 2

Yes. Well, I think what's important about the long term data is to see patients continue to gain ground. They don't plateau, 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?

Speaker 2

Just like growing up, you had took time to learn them, right? So there's a developmental component, particularly in receptive communication and expressive 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 those complex developmental functions 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, get the drug approved, but the long term and continued improvement will be why patients stay on drug and why the product will penetrate the population if successful in Phase 3.

Speaker 6

Thanks so much for answering our question.

Operator

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

Speaker 6

Great. Thanks so much for taking the question and congratulations on the progress over the quarter. I wanted to ask on cetuzumab, I guess a few little parts to 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 cetuzumab. It looks like the BMD and Z scores are continuing to improve over time.

Speaker 6

Do you expect to provide additional color as it relates to differences in fracture rates over time with cetuzumab 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 comments as it relates to that enrollment in the ORBIT study and the types of patients you're seeing in that trial versus the Phase 2 portion of that study?

Speaker 2

Sure. So with regard to the second half, we haven't set a plan now, a particular set of data that we might present 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 an interim. But right now, I'm not sure if we will put out more data, but the patients clearly have continued improvement over time and 14 months is certainly not the end of the story. They continue with the patients 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.

Speaker 2

So we definitely think that's true. We may put out some point in time, but I think most people are eyes already turned toward interim analysis in 2025. So we haven't committed to other more data yet. With regard to the ORPID 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 IIs and 7 Type IIIs and IVs.

Speaker 2

And it's a significant larger Type 3s and 4s in the Orbit study, which is what we wanted. We wanted to get more severe patients that had more fractures, that had more medical need. And we're able to enroll a lot of number of those. I think actually the Phase 2 data stimulated them to get involved because before they were apprehensive, once they saw data, then the doctors started putting in their most their most the 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 2 data.

Speaker 6

Got it. Thanks so much for that 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 3 portion of ORBIT?

Speaker 6

And I guess, did you enroll potentially more severe patients than expected? Any thoughts on how that may impact the tower?

Speaker 2

Well, we originally started with 195 patients study. And then when we saw our first look of data at 6 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 at that large because there's you want to get enough Type 1, Type 3s and 4s to look at the subsets, right? And you also had peds and adults, right?

Speaker 2

So you have to look at the age subsets, right? So the number 150, 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 fraction 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 in the age groups, what we put, I think, was a good design that will capture the amount of data across all types of OI.

Speaker 6

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

Speaker 1

Thank you.

Operator

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

Speaker 8

Great. Thanks for taking our question. This is Lisa on for Luca. This question is for Emile, more of a big picture question. Wondering if we can get your thoughts on the future of the rare pediatric disease voucher program.

Speaker 8

It sounds like this is set to expire on rare disease drug development going forward? Any color there would be much appreciated. Thanks so much.

Speaker 2

Yes. 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 2 PRVs available to us for if we file for UX-one hundred and eleven 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.

Speaker 2

In the long run, the PRV vouchers really change the equation on what happens in some of the ultra rare diseases. And for us, we've sold 2 vouchers, something like $170,000,000 $180,000,000 of additional cash for Ultragenyx has had a major impact on our ability to develop other rare disease drugs. We submitted that information. We are highly supportive of the PRV. We think there's bipartisan support on the Hill and there's rarely that for almost anything.

Speaker 2

So right now, I feel that it will get done, but it hasn't happened yet and election year is a crazy time to do things, but we think it's something that rare, doesn't matter with regard to what part you are if you have a rare disease. So we hope the PRV will get the support. We are certainly providing it.

Operator

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

Speaker 8

Hi, this is Qingming on for Lisa. Thanks so much for taking our questions. So, we noticed that Amgen is an open label Phase 3 study for romosozumab in OI and they have indicated that if the Phase 3 study is positive, they may have an opportunity to pursue approval and launch in the OI. So we're just wondering what implications do you think it would have for cetirizumab if Amgen decides to pursue approval in OI? Thank you.

Speaker 2

Hi. Well, that's new 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, osteoporosis is a huge indication, it's growing, there's a big shift toward anabolic agents in osteoporosis.

Speaker 2

I really think that's their focus. With regard to OI, we've seen their Phase 2 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 marrow dense improvement and we will then be superior in our fracture reduction.

Speaker 2

So I think you should look at this as an unclear story. What they've done in their Phase 3 is not optimized the drug nor the presentation for OI. And so I really don't have concerns right now because we know our data looking far superior. For them to get to our data, they would have to change their dosing dramatically Phase 3, which is not likely to happen at this point. So at this point, I think they will be inferior to us and I think that will be a factor.

Speaker 2

Now could they use a higher dose of Brahma? Potentially, but then the differentiation regard to pricing goes away if you have to give 5 times or 8 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 has been their main space for it and hasn't been listed as part of their rare disease franchise at all.

Speaker 2

So I'd be surprised that they're changing that.

Speaker 8

That's helpful. Thank you.

Operator

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.

Speaker 1

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

Operator

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

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Earnings Conference Call
Ultragenyx Pharmaceutical Q2 2024
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