Ultragenyx Pharmaceutical Q4 2023 Earnings Call Transcript

Quartr
Provided by Quartr
February 15, 2024

There are 16 speakers on the call.

Operator

Good afternoon, and welcome to the Ultragenyx 4th Quarter and Full Year 2023 Financial Results Conference Call. At this time, all participants are in a listen only mode. At the end of prepared remarks, you will have an opportunity to ask questions during the Q and A portion of the call. It is now my pleasure to turn the call to Joshua Higa, Vice President of Investor Relations.

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 Takis, 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. In 2023, we generated significant momentum across our commercial and clinical programs that have set us up for a Catalyst Bridge 2024. On the commercial front, We progressed international regulatory and reimbursement negotiations across our marketed products continuing to add to new approvals and positive reimbursement decisions. This geographic expansion along with growing men in our existing markets put us in position to maintain our trajectory of robust year over year growth. On the clinical side, we released new data on our key programs in 2023 and successfully advanced enrollment of our priority programs that can accelerate value creation for our company this year and in the coming years.

Speaker 2

At our Analyst Day in October, we shared exciting data from 3 programs that all will have additional data catalysts in 2024. On UX-one hundred and forty three for osteogenesis imperfecta, interim Phase 2 data showed rapid and substantial increases in bone marrow density and Z score after just 6 months of treatment. This led to a 67% reduction in annualized fracture rate with 20 of the 24 patients showing no radiographically confirmed fractures at 6 months. On GTX-one hundred and two for Angel syndrome, Data from the long term extension cohorts in the Phase onetwo study demonstrated clinically meaningful improvements across multiple neurodevelopmental domains including cognition, receptive communication, gross motors, behavior and sleep. These data show we can repeatedly dosed GTX-twelve for much longer than 1 year with acceptable safety profile.

Speaker 2

On UX701 for Wilson disease, The data we presented showed 4 or 5 patients in the lowest dose cohort had begun tapering their standard of care, including 2 We're completely off key letters and or zinc therapy. While still early for the UX701 program, We are encouraged by the data we have observed. Our momentum is continuing into 2024 with multiple clinical development updates. Last week, GTX-two hundred and two was granted priority medicine or PRIME designation by the European Medical Authority Based on the positive early clinical data from the long term extension cohorts and the potential of DTX-twelve to address the unmet need for a treatment in this disease. The clinical data we've shared with The Street along with positive U.

Speaker 2

S. And European regulatory interactions give us confidence that we will be able to navigate development path for this program. For UX-one hundred and eleven and Sanfilippo A syndrome, we released Phase 3 data last week extension and newly treated patients at the World Symposium Annual Research Meeting in San Diego. The results we shared demonstrated Treatment with UX-one hundred and eleven resulted in rapid and sustained decreased levels of heparan sulfate in the cerebral spinal fluid And the sustained reductions in CSF heparan sulfate exposure over time was correlated with improved long term cognitive development. Our discussions on accelerated approval pathway with the FDA are ongoing and we continue to believe there's a strong case to be made in this program.

Speaker 2

Looking ahead, we are entering 2024 in a robust financial position with $777,000,000 on the balance including proceeds from our equity offering in Q4 that raised $326,000,000 We're also continuing to focus our spend and resources on the key clinical programs that will drive value for our company, many of which will be reporting data in the coming months. Our Chief Medical Officer, Eric Crombez, will review more of these updates in his section. There's a lot to look forward to as we continue our efforts to lead the future of rare disease medicine. Now I'll turn the call over to our Chief Commercial Officer, Eric Harris, To provide an update on our commercial efforts last year that led to a 20% revenue growth in 2023.

Speaker 3

Thank you, Emil, and good afternoon, everyone. I'll start with Crysvita's performance in North America. I want to remind everyone that on April 27, 2023, We successfully transitioned the promotion of Crysvita in the U. S. To Kiowa Kirin and that Crysvita will continue to generate growing revenue for our company.

Speaker 3

During the transition period, the Ultragenyx field team continued to find patients from community physicians, While introducing key accounts to Keyawa Kirin field teams, our patient support services team supported the transition of patients from the Ultragenyx Hub to the Kiowa Kirin Hub to ensure continuity of treatment and reimbursement. In 2023, the smooth transition and additional field resourcing help support the growing demand for Crysvita in the U. S. And Canada. In fact, there were approximately 500 start forms generated in 2023 from a continually growing base of unique prescribers and patients on reimbursed therapy.

Speaker 3

The success we saw in 2023 has led us to further amend our agreement with Kiara Kirin that will allow our experienced field team from OTGENX to continue to support Crysvita in the U. S. Through this year. With a robust demand from 2023, a fully transitioned patient support services hub and the support of Ultragenyx's Focused Field Team, we feel confident that 2024 will be another strong year for Crysvita in North America. Shifting to Crysvita in Latin America.

Speaker 3

We finished the year with over 500 patients on reimbursed therapy, which included approximately 50 new patients who began commercial therapy in Q4 of 2023. Over the course of the year, We added approximately 200 new patients to our growing base of patients on commercial therapy. While most of the current demand in Latin America is driven by patients, we are seeing an increasing uptake in adult patients across the region, reflecting a similar pattern that we saw in North America. In Latin America, we expect quarter to quarter variability in revenue driven by uneven ordering patterns, but remain confident and the underlying demand growth for our products. These combined efforts across our global organization generated 2023 Crysvita revenue of $328,000,000 which is a 17% increase compared to 2022.

Speaker 3

For dojoVie in the U. S. And Canada, the demand for start forms remains strong. In 2023, we added approximately 115 start forms and 95 patients on reimbursed therapy, resulting in over 470 reimbursed patients in the U. S.

Speaker 3

Since launch. The number of prescribers continue to grow, adding approximately 40 new prescribers in 2023. In Latin America, we are making steady progress in finding patients despite the lack of newborn screening in the region while expanding access for Dijovy to more patients. Most recently in Mexico, Dajovy was approved by the HTA for inclusion in the National Medicine Compendium, which is an important step toward increasing reimbursed patients in 2024. Across the EMEA region, the Jovi is driven by named patient sales request As we continue to deepen the awareness of LC FAOD with key stakeholders through our medical teams, though the majority of current requests are coming from France, We are seeing an increased demand throughout Europe and the Middle East.

Speaker 3

In 2023, The teams generated $71,000,000 in AJOVY revenue, which is 27% growth compared to 2022. Lastly, on Efkiza. We continue progressing steadily across our launch markets in EMEA, Canada and Japan. In EMEA, European HTAs have provided a proven with positive clinical recommendations and we are working through the reimbursement processes. On December 18, we received approval from the European Commission for an expanded indication for brefkiza in children aged 5 years and older with HoFH.

Speaker 3

This approval further validates the drug's clinical value and expands the addressable patient population in the EMEA region. In Canada, both HTA bodies, CADET and ANS, have provided positive clinical recommendations for FTEZA. The team is preparing to accelerate the public reimbursement process with the Canadian authorities in the coming months. In the meantime, we are working to get private payers on board to expedite reimbursement. The initial uptake on the start forms has been steady since Health Canada's approval.

Speaker 3

In Japan, we received regulatory approval on January 18 and pricing discussions are underway with Japanese authorities. Following reimbursement approval, we expect to launch Efkeza in Japan next quarter. The team is busy educating the physicians on the Efkeza label and identifying appropriate patients who could benefit from the treatment. Building on the success in 2023, we expect continued strong performance across our portfolio in 2024. Crysvita will continue to drive the majority of the revenue followed by DEJOVY and FKEZA.

Speaker 3

With that, I'll turn the call to Howard to share more details on our financial results and 2024 guidance.

Speaker 4

Thanks, Eric, and good afternoon, everyone. I'll focus on full year corporate financials since we just covered our individual product performance. Starting with total revenue, for 2023, we reported $434,000,000 representing 20% growth over 2022. Total operating expenses for the year were $1,000,000,000 which included R and D expenses of 648,000,000 SG and A expenses of $310,000,000 and cost of sales of $45,000,000 Operating expenses included non cash stock non cash stock based compensation of $135,000,000 For the year, net loss was 607,000,000 or $8.25 per share. As of December 31, we had $777,000,000 in cash, cash equivalents and marketable securities.

Speaker 4

In 2023, net cash used in operations was $475,000,000 which was higher than forecasted due to timing of when certain receipts and payments landed around year end. Our 2024 net cash used in operations is expected to be less than $400,000,000 which is consistent with the guidance we provided last month. We are also reaffirming the 2024 revenue guidance ranges we stated last month. Total revenue is expected to be between $500,000,000 $530,000,000 which represents 15% to 22% growth versus 2023. Crysvita revenue is expected to be between $375,000,000 $400,000,000 which includes all regions and all forms of Crysvita revenue to Ultragenyx.

Speaker 4

Specifically, it includes Crysvita product revenue from Latin America and Turkey and the cash and non cash royalties from North America and Europe. Our Crysvita guidance range represents 14% to 22% growth versus 2023. Dajolvii revenue is expected to be between $75,000,000 $80,000,000 which represents 6% to 13% growth versus 2023. Our Digolby projections represent a blend of faster growth in countries where we commercialize and lower growth in countries where we respond to name patient requests. With that, I'll turn the call to our CMO, Harrick Krombez, who will provide an update on our key clinical data readouts expected this year.

Speaker 5

Thank you, Howard, and good afternoon, everyone. In addition to the UX-one hundred and eleven Phase 3 data we presented at the World Symposium last week, we have a number of important clinical data readouts planned for 2024. These include GTX-one hundred and two expansion cohort data to be presented mid first half, DTX401 Phase 3 data in the 2nd quarter, then UX701 dose finding data and finally, UX140 3 longer term follow-up data from the Phase 2 part of the ongoing Phase twothree study. For UX-one hundred and forty three, There is also the potential for the Phase III study to read out pivotal data from the first interim analysis around the end of the year. We have set a strict P value of 0.001 for unblinding for this first interim analysis.

Speaker 5

This means that the alpha spend is effectively 0 while providing the opportunity to end the study early if the data are compelling and the primary endpoint is met. We have also built in a second interim and final analysis for the study that would occur in 2025. Regardless of the timing, The reduction in the annualized fracture rate that we saw in the Phase II study and shared at ASBMR last year gives us confidence we will see a clinically meaningful and statistically significant reduction in clinical fracture rate in the Phase 3 study. Shifting now to the 2 near term data readouts for GTX-one hundred and two and DTX-four zero one. I'll start with GTX-one hundred and two for the potential treatment of Angelman syndrome and the Phase II expansion cohort data that we expect to share in the next few months.

Speaker 5

The first part of the study included a dose escalation stage to understand initial safety and efficacy. Last October, at our Analyst Day event in New York, we disclosed longer term extension data demonstrating that many of these patients have achieved to highlight the clinical meaningfulness of these changes. Earlier last year, we began dosing a larger number of patients in expansion cohorts to further study the dose regimen that we intend to evaluate in a Phase III trial. These expansion cohorts include higher loading doses, and enrollment was completed at the end of last year with 53 patients enrolled globally. The upcoming expansion cohort data in mid first half of this year will focus on the 20 plus patients who have been on therapy for at least 100 days.

Speaker 5

We intend to present safety and efficacy data in a similar format to what was shown at Analyst Day, specifically showing domain by domain changes with comparisons to natural history. With higher loading doses in a greater number of patients, We expect to verify the meaningful efficacy that was presented at Analyst Day. These data will inform dose selection and evaluation period for the Phase 3 study. Our discussions with the FDA on Phase III planning continue to go well and we anticipate that the expansion data will support an end of Phase II meeting in mid-twenty 24, which would enable Phase III study start up later in 2024. The next Near term data readout is for DTX401, our investigational gene therapy for the treatment of glycogen storage disease type 1a.

Speaker 5

We have one of the largest late stage gene therapy pipelines, and this will be our 1st Phase III data readout. All of the patients in the Phase a clinically meaningful response to DTX401 that has proven durable with the earliest treated patients entering their 5th year of follow-up. In the randomized placebo controlled Phase 3 study, we expect to see patients with clinically meaningful and statistically significant reductions in cornstarch therapy. We expect to unblind and share top line data from the DTX401 Phase 3 study in the Q2 of this year. I'll now turn the call back to Emil to provide some closing remarks.

Speaker 2

Thank you, Eric. We've made incredible progress across the clinical pipeline, which sets us up for a number of data catalysts this year. I'll close by summarizing those catalysts, so everyone can get a better sense of what to expect. As Eric mentioned, the next few months we'll share the expansion cohort data from the GTX-one hundred and two Phase 2 study. This is expected to be followed by the top line Phase 3 DTX401 data in the 2nd quarter.

Speaker 2

Next, we plan on sharing the UX for Wilson disease stage 1 data in mid-twenty 24. This will be data from the 3 dose escalation course that recently dosed the last patient. Closing with UX-one hundred and forty three for Osteosyn imperfecta, we expect to share longer term Phase 2 data in the second half of the year. Enrollment of the Phase 3 studies is going well and we are on track to complete enrollment with approximately 150 patients in the ORBIT study around the end of the Q1. The COSMIC study is also enrolling well and is on track to enroll approximately 50 patients or more around the same time or just after.

Speaker 2

2024 is an important year for Ultragenyx. We'll continue expanding global access to our commercial products, bringing these important therapies to more and more patients. Is expected to generate more than $500,000,000 in revenue and support our path toward profitability. We also expect to share meaningful data updates from 4 of our later stage clinical programs, making this one of the most data rich years in our company's history. With that, let's move on to your questions.

Speaker 2

Operator, please provide the Q and A instructions.

Operator

Thank you. Our first question will come from the line of Gena Wang with Barclays. Your line is open.

Speaker 6

Thank you for taking my questions. I have one question regarding the GTX-one hundred and two in Angium and one for sotrasimab. So for GTX-one hundred and two, you received the PRIME designation. What is the early feedback regarding approval path and the Phase 3 trial design? And have you met with the FDA also regarding the Phase 3 trial design?

Speaker 6

And for sacituzumab, how will long term Phase 2 data In second half twenty twenty four, we'll inform the first interim for OpEx Phase III before year end twenty twenty four.

Speaker 2

Very good. Thanks, Gina, for the questions. So the PRIME designation was just a presentation of the data that we've seen so far and Basically, I recognize the close of day we saw. We have not settled on a Phase 3 plan with the European authorities. That's something to become.

Speaker 2

With regard to the FDA, the PRIME designation will have no influence on the FDA. We have Initiate our conversations with FDA. We've had good discussions. We're making good progress and we feel comfortable about putting together a plan when we have our Phase 2 data in hand when we meet them within the Phase 2, but we're encouraged by the discussion and think there's a way forward in terms of finalizing a plan for Phase 3. We have said just for reference that we're planning the Phase 3 to be around 100 to 120 patients in a randomized double blind trial design and the FDA knows that and I think that's a traditional design, I don't think there should be any problem with European authorities either with that basic design.

Speaker 2

So we'll get the Phase 2 endpoint I mean Phase 3 endpoint settled as we move through getting all the data. With etrusumab V2 data, it will tell us a little more about the fracture reduction rate over a longer period of time. It appeared from before there were very few fractures after the 5th, 6th, 7th month of treatment and we'll get a lot more patients now further to give us a good sense of the level of reduction over longer periods of time. That will help us understand the true maximum effect that we might see on fracture reduction. Since the frac reduction is up already at the 67% estimate rate, that puts us in good position to potentially have a positive interim.

Speaker 2

It will depend on the variation we see in patients. But we felt that that level of efficacy And any higher efficacy would put us in position of potentially being able to end the study sooner if we have profound highly statistical significant results. We could have a very good result though, still not hit that standard and we'll have another interim and final in 2025. So We're very encouraged about sotuzumab in the path forward. The Phase 2 data should help us see how great it is and understand a little bit more about the path forward.

Operator

Thank you. One moment for our next question. And that will come from the line of Maury Raycroft with Jefferies. Your line is open.

Speaker 1

Hi. Thanks for taking my questions. Based on the totality of your Angelman data so far, including data from your natural history longitudinal study. As you think about a Phase 3 design, do you have a sense of what the optimal time frame is to assess efficacy and what age group could show maximum benefits?

Speaker 2

Yes. So if you look at the study data we put out last year at Analyst Day, We continue to gain ground over time, right? So it looks like going a little longer like day 170 is early. And if you look at day 254, the data looks much stronger. And our view is it could be anywhere from around day 254 to day 330, somewhere in that range is the likely time frame we would do the study.

Speaker 2

Obviously, the longer it is, that means the more time on placebo. It gives more time for separation of the groups. But it's somewhere in that time frame and the Phase 2 data will help us try to figure out what's the right number. I'd want to do the study not long wire that needs to be to show meaningful profound results. In terms of age, I think right now, Our plan is to continue with the same age range we're using in the Phase 2, the 4 to 17 year old.

Speaker 2

Early on, people thought only the young patients would respond, but we've been seeing Good responses in older kids too. So I don't think that should limit we shouldn't need to limit Phase 3 in order to get the best efficacy. I think we conclude that whole group 4 to 17 in our Phase III design. Our expectation though is to do A separate study, an open label study to help look at younger kids, potentially older kids and the other genetic types to fill out the data set. With the main Phase III study, we expect to be 4 to 17 year old and be somewhere between 250 days to 3 30 days

Speaker 3

Long. Got it. Okay. Thank you.

Operator

And one moment for our next question. And that will come from the line of Anupam Rama with JPMorgan. Your line is open.

Speaker 7

Hey guys, thanks so much for taking the question. Maybe just a quick one

Speaker 5

for me. What was the feedback on the 111 program, MPS III program update at world and where are you there with the FDA discussions in terms of what are the push pull levers year on like an accelerated approval process emerging?

Speaker 2

Well, in the meeting there, we had really positive feedback from Because I think the extended data is continuing to show good developmental progression among the longer treated patients That's consistent with the heparan sulfate and being predictive of good clinical outcomes. And so we're encouraged and There's been a number of people using the HS marker and showing similar predictive value. Our discussion with FDA has been have been going on for a while. I think Peter Marks has been very encouraged with the idea that we should be moving with biomarkers and A workshop is planned organized by Reagan Udall February 21st, which will look at heparan sulfate across multiple programs. We feel the data there should encourage the FDA to take the stand of accepting heparan sulfate as a reasonably likely to predict clinical benefit marker and start doing salary approvals in the MPS brain disease area, which If it happens, I believe will help us move forward in other rare genetic disorders, particularly that affect the brain.

Speaker 2

So I think we're encouraged about the progress forward of the workshop, the data we've released, the data others have released tell us that we have a hand on how to treat MPS disease and particularly MPS IIIA and that's a good thing because there hasn't been a single treatment for MPS brain disease approved today.

Operator

Thank you. One moment for our next question. And that will come from the line of Hazin Ahmad with Bank of America. Your line is open.

Speaker 8

Hi. Thanks for taking my questions. Sorry for the background noise. I have a couple just on 701 for Wilson. You've changed the readout timeline.

Speaker 8

I think originally it was first half and now you're It's mid-twenty 24. Is that just nomenclature? Or is there a reason for a slight time shift? And then, I guess going back to Angelman, a question that we've been getting a lot of recently is with relation to the composite endpoint that we've talked about that includes measures including Bayesian CGI, but Have you had detailed discussions with SBA on using that composite endpoint? And I think the main question around that is coming from the potential of a competitor to have their own Angelman data around the same time as yours and how that Might affect FDA's viewpoint of using a more traditional endpoint?

Speaker 8

Thanks.

Speaker 2

Okay. So the timeline in Wilson is dependent on the last patient roll. We enrolled the last patient cohort 3 just early this year. We want to give them enough time, at least 6 months to kind of have an opportunity to titrate their chelators, get through the whole treatment process and titrate chelators. So it's slightly off from different from where we have, but not meaningfully.

Speaker 2

So that's the timing. We want to make sure to give patients enough time to be able to get off key layers if they can. So that's the basic story there. With GTX-one hundred and two, we've had discussions on both the MDRI and other ways of looking at the endpoints of the FDA. And I think they're open to various ways of looking and I think they showed a lot of flexibility in many ways.

Speaker 2

Whether we do MDRI now will be just a question whether we want to press our case on using something novel or whether we should stick to picking a traditional single endpoint or 2 endpoints for the primary. But we're still working through that with FDA. I think it's been good, but Not really worried about the competitor. Honestly, our efficacy will be the driver of what we do. I don't think that their competitors change the outcome on the endpoints.

Speaker 2

They are behind us at this point and I think the efficacy data they put out has not been Impressive. So, at this point, I think our future is all in our hands. And honestly, I think we have some of the best team in developing endpoints methodology around it and support for it. And nothing in our conversations with FDA suggests that they're listening to anyone else, particularly in this, they seem to be willing and able and ready to work with us on our final solution on the endpoints.

Operator

Thank you. One moment for our next question. And that will come from the line of Dae Gon with Stifel. Your line is open.

Speaker 9

Great. Good afternoon. Thanks for taking our questions. I'll just ask 2 on GSDIa. I guess the first one is, Emil, can you shed some more insights on the cornstarch reduction?

Speaker 9

So we've heard from some docs that sleeping through the night is also If not more important than the reduction itself. So when you think about the outcome here, what do you consider clinically meaningful level of cornstarch reduction? And what data will you provide to address the sleeping aspect for the physicians? And then kind of sticking with GSD1a, Can you talk about the training and monitoring of these investigators to ensure the cornstarch reduction is done appropriately versus just slower than expected out of caution. Thanks so much.

Speaker 2

Good. I'll deal with the first question and maybe Eric you could deal with the second question about training on the site and so forth. So we haven't set a minimum threshold of change for cornstarch because we agree with you that What is probably more important than the actual reduction is whether the patients are critically dependent on cornstarch to survive, Because the problem with cornstarch is not taking cornstarch. The problem is that each patient lives each day with a gun to his head thinking, if I forget to make cornstarch, I could die. That is a horrible burden to live with and have to take something every 3 hours.

Speaker 2

So what we know from our Phase III study is that patients Many patients were able to have no cornstarch at night and their glucoses were maintained. They did not drop to 0. They were maintained and supported. So What data will we have? Well, we're looking at primary clinical statistical significance from cornstarch reduction.

Speaker 2

We'll also look at the number of cornstarch administrations they take, whether they're taking at night, we'll have tedious glucose monitoring, which allows us to monitor glucose control during the night, which will also be something we'll be looking at. So in addition to the cornstarch, you'll hear about the other characterization of the cornstarch dependency, which I think are important part of the story. And it's important part why the amount of reduction we're seeing is transformed for patients where they feel like they can go out of the house and exercise without feeling that they're going to get hypoglycemia and drop somewhere. And we've had many patients tell us they feel safe now that that's not going to happen to them and many who don't take starch at night and sleep through the night. So I think those are all aspects of what will come out with the Phase 3 data to help provide the clinical meaningful argument in addition to the quantitative around cornstarch reduction.

Speaker 2

Now Eric, maybe you can provide a little more on The training and how we're doing this with sites?

Speaker 5

Yes. To your point, the training and monitoring is very important here. We really did want to rely on our study teams, principal investigators who gained a lot of during the Phase II I part of this program to continue on as trial sites for the Phase III. Because of the double blind nature of the Phase III study, we also wanted to build an independent group of experts, physicians, Truly, the biggest experts in GSDIa who aren't participating in clinical trial sites truly work with the sites and guide them to make sure we're doing this consistently and safely.

Operator

And one moment for our next question. And that will come from the line of June Lee with Tuohy Securities.

Speaker 7

This is Mehdi on for June. I have two questions. Could you please provide some Clarification on the patient mix that you are envisioning for Phase 3. Would you exclude UPD patients or like patients with prior experience with ASOs? And the other question is on cetirizumab.

Speaker 7

What gives you confidence that a potential chronic dosing would be on

Speaker 3

the label for this treatment? Thank you.

Speaker 2

Yes. So you're speaking of GTX-one hundred and two, correct? Yes. So For the genotypes, we're going to stick to the genotypes we have been studying, which is the deletion type, which is 70% of the patients. The UPD And missense patients wouldn't be in the randomized control Phase 3.

Speaker 2

But our intent is to provide a basket study where we'll look at A cohort of those type patients open label to help look at their efficacy and provide support for preclusion on the label, But they won't be part of Phase 3 because we as a habit and method within the company, we don't expand genetic types or types of patients we haven't treated, if we haven't studied them already in Phase 2. So it will the Phase 3 will be all deletion type. Those are the most severe patients, improving benefit in the most severe patients, I think puts us on path to be able to support efficacy with smaller studies to deal with the other types. Now patients who had prior experience, for example, patients have been in the Roche program, we've had a number of Roche patient inquire. The challenge is very complicating right now, particularly for those that had safety events in another ASO to drop into a Phase 3 study.

Speaker 2

It's not something we would do. We're going to look at ways what we can do to look at access for those patients going forward in our program. We just haven't done it yet. We still have to work out our safety we take on those complexities, but there's certainly patients interested in crossing over at this point in time. So remind me, the last question you had was on which program?

Speaker 5

I believe it was on chronic dosing for OI.

Speaker 2

Chronic dosing for OI, okay. Why do we believe we can get chronic dosing? Well, we know that you probably need it. First of all, osteoporosis and Oscea and imperfecta are very different diseases. They're very different diseases, particularly the age of the patients, the state of their bone and the biology of their bone disease.

Speaker 2

What we know from the asteroid study that was conducted by Mireo is that when they took them off the cetuzumab and put them on just bisphosphonates, they were losing bone marrow density. Their bones were turning back around the direction they gained, it's clear that you need chronic dosing. What we know now from treating patients chronically because we had including one kid that we showed you 17 months of treatment as they continue to gain ground and do better and better. So everything we said in the OI indication, their bones are different. And particularly, they're younger and they are have an induction effect from their genetic disease that makes them different.

Speaker 2

By stimulating, we're able to maintain their bone marrow density or coroic further. And what we do believe, there may be a point at which we need to move to maintenance dosing where you don't need to make their bones more dense. At that point, we'll look at going into a less frequent maintenance dosing regimen.

Operator

And one moment for our next question. And that will come from the line of Yaron Werber with TD Cowen. Your line is open.

Speaker 10

Great. Thanks. This is Brendan on for your own. First, just another quick one on Sanfilippo. I understand talks with FDA are still ongoing.

Speaker 10

But just wondering when you think you might know and be able to make a decision on timing to regulatory filing and whether based on how those talks are going you expect that could happen this year? And then just really quickly on GSD1a, I wanted to see how soon after the Q2 readout you expect to be file. Has FDA given you really any confirmation on how long they want you to follow these patients after that primary endpoint just to understand durability or What have you, just before you get that submitted? Thanks very much.

Speaker 2

Very good. Good. So for MPS IIIA, The workshop coming up, I think, will be an important touch point. And I'd expect that after that, I would assume this first half have a read on whether we could file off of the biomarker based data. I will tell you that we've collected almost enough clinical data to be able to file off clinical data alone.

Speaker 2

However, we think it's more meaningful to be able to get accelerated approval on the biomarker, but we should know this first half. The workshop being an important moment, but the follow-up meeting that may occur with the review division then will let us know what our path is. Either way, we can find a way forward for MPS IIIA. We just think it's better for the field, both us and the field, if we are able to get our approval and open the door now to treating more ultra rare diseases. For GSD1a readout, we haven't put a timeline for filing.

Speaker 2

We have noted our plan to bring the manufacturing in house, which will require some time, but we are that will be an important part of what we have to do. But we'll have to go and meet with FDA to understand from a pre BLA meeting more precisely what is in all the different packages, the CMC package and the rest of it. And so that will help determine what happens. But We're if the data are positive, which we expect, we'll be working to move forward to filing as diligence as we can given the parameters I've stated.

Operator

One moment for our next question. And that will come from the line of Kristin Kluska with Cantor Fitzgerald. Your line is open.

Speaker 11

Hi, everyone. Thanks for taking my questions. So with the Phase 2 cetruzumab data guided to the second half of the year, I think that puts you at Mean of at least a year and a half worth of follow-up. So I wanted to ask if there's anything that you're going to be looking for beyond fracture prevention is just course is the essential goal. But then also to your comments earlier about chronic dosing, What do you think about in OI and chronic dosing in general, if there could be further improvement or even preventing further impact relates to some of the other features of OI such as the deformities, the bone structure, etcetera?

Speaker 11

Thank you.

Speaker 2

Yes. So you're right. I think that we're probably in that range of 1.5 years. And if you could saw like the patient we described that had 17 months treatment. He wasn't using wheelchair anymore and he's running around and playing.

Speaker 2

I think that's kind of what we're hoping for is to look at those secondary clinical signs that Not only a reduction of fractures, but people feel better, are more active and still not having fractures. So we're going to look for that clinical meaningful side of the story as well in those patients. Our thinking and this relates to the maintenance dosing is that if we improve the bone marrow density sufficiently so They stop having fractures, have very few fractures and we expect 2 things to happen. We should be able to go to maintenance dosing where we give cetuzumab Every 2 or 3 months, it allows us to maintain the normal density that they have and not lose ground. But We'd also expect that when you stop having fractures, you will stop having progressive deformity and in particularly the place we're most interested in is in the spinal column.

Speaker 2

The spinal column degeneration is absolutely the most devastating part of OI, particularly Type 3s and 4s, the ones that end up in wheelchairs, whose lives are devastated, preventing which we hope to be able to see at that point in time would be the kind of thing that would prevent the deformity of their spines, The decline in spinal function and the wheel becoming wheelchair bound, those are the kind of things which are can change the future. It's partly why we're running the COSMIC study in the 2 to 4 year olds to try to capture that result. So when we Head to a filing for approval, we can establish a new standard for care that you need to be treating OI patients with cetuzumab at a young age to help prevent the deformities going forward. So hopefully the COSMIC study will add to that question that you've asked about changing deformities. If you could do that, it could be that you could stop OI Type 3s and force from ending wheelchair bound and what a terrific result that would be and it's what we think It's possible with what we've seen so far.

Operator

One moment for our next question. And that will come from the line of Salveen Richter with Goldman Sachs. Your line is open. Hi.

Speaker 12

This is Lydia on for Salveen. Thanks so much for taking our question. So we just have one on UX701. Could you just help us frame the clinical update expected this year, around how much proof of concept we could expect here? Thanks so much.

Speaker 2

Yes. So the proof of concept, the information you're going to get are 5 patients at 3 doses, right? So it's still relatively small sets of data. What we'd be looking to see is can we eliminate the need in at least some patients for chelators that is we can remove their chelators and still maintain urinary copper that is we can replace the chelators. The second thing Can we restore copper distribution?

Speaker 2

That is a place where the gene therapy can exceed what you obtain with chelators because We didn't get into the Wilson gene therapy business just to replace chelators, just to get rid of a treatment. We got in there because we think You can have a more profound beneficial treatment that restores copper distribution as well as detoxification. So we'd want to be able to show that both those things are happening. If we can show that both those are happening, patients at the optimal dose and done with safety, it sets us up for immediately rolling a Phase 3 study at that dose and regimen that will allow us then to potentially disease. The stronger the benefit of the copper distribution on their outcomes and the more likely the drug will become adopted by a larger fraction of Wilson patients.

Speaker 2

If it's we're great at removing the toxicity and then it could be the 23rd percent of the patients that are not tolerating chelators very well that it would be beneficial. And our expectation though is it could be more beneficial than you might Imagine given what's known about chelators and that will open the door to having a larger fraction of Wilson patients that would respond. So it will give us At least the beginning framing of those two aspects of the Wilson disease. But remember, it's only 5 patients per group, so we cannot expect to have definitive clinical outcomes results in that grouping to tell us the answer. But with the Phase 3 study following that, we'd have enough patients in there to start say something more about the clinical meaningfulness or the secondary neurologic effects otherwise that you might obtain by having restoration of copper distribution.

Operator

One moment for our next question. And that will come from the line of Yigal Nochomovitz with Citi. Your line is open.

Speaker 13

Hi, team. This is Asha Poubarak on Freegal. Thanks for taking my question. I had a follow-up on an earlier Angelman discussion. I guess, as you're thinking through various scenarios between a more novel endpoint for Phase 3 versus a more traditional endpoint.

Speaker 13

I'm curious how you think the expansion data you're planning on sharing with us here might capture the potential for a more novel endpoint. And if you lean towards the more novel end of the spectrum and you take that to regulators, is there maybe potential that you need to generate additional data beyond this expansion cohort submit before you start the Phase 3. I'm just curious how you're thinking about that. Thanks.

Speaker 2

Yes. Well, our focus I mean, I think our focus in terms of endpoint choice to be the main ones we've already shown that we've tested before and we're adding to. We're not necessarily expecting brand new endpoints to come out, but so we'll be dependent primarily on what we see. The thing that will happen in the study though is that we'll get a large number of patients loaded the same way, right, which we haven't had, which will give us a better or more precise estimate of the change we see and have it be more reliable, not wishful thinking, but to see a large number of patients showing a very similar pattern of result. Our goal expectations are from the endpoints, we've talked about 5 domains, which the Bayley was for 3 of those domains and 2 other endpoints for the behavior and sleep, those are going to be the core 5 domains that we're going to be working with.

Speaker 2

There will be other assessments for fine motor and expressive communication, but the five we've talked about will be the main drivers. So I don't really think there's going to be a point where we're going to start fresh with a new endpoint to restart over. That's not something we need We think we have enough data among the ones we know to come up with a good conclusion and structure the endpoints in a way that gives us the best insight in how the drug works and gets regulatory agreement, but we certainly wouldn't want to start off fresh and restart the discussion. We do believe we'll have enough to make that conclusion with the agency.

Operator

One moment for our next question. And that will come from the line of Jeff Hung with Morgan Stanley. Your line is open.

Speaker 10

Thanks for taking my question. For UX-one hundred and eleven, you mentioned that you collected almost enough clinical data to file off the clinical data alone. What length of long term follow-up do you need to accurately measure potential for improved development with sustained HS normalization? How should we think about the time course for developmental?

Speaker 2

Well, this is one of the areas for discussion with the agency. Originally, they had told that VIONA and in our discussions had a requirement to see at least patients reach age 5 years. However, we've been able to show that between 24 months and 60 months between in that period, there is the most rapid decline normally in natural history. And then if you look at the estimated yearly change in development and the trajectory of development, you can readily distinguish patients during that period. We have a number of patients now that have already gone past 60 months or 5 years.

Speaker 2

But between 4860 there are a number of others that are also showing good development and we think the combination of those patients may be already enough clinically to demonstrate the benefit, which was part of that update. But we're working to understand in our new analysis we Joe, I know this estimated yearly change in its relationship to area under the curve exposure helps provide better insight into how to understand trajectory of development over time. And we think this means we can interpret better what's happening between, let's say 30 months of age 60 months of age to know what is the trajectory of a patient with sample ethyl that's untreated And what's the trajectory of someone who has adequate heparan sulfate reduction? And so those would be what we'll be pressing for. But Even just patients from 48 to 60 months, minimum of 48 to 60 months, we already have clinical data saying the drug is effective.

Speaker 2

So it is another way for us to go forward, but far more valuable to get an accelerated approval to include all the data on all the patients and accept the 48 to 60 minuteimum treatment data as simply evidence towards the reasonably likely to predict standard.

Operator

One moment for our next question. And that will come from the line of Joseph Schwartz with Leerink. Your line is open.

Speaker 14

Hi all. Thanks for taking our questions. This is Will on for Joe today. So just two quickly from us, both on Angelman. So previously it was noted that you expect to see more of an effect as compared to the prior data cut given the higher doses in the expansion cohort.

Speaker 14

So I just wanted to make sure that this is still the expectation. And then also for Angelman, we often hear that these patients are constantly gaining skills and there may be some increased hope in the community, which could lead to a placebo response. So just wondering what strategies can help mitigate a potential response in

Speaker 2

a pivotal trial? Thank you. Thank you. So Our expectation that loading at higher doses that the improvement should be accelerated relative to what we've seen, We haven't changed our view on that. The thing I would say is remember that in the Phase 2 data we showed you for extension, we went all the way out to 500 days of treatment, right?

Speaker 2

So the magnitude effect you see at 500 days is not going to be the same that you're going to see at 170 days. But We do expect that the higher low dose should and the large number of patients that should make us allow us to verify that we're seeing a real effect. Now with regard to the placebo response, I think the longer term data already show you that there's it's not a placebo response because they continue to gain ground. The placebo effect doesn't go on forever. It goes on for a while then people eventually recognize something's not happening.

Speaker 2

But to be able to see linear continued gain of ground over time is beyond what you would see with the placebo effect. In the Phase III though, you have to worry what you're thinking. Well, what if people are optimistic? What we are doing in a lot of the key endpoints use 3rd party psychologist evaluators like for the Bailey. The 3rd party evaluators looking at the kid doing things.

Speaker 2

While the patient report may have some impact, they are looking for the kid to do things. So that helps provide some objectivity that we're seeing the kid actually do things and it's not just wishful thinking. That said, Our expectation is to have a large enough effect and a large enough population of patients to be able to power path a placebo effect. In addition, the longer time frame we've been talking about, which is maybe 250 days or 330 days should be well past the normal window of what placebo would be. I think when you look at how many domains are improving in patients, 2 to 5 domains improvement in most of the patients, it will become evident to people who's responding, who's not responding.

Speaker 2

And so The issue you raised is certainly one of importance and we've been thinking a lot about it. But I do think the Magna effect, the length of time are factors which will help reduce the risk of a placebo response clipping or impairing the results of that study.

Operator

And one moment for our next question. And that will come from the line of Jack Allen with Baird.

Speaker 15

I have two quick ones. The first one has to do with the commercial products, namely dogevy and Crysvita. I know there's some seasonality in the 4th quarter numbers, but when you analyze out the 4th quarter numbers, it like you're already at the lower end of guidance. I was hoping you could provide some more color as it relates to how we should think about the growth of those two products over the course of 2024? And then on GSD1a, any thoughts on your early market research here?

Speaker 15

Is there a subset of patients that are more severe that could be asked to early adopt a gene therapy here?

Speaker 2

That's for GSD1a? Yes. Okay. So with D'Ojjome and Crysvita, guidance is always an art form, but our View is that we're continuing to see something close to 20% growth. DUXHAULBI may be a little slower because some of the territories we just have We're responding to name patient sales.

Speaker 2

I think Eric made that clear. We're in the territories that we're commercializing, we're continuing to see the 20% growth rate. I don't think there is any issue with this. We're trying our best to navigate guidance and give The Street numbers we feel confident in achieving. And I think looking at 20% growth rate, I think is I think still excellent growth rate.

Speaker 2

So The lumpiness Q4s and in these patterns with Latin America have been a recurring theme. It is what it is. I think ultimately it's just It swings up and down. I think Q4 tends to be higher as there's some buying before the winter months and before the New Year, but I and it's just something that we always have to manage overall. So you have to we have to smooth it out and come up with guidance that make But I feel good about the guidance we have and 20% growth rate should be excellent.

Speaker 2

With regard to GSD1a, 81% of the patients have severe genotype or null like genotype, right, 81%. So it's the vast majority of patients are severe. There's milder, but majority are severe. And so we'd look at the population being more homogeneous in that regard than many of our gene therapy disease that we study. So at this point, I would look at most of the patients being highly dependent on starch, having very severe phenotype and Probably in greatest need and most danger from that disease in terms of crashing and dying suddenly.

Operator

And one moment for our next question. And that will come from the line of Ed Arce with H. C. Wainwright.

Speaker 7

This is Thomas Yip asking a couple of questions for Ed. Thank you for taking my questions. So just for GTX-one hundred and two and Angelman, among the 20 patients in the expansion cohort, can you tell us What are some of the longest treatment duration that these patients have been in the Phase III study? And also what are some additional endpoints that investors can focus on compared to the previous data set? Thank you.

Speaker 2

I heard the extension cord. You're asking from the ones we presented how long they go out. By the time we get to end of Phase 2, we'll have patients who have had 2 years of treatment probably, But it will be somewhere between a year to 2 years of treatment of exposure for all those patients, so quite a long time. And we have patients a good chunk of patients were already beyond age day 504 at the Analyst Day meeting. So I think actually that's a good shows you that chronically exposed accumulating drug doses are not going to cause the safety problem in this disease.

Speaker 2

So I think that's an important part of the safety profile that we can keep doing these treatments and not have an issue. Re state your second question because I didn't quite catch it.

Speaker 1

I think the second question was about additional endpoints that they should be considering beyond perhaps what we've already said?

Speaker 2

I see. Well, we have a lot of different ones we're looking at, but I think the ones we've talked about, the Bailey or the core, The either the age range of severity assessment for behavior or sleep or an alternative behavior sleep scale could be used. Those are 2 alternatives. There are scales we've used before. We've seen them before.

Speaker 2

We just haven't We haven't didn't include we didn't have them in the most recent extension data. So we'll get a little more information on those alternative ways of doing it. I would say to you in our discussion with FDA, they were highly flexible to us calling out questions and just pulling up Like a few key questions on those endpoints and relying on those for the endpoint, they were I think showed great collaborative flexibility and not rigidity with regard to choosing those endpoints. And so within our existing data set, we can even just pull out questions, for example, and hone in on those questions and use those for particular for behavior or sleep. So our goal would be not to go with new things we haven't seen before, but to Look at what we have and pull out the best data source that are sensitive to the change and are clinically meaningful for patients in coming up with those, but there won't be brand new things you've never seen or that we don't have any data on.

Operator

Thank you. I'm showing no further questions in the queue at this time. I would now like to turn the call back over to Joshua Higa for any closing remarks.

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 all for participating. This concludes today's program. You may now disconnect.

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Key Takeaways

  • Ultragenyx reported $434 million in 2023 revenue, up 20% YoY, driven by Crysvita ($328M, +17%), Dijovy ($71M, +27%) and the launch of Efkiza across EMEA, Canada and Japan.
  • The company ended 2023 with $777 million in cash and marketable securities and reiterated 2024 revenue guidance of $500–530 million (15–22% growth) with expected operating cash usage below $400 million.
  • UX-143 for osteogenesis imperfecta delivered Phase 2 interim data showing a 67% reduction in annualized fracture rate at six months and substantial bone density gains, leading to a Phase 3 interim analysis planned by year-end 2024.
  • GTX-102 for Angelman syndrome received EMA PRIME status and Phase 1/2 extension data showed clinically meaningful improvements across cognition, communication, motor function, behavior and sleep; Phase 2 expansion data are expected in H1 2024.
  • Key clinical catalysts in 2024 include H1 data for GTX-102 expansion cohorts, Q2 topline results from DTX-401 (GSD Ia) Phase 3, mid-year UX-701 (Wilson disease) dose-finding updates and longer-term follow-up for UX-143.
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Earnings Conference Call
Ultragenyx Pharmaceutical Q4 2023
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