Ultragenyx Pharmaceutical Q1 2024 Earnings Call Transcript

Quartr
Provided by Quartr
May 2, 2024

There are 16 speakers on the call.

Operator

Good afternoon, and welcome to the Ultragenyx First Quarter 20 24 Financial Results Conference Call. At this time, all participants are in a listen only mode. At the end of the prepared remarks, you will have 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. You may begin.

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. This is the year that we're harvesting the exciting results of multiple years of focused execution across our key clinical programs, and we've shared a lot of meaningful data already this year. At the World Symposium meeting in February, we presented positive biomarker and long term cognition data from our UX-one hundred and eleven gene therapy in Sanfilippo syndrome. The data showed the treatment resulted in rapid and sustained reduction of CSF heparan sulfate and that this was correlated with improved long term cognitive development. We also participated in a workshop on the heparan sulfate biomarker hosted by the Reagan Udall Foundation.

Speaker 2

This workshop brought together FDA representatives, patient advocates, scientists and industry leaders to discuss the overwhelming body of data supporting the use of CSF Heparin Sulfate as a biomarker to enable accelerated approval in neuropathic MPS diseases. The support of Peter Marks and the FDA in recognizing this biomarker as a surrogate endpoint to support accelerated approval would be a profound benefit for the MPS communities and companies working on these diseases and really to all companies working on gene therapies or other type precision medicines. Shifting to cetuzumab, just this week we announced that we've completed enrollment in our Phase twothree Orbit study and our Phase 3 COSMIC study in osteogenesis imperfecta. The Phase 2 data presented late last year was clearly compelling for the study investigators that led to accelerate interest and enrollment in the program. At 2 weeks ago, we announced strong positive interim data from the Phase onetwo study of GTX102 in Angelin syndrome.

Speaker 2

The interim data we shared confirmed in a larger body of data that GTX102 can fundamentally change the development trajectory of angio-1 patients. Importantly, the magnitude of the effect across all domains and expansion cohorts was found to be similar or greater than what we observed previously with the dose escalation cohorts. Ongoing treatment with GTX-two resulted in continuous and sustained improvement of these patients as evidenced by the long term data in the dose escalation cohorts. And we've demonstrated the safety profile can be successfully managed. This Phase onetwo study is valuing the most severe Angelman syndrome patients, those with genetic deletions, where there's typically no improvement on the Bayley scale.

Speaker 2

This is observed in both natural history and placebo controlled studies. For example, our recent Angelin clinical study after 1 year, their placebo group showed only a 0.8 point improvement in Bayley-three cognition score. What we saw in our study was a 5 point improvement in the Bayley-four score beginning as early as day 170 in dose expansion cohorts and almost double that at 1 year in the dose escalation cohorts. We also saw that this improvement continued through day 758 in the dose escalation cohorts. The magnitude of the change we observed with the Bayley was further supported in multiple other assessments, including age of severity assessments and the aberrant behavior checklist.

Speaker 2

The improvements in the vein of sleep and behavior or hyperactivity at day 170 were better than what we saw after a year or more in the prior cohorts. Families also talked about their kids being calmer, more attentive, more aware of the world around them. This allowed greater independence across multiple facets of development like eating, sleeping and mobility. The improvements in cognition and motor function really came across in the videos that we showed on April 15th call. The patient was able to solve puzzles and navigate more challenging walking path, which provide a small real world sample of the significant changes we're seeing in the charts and graphs.

Speaker 2

The combination improvements across cognition, receptive communication and motor function provide a real sense of the potentially transformative nature of this therapy. The multi main responder next or MDRI also resonated with physicians and families. The MDRI brings all the domain of movement across the study population together and it's a great way to look at changes across the individual patients for a heterogeneous patient group. MDI analysis across the 4 domains of cognition, receptors, communication, behavior and sleep resulted in a statistically Further, the majority of the patients in the expansion cohorts achieved improvements in at least 2 and up to all four domains. Importantly, the data we presented show that GTX-one hundred and two has a tolerable safety profile.

Speaker 2

Lower extremity weakness is now a rare, well understood trans event that occurred in 2 out of 53 patients in extension cohorts who had completed the loading phase. Both patients were in the cohort A and B and no events observed in cohort C through E. The events were classified as mild and moderate and all resolved quickly with the patient remaining in the study. 6 earlier patients with this safety issue from the beginning of the study are all on chronic dosing and received multiple doses without any issues. Given our understanding of this issue and recent feedback from regulators, we're comfortable with the current safety profile is acceptable and manageable and we'll continue providing routine safety updates only with our efficacy updates.

Speaker 2

We've heard strong enthusiasm from KOLs over the past couple of weeks, including those reviewed by our analysts, some of you might be on the call. These treating physicians expressed comfort with the safety profile and the route administration of these patient population and the broad agreement that treatment GATX-one hundred and two resulted in clearly meaningful efficacy in these patients, where you just don't typically see any improvements. With all this put together, we have a strong product candidate and plan for Phase 3 development. We're confident this product candidate has the potential to be a transformative treatment for patients with Angelman syndrome. Now I'll turn the call over to our Chief Commercial Officer, Eric Harris to provide an update on our commercial efforts that led to another successful quarter.

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 Kiara Kirin has been responsible for driving Crysvita's revenue in North America since the transition in April of last year. We have continued to augment their efforts through additional field support to ensure a smooth transition, maintain patient continuity and help them generate additional start forms. The demand for Crysvita in the U.

Speaker 3

S. Remained strong in Q1 2024. Approximately 60% of the star forms came from adult patients prescribed by community physicians, resulting in nearly 70 new prescribers in the quarter. This is encouraging given adult penetration is in the low 20s and this implies Crysvita has ample room to continue growing. As is typical, this quarter had some seasonality as patients work through the reauthorization process with their insurance providers at the beginning of the year.

Speaker 3

We are confident in our full year U. S. Revenue projections given the strength of the underlying demand. Shifting to Crysvita in Latin America, where we lead commercialization. Our team delivered another successful quarter in LatAm by adding approximately 50 new patients to Crysvita totaling over 550 patients on reimbursed therapy since launch.

Speaker 3

While Brazil drove more than 60% of Crysvita's LatAm revenue in Q1 2024, we also saw a significant uptick from Argentina and Mexico. We are particularly excited about Mexico, the 2nd largest market in LatAm, which recently cleared all pediatric and adult reimbursement hurdles. IMSS, Mexico's largest payer, approved Crysvita for pediatric patients in about 2 years versus the 3 to 5 years it usually takes for such approval. This recognizes the value they see for Crysvita in pediatric patients. Our team is now busy getting Crysvita on local hospital formularies to expedite reimbursement for these patients.

Speaker 3

As I mentioned on previous earnings calls, we expect quarter to quarter variability in LatAm revenue driven by uneven ordering patterns, but remain confident in the underlying demand growth for our products. Moving on to DYJOVY. Growth of new start forms remains strong. In the U. S, we added over 30 start forms and 15 patients on reimbursed therapy, resulting in over 4 85 reimbursed patients since launch, with approximately a 65 to 35 split between pediatric and adult patients.

Speaker 3

The number of new prescribers continue to grow, adding approximately 10 new prescribers in Q1 2024. As you know, Dajovy has not yet been approved by the European Medicines Agency. So across Europe and the MENA region, Dajovy is driven by named patient sales request. Approximately 200 patients are treated under MPS across 12 countries as of the Q1. The majority of demand is from France, but we are receiving increasing requests from other countries within the EMEA region.

Speaker 3

2024 is an important launch year for EKEZA. As of Q1 2024, we are treating nearly 100 patients in EMEA through MPS and regular reimbursement processes where we have approval. We expect to launch Arkeza in more EMEA countries in 2024. In Canada, we started enrolling patients in our hub after Health Canada's approval last year. Our next step is to secure reimbursement agreements with public payer authorities in late 2024 or early 2025.

Speaker 3

The team is also working closely with private payers to secure reimbursement in 2024 for enrolled patients who have insurance through these private plans. In Japan, we received the regulatory approval in January and pricing and reimbursement approval in April. The launch is underway. The HoFH physician and patient community in Japan is very excited about Eptiza. They started to receive start forms in our hub and we expect a robust launch in 2024 as we continue to educate physicians and patients on the benefits of the Efkiza label for appropriate patients.

Speaker 3

Overall, Q1 2024 was a strong quarter for Ultragenyx, generating $109,000,000 in revenue. Given the strong underlying demand for our 4 commercial products across all regions and the upcoming Eptiza launches, we remain confident in delivering our 2024 revenue guidance. With that, I'll turn the call to Howard to share more details on our financial results for the quarter.

Speaker 4

Thanks, Eric, and good afternoon, everyone. I'll briefly summarize our financials that were reported in our press release earlier today. As Eric noted, we reported $109,000,000 in total revenue for the first quarter of 2024. Crysvita contributed $83,000,000 including $40,000,000 from North America, dollars 36,000,000 from Latin America and Turkey, and $6,000,000 from Europe. Crysvita net sales and underlying patient demand continued to grow meaningfully compared to the prior year, including in North America.

Speaker 4

As a reminder, the transition of North American commercial responsibilities to KKC in April 2023 and going forward, our revenue in the region shifted from a profit share to a royalty. This is calculated using annual revenue tiers based on net sales with royalties ranging from the mid-20s up to 30%. As a result, our Q1 revenue started at the low end of the royalty range and we expect the blended rate for the full year to be at the upper end of the range. With the increasing royalty rate and growing underlying demand, we expect North American Crysvita quarterly revenue to meaningfully increase throughout the year. DYJOLVI revenue in the Q1 was $16,000,000 and Mepsevii revenue in the Q1 was 7,000,000 dollars Our total operating expenses in the Q1 were 2 74,000,000 which included R and D expenses of $178,000,000 SG and A expenses of $78,000,000 and cost of sales of 18,000,000 dollars Operating expenses included non cash stock based compensation of 37,000,000 dollars In the Q1, net loss was $171,000,000 or $2.03 per share.

Speaker 4

As of March 31, 2024, we had $569,000,000 in cash, cash equivalents and marketable securities. In the Q1, net cash and used in operations was $191,000,000 The Q1 of the year is typically a larger use of cash than the other three quarters because it includes items like the payment of annual bonuses. This quarter also ended with a relatively high accounts receivable balance due to the timing of receipts from our commercial activity. Importantly, our guidance for 2024 net cash used in operations remains unchanged from what we provided last quarter and is expected to be less than $400,000,000 for the year. We are also reaffirming our 2024 revenue guidance ranges.

Speaker 4

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. 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 23.

Speaker 4

Our de jolby 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, Eric Krumbez,

Speaker 2

who will provide an update

Speaker 4

on our upcoming clinical data readouts.

Speaker 5

Thank you, Howard, and good afternoon, everyone. Amol already went through the exciting GTX-one hundred and two data that we shared last month, so I will focus most of my comments on some of our other programs. I would, however, like to reiterate the enthusiasm that we are hearing from patient advocacy organizations and the treating community, who all feel that GTX-one hundred and two has GTX-one hundred and two program. We have clear and clinically meaningful efficacy and we are transitioning to Phase 3 study startup. The Phase 3 will be a global randomized placebo controlled study that is expected to enroll approximately 100 to 120 patients.

Speaker 5

We expect to finalize these plans, including endpoints and study duration and an end of Phase 2 meeting that has been scheduled with the FDA in mid-twenty 24. We plan to initiate the Phase 3 around the end of the year. Shifting to DTX401, our investigational gene therapy for the treatment of glycogen storage disease type 1a. Phase 3 data from this program, which we expect this quarter, will be the 1st pivotal data set from our large and late stage gene therapy portfolio. All of the patients in the Phase III study demonstrated a clinically meaningful response to DTX401 that has proven durable with the earliest treated patients in their 5th year of follow-up.

Speaker 5

The randomized placebo controlled Phase 3 study enrolled 49 patients and we expect to see clinically meaningful and statistically significant reductions in daily cornstarch therapy. Our experience with the Phase onetwo program helped us to better understand the importance of reducing dependence on overnight cornstarch and the great fear that all patients with GSDIa and their families have regarding missing a cornstarch dose and the resulting potential for hypoglycemia during sleep, which can be fatal, especially in children. As seen on our Phase onetwo results, we do expect the Phase III to show improved glucose control during the day and also importantly overnight improvement. We plan to share top line data within the next couple of months. I'll close with sotrutumab, our fully human monoclonal antibody for treatment of osteogenesis imperfecta.

Speaker 5

We recently announced completion of enrollment in our Phase 3 ORBIT and COSMIC studies. We ended up over enrolled in record time with 158 patients in ORBT and 66 patients in COSMIC. And this could not have been done without the efforts and strong support from the patient and treating communities. We expect to share additional data from the Phase 2 portion of the ORBIT study in the second half of this year. This data will include at least 12 months of follow-up and build on the data we presented last October.

Speaker 5

I'll now turn the call back to Emil to provide some closing remarks. Thank you, Eric.

Speaker 2

In the first part of the year, we made significant progress advancing our clinical pipeline and I'll close by quickly summarizing our key clinical catalysts for the rest of the year. Later in this quarter, we expect to share top line Phase 3 DTX401 data from our gene therapy for GSD1a. We've scheduled the 102 and the Phase 2 meeting with FDA in mid-twenty 24 that would enable initiating our Phase 3 around the end of the year. The UX701 for Wilson disease stage 1 data is expected in the second half of twenty twenty four. This will be approximately 6 months after the last patient was dosed in Phase 3 plus some time for all the data to be collected and analyzed.

Speaker 2

On UX-one hundred and forty three, we expect to share updated long term Phase 2 data in the second half of the year. For the UX-one hundred and forty three Phase 3 portion of the ORBIT study, there are 2 interim analyses planned with the first anticipated by the year end or early 2025. The first analysis will have a stringent threshold of P less than or equal to 1. If the threshold is not met, a second interim analysis will occur a few months later followed by a final analysis at 18 months. Interim analyses will not report to the company by the Data Monitoring Committee unless they are positive.

Speaker 2

In the event of a positive interim analysis, we would share that outcome, but top line results will not be announced immediately as the study would require patients to complete a final visit and time to collect and prepare the data for a formal analysis. For those of you keeping track, we may have 3 products at or near readiness for BLA filings in Sanfilippo syndrome with UX-one hundred and eleven, GSD-1a with UX-four UX-four zero one and osteogenesis imperfecta with cetrotumab over the next year or so. We are at a company defining inflection point that builds on our strong base of growing commercial products and positions us to transform the lives of even more rare disease patients. With that, let's move on to your questions. Operator, please provide the Q and A instructions.

Operator

Thank Our first question comes from the line of Yigal Nochomovitz with Citigroup. Your line is open.

Speaker 6

Hi, great. Thank you so much for taking the questions. I just had one on DSD-1a, sort of program that we haven't talked about it too much, but you're coming up on the pivotal data. Could you just remind everybody what is required in terms of the primary endpoint to reach positive studies? What are the timelines in terms of the filing strategy for this program?

Speaker 6

And then thirdly, can you just give a little bit perspective on the incidence and prevalence of GSDIa and how you would think about pricing this product? Thank you.

Speaker 2

Yes. So for the GST-1 hundred program, the primary endpoint is the continuous variable now of some cornstarch utilization. And so we'll be comparing the decrease in cornstarch utilization for the primary between the treated and placebo group. That's is also requires that the patients have good glucose control for that reduction in starch. That's the primary endpoint agreed with the FDA.

Speaker 2

In terms of filing strategy, we are transitioning the manufacturing into our plant and we plan with the data to go to FDA and have a discussion and lay that out. So we'll provide more detail on the filing timeline when we have it. But transition to the manufacturing and we'll need to talk to the FDA in setting it, but it's on path assuming our data are positive. Now the last incidence prevalence and pricing. We believe there's around 8,000 patients with GSD1 in the commercial territories and that might be a little under 2,000 that are in the U.

Speaker 2

S. With the disease. That's an estimate. We haven't set pricing at all at this point. We're thinking about it, but it is a severe disease.

Speaker 2

It is an urgent disease. Patients are on a treadmill every day trying to stay alive. And we've seen from the enrollment of the study that there's a desire. So while prevalence of pricing have an impact, I think the degree of urgency is what defines success in gene therapy launches to date. I think GSD1 is urgent.

Speaker 2

I think people want to get treated. They want to get off the treadmill. They want to, as I say, put the gun down. They point at their head every day about managing their glucose. So we're excited about the potential, but there's still obviously more work to do.

Speaker 6

Thank you very much, Emmanuel.

Operator

Thank you. Please standby for our next question. Our next question comes from the line of Noopan Rama with JPMorgan. Your line is open.

Speaker 2

Hey, guys. Thanks so much for taking the question. Emil, just thinking about the GTX 102 update last month, just in your discussions with The Street, what do you think are the most misunderstood or divergent points of feedback you get relative to say the physician or KOL feedback you're getting post AAN? Thanks so much. Well, I think that there's still difficulty appreciating the meaning of the changes in Bailey, for example.

Speaker 2

And I think what we heard from some of the KOL feedback that they're excited about the changes. These are meaningful changes and they know the Bailey doesn't for cognition. So I think that's one of the major ones. I think there was some misconception about the safety lower extremity weakness that was reported. It was really one patient moderate, one mild.

Speaker 2

They resolved quickly. But it's out of 53 patients now through the full load. So it's a relatively small thing. It's reversible. I think people are still overstating the meaningfulness, but I think if you talk to KOLs, they say it's not a deal.

Speaker 2

It's not going to be change things. And the regulators said, yes, fine. It's all good. They didn't ask us to do anything. Just move ahead.

Speaker 2

And they went ahead and accept end of Phase 2 schedule already. So I think we're on path. I think these are the 2 things that need to be straight. But what I'd say the magnitude of the data we saw, the speed and the combination of domains is something quite exceptional. And I think people aren't seeing that multiple domains of improvement for one treatment in treatment areas that normally don't change.

Speaker 2

And we need to keep telling our story. And I hope that if people talk to more KOLs and seeing the data understand it, that might help people inform what the meaningfulness of what we're seeing and how unusual it is for this disease to see any change at all. So we're excited about it and thank you for the question Anupam.

Operator

Thank you. Please stand by for our next question. Our next question comes from the line of Tazeen Ahmad with Bank of America Securities. Your line is open.

Speaker 7

Hi, guys. Thanks for taking my questions. Just in terms of timing for the orbit and cosmic studies for OI, do you think that they're going to read out at around the same time? And is it your plan to submit for the different age groups as part of a single application or is it going to be scattered?

Speaker 2

Well, fortunately both studies over enrolled but got to the same point almost the same time. And I actually think the younger patients will probably as historically true even respond faster. So I actually think both studies will have will probably read about the same time. And our expectation would be to file for the full age range based on that data. So we're actually in good shape to do that.

Speaker 2

I think it's the right thing. I think it would be tough to submit one part of the age range and not the youngest. So with the young patient we're excited getting enrolled puts it in play to have both studies in parallel and gets them both in the filing. That's our plan.

Operator

Okay. Thank you. Thank you. Please standby for our next question. Our next question comes from the line of Gena Wang with Barclays.

Operator

Your line is open.

Speaker 8

Thank you. Regarding the GTX1002 Phase III trial design you're seeing to finalize with FDA. So what will be your single domain for primary endpoint? Is that the daily 4 cognition? And also, will you use full loading doses or 3 loading doses since you're also exploring the 3 loading doses in Cohort C2E?

Speaker 8

And very quickly on the ORBIT trial enrollment. Emma, did I hear you correctly the timing, the first interim analysis that will still be the same before year end or could that be earlier than initial assumption since now you complete enrollment ahead of expectation?

Speaker 2

Very good. So on the GTX-one hundred and two Phase 3, the primary endpoint we're most likely looking at is the Bayley cognition score that we've talked about. It's an integration of multiple things that happened. They're improving the most. It proves rapidly.

Speaker 2

It's a validated tool. It's well known. I think these are features. The FDA is certainly aware of this endpoint in choice. We've had discussions on it.

Speaker 2

We'll include other domains within the secondaries. And the MDRI will be, we think, one of the key secondaries. That's our expectation in the plan. But I think we've got great data on all of these and could potentially use other ones if we wanted to. But I think daily cognition is most likely.

Speaker 2

With regard to 3 or 4 doses, let me clear the cohorts that we're testing all have the same number of doses through day 170. It's just, in the cohorts A and B, they're actually getting 4 and then there's a 3 month separation. And the other cohorts there is we have the 4th dose is separated by a month. So it's a slight difference between the 2. So it's not really 3 versus 4.

Speaker 2

It's really 6 doses over about a 6 month period, just exactly how they're spread out. We will make a final decision on that with the agency looking at all of our data. But I don't think there will be a material difference between 2. We were just testing them out just to see if there was any difference in how patients would behave or safety would be like. But right now, we feel comfortable doing either.

Speaker 2

Now on the UX-one hundred and forty three timing, we got done here in April essentially. The timing for the interim, it depends a little bit on when we think the fractures would be hit and timing. Our expectation is coming towards the end of the year, possibly early in the next year. So it's around that same timeframe. It's not really changed.

Speaker 2

We just want to be clear that we have to there's a lot of factors that come in and doing the interim. And so, it also is happening in December, let's say, December, January. So there's a lot of other things going on. But we're not really changing that. I think it could begin it could happen in early January before we would hear.

Speaker 2

Keep in mind that the actual process may begin for sure and that it takes time to get through it because they have to clean the data, prepare it, analyze it, DMC meeting and then release it. But so our expectation is DMC opportunity for review would be end of the year, early next year. If it's positive and hits less than P value less than 1, then we would hear about it. If it's not positive, then it will go on to the next one. We set that stringent standard, so it may not mean much to miss because I think it could be a great result, but it's not quite 0.01.

Speaker 2

But that's the timing. Hopefully, that's clear for you.

Speaker 8

Yes, very clear. Thank you.

Operator

Thank you. Please stand by for our next question. Our next question comes from the line of Daigou with Stifel. Your line is open.

Speaker 9

Hey, good afternoon. Thanks for taking our questions and congrats on the progress. I'll just bundle the questions and ask 2 straight away. So on the GTX-one hundred and two, when the press release talks about other regulatory meetings in the second half. I mean, you've obviously had conversations with the FDA, but what do you think are some of the divergences or differences that they might bring up in terms of endpoints, for example, or even trial design like enrollment and duration?

Speaker 9

And then second question, just going earlier to the 401 GSD1a, Can you provide a little bit more color on how you're thinking about presenting the euglycemia throughout the night since that's such an important aspect for KOL? Thanks so much.

Speaker 2

Sure. So the other X-ray meetings is just normal habit with a product of this important to the size that you're going to talk to the European authorities and you're talking to the Japanese authorities about what we're doing. The FDA review is really the dominant view, will drive the decision making. We've had preliminary discussions, so it's not like we haven't had any. The design of the study is pretty standard.

Speaker 2

The expectation is likely to be day 3, 38 or 48 week study. So I think these are pretty standard choices. I don't expect there to be much problem with them. And I don't actually think there's going to be a lot of differences. If there were some difference on endpoints or we can of course customize the statistics plan for each region, which we have done in other programs when necessary.

Speaker 2

But I think the hardwired pieces, randomized trial, 100, 120 patients and that basic design, I think that's going to be a universal. I don't think there's going to be any problem. So the rest of it is going to be more about statistics and positioning, if anything. We're comfortable though that what we're proposing is pretty straightforward. And I don't really think that will be a problem.

Speaker 2

But of course, there can be feedback. As I said, the FDA's position would dominate in our choices for going forward. With regard to the GSDIa

Speaker 5

program,

Speaker 2

during we've been presenting the data looking at the fraction of time between the low and the high, right? That's been mostly what we've been doing, Eric, right? And we'll likely look at the nighttime on the CGM monitor, where the patients are asleep and CGM is monitored. And we'll look at those tracings. When we did that during Phase 1, too, I was the most impressed with you take kids who were not taking starch at night any longer and you can watch their glucose and you can see their glucose turn the corner and stabilize.

Speaker 2

And so you knew their livers were turning on and releasing glucose. So we're going to look for that pattern that they can safely go through the night and that their livers are going to keep them safe. So we'll be able to do that if you're looking at CGM. I wasn't sure you think there's anything else, Eric?

Speaker 5

Yes. We are maintaining the controlled fasting

Speaker 2

challenge in the hospital setting. So we will bring them

Speaker 5

in, fast them overnight and really large amount of data we'll be getting from the CGM on a daily basis. Okay. So really large amount of data we'll be getting from the CGM on a daily basis.

Speaker 9

So am I understanding it correct, it's going to be an average graph, if you will, across the treated and untreated across the 48 weeks of what the low versus high would be on an every night basis?

Speaker 2

Yes. So for each patient, there's an interval time where we're doing intensive monitoring of their glucose levels. During those periods, we'll take that to create an average for each patient of where they are in their range, right, set their target. We're not averaging and then doing the mean of it. We're taking each patient for their own control range.

Speaker 2

And then we'll do the mean of that. And you'll see a graph, which we've had before like a bar chart that shows, where the two groups, how they're ranging over time between the high and the low. So we can talk more about that, but there's a way to present this over time. So you can kind of see the sense of improving control, decreasing hyperglycemia and maintaining no hypoglycemia and tightening up over time, which is what we've been watching in our other patients. Right, right.

Speaker 9

Okay. Thank you very much.

Operator

Thank you. Please stand by for our next question. Our next question comes from the line of Christine Kluska with Cantor Fitzgerald. Your line is open.

Speaker 10

Hi, good afternoon. Thanks for taking my questions. We often get asked about setting expectations for the 1st interim readouts for stetrusumab. Could you please help us frame what are some of the factors that are controllable that we can kind of help to predict in advance? And then some of the items where we're less sure about it and again how to help frame these two expectations?

Speaker 10

Thank you.

Speaker 2

Well, I think our Phase 2 data kind of lay down what I think we're going to expect. I would expect it to be that a reduction would be very similar to what we've seen, if not better. So we found there with only a minimum of 6 months, an average of 9 months exposure, right, 67% reduction. The patients we're enrolling are very comfortable with that. If anything, enrolled patients might have a higher fracture rate, I think.

Speaker 2

And so we would expect that reduction to be something what you'd expect to see. Those are I don't know if you consider when you enroll patients with fractures, it's not exactly controllable. They are who they are. But because we have the threshold requirement to get in the trial, we're essentially eliminating patients who would have very low fracture rates and wouldn't necessarily be able to demonstrate benefit in that period of time. I think with the type of patients enrolled, the number of which type, I think we've set ourselves up to replicate what we saw before.

Speaker 2

And I really don't see any uncontrolled factors. I don't know, Eric, if you have anything.

Speaker 5

Yes, definitely. I mean, I think the biggest controllable factor was really enrollment rate and the studies are fully enrolled. Yes, the types of patients and it was good to get a good mix of 1, 3 and 4 in there. I would say, yes, I would agree. The uncontrollable factor may be, especially when you're first initiating treatment in the 1st couple of months, you may have some patients who are having fractures before sotrusumab really takes effect there, but there is a degree of unpredictability with fractures.

Speaker 2

There's probably also the fact that some people some of the kids like feel really good and start being more active. People were worried maybe that caused more fractures, but it didn't look like that was true or that as they fell, they didn't fracture. So we actually are not concerned about the fact that his might feel good and start being more active. It doesn't look like it's going to cause a problem that looks like their bones are stronger, they're doing great. So the truth is the more activity probably strengthens the bone faster because the action actually puts strain in the bones, the bones actually are strengthened by that actual action.

Speaker 2

So thank you for the question.

Speaker 8

Thank you.

Operator

Thank you. Please stand by for our next question. Our next question comes from the line of Maury Raycroft with Jefferies. Your line is open.

Speaker 1

Hi.

Speaker 11

Maybe I'll ask one on Wilson's disease. Just wondering how you're assessing changes in global copper metabolism and what drives the time point of the endpoint or the timeframe for when you can measure benefit and get adequate insight into benefit?

Speaker 2

Well, the 2 main ways we're looking at copper is how much free copper is coming out in the urine, right? The urinate copper, which is a sign of how much is sort of oozing out of the tissues and coming out with a chelator. So if you get rid of the detox ifying, if you detoxify copper through the bile, then you should have less coming out in your urine. So that's the detox side of the equation. On the other side of the question is loading copper on the cerutyl plasma, your plasm oxidase activity.

Speaker 2

So we'll be measuring the seur plasm activity, which is a very sensitive way of looking at copper loaded correctly on ceruloplasm. So those 2 biomarker assays will give us a sense of the overall comp of metabolism. I wasn't sure Eric, was there anything else to add?

Speaker 5

Yes. We're doing a liver biopsy sub study, so it will be great. This is really the time we've been able to do for biopsies. We made it optional, but the majority of patients did opt in for that. So it will be interesting to look at copper concentration and histopathology in those samples.

Speaker 11

Got it. Maybe just a quick question on cetruzumab. We see that you've got a title at Endo and you're guiding to which is I think scheduled for June 1 and you're guiding to having a longer term Phase 2 data in the second half of this year. Just wanted to clarify, will that presentation at ENDO be an ENCORE or should we expect what should we expect in that update?

Speaker 5

Yes. That will be a pure ENCORE presentation.

Speaker 11

Got it. Okay. Thanks for taking my questions.

Speaker 2

We'd like to see good news again, frankly. It's okay.

Operator

Please standby for our next question. Our next question comes from the line of Jeff Hung with Morgan Stanley. Your line is open.

Speaker 12

Thanks for taking my questions. For the tatuzumab Orbit Study, if you go to the 2nd interim, what would the bar be for stopping the study at that point? And in that scenario, would you have greater confidence for stopping the study early with the 2nd interim? And then for the COSMIC study, what would it take for you to stop the study early in that?

Speaker 2

Yes. So the second item as we've planned it right now would be at 0.01. So that's much less stringent, right? That's 10 fold larger P value. And then the final is 0.04.

Speaker 2

So I think the reason the second is less stringent is that at that point everyone would have at least a year of treatment. So we felt there was less regulatory issue there. And then 18 months would be the 0.04, it's just sort of the backstop if we have to go that long. For COSMIC, remember it's an open label study, randomized but open label. And so we'll be looking at the X rays of the DMC.

Speaker 2

And our DMC will be looking, since these are little kids, one of the questions will be is if there is a stark separation in the fracture rates in that study, the DMC would probably be obligated to end the study and not keep kids on an inferior treatment. And so while we haven't set criteria for that, they will be looking at the study during the year. And if they were to hit a strong separation of the groups that they felt was unescripty and that could stop. Our expectation is that the younger patient will respond faster. And since they've finished enrollment, we think by the time we're doing the 1st interim of the one study, the other study should be pretty far along.

Speaker 2

And if the one hits, I think the other one will be should be ready. So we'll probably be pretty closely coordinated with the 2. But the DMC will be all along have the opportunity to look at the data and determine is there a reason to stop that study. And remember going another year is a big deal if you're 2 years old and you have a bone issue, right? So, it's a lot different in that study.

Speaker 2

But fortunately being open label, DMC has a chance to take action at each time they take a look.

Speaker 12

Great. Thank you.

Operator

Thank you. Please standby for our next question. Our next question comes from the line of Joon Lee with Chorus. Your line is open.

Speaker 9

Hey, thanks for the updates and for taking our questions. For the Angelman program, are you talking to CBER or the neurology department? And if it's not CBER, would it be possible to request UTX-one hundred and two be reviewed by CEVER? And during the end of Phase 2 meeting, how strongly would you be advocating for MBRI as an approvable endpoint or has that ship already sailed? Thank you.

Speaker 2

Well, we're under CDER. We're actually in we said before in the psychiatry part of the And that's where we've been the whole time. So and they're actually doing a great job, Tiffany for joining the leader of that group. And then we've had good meetings and she's great to work with. So I'm actually we're very happy with the setting we're in and how it's going.

Speaker 2

So they're in Cedar and there's really no purpose. It's not it's really a well characterized drug. So it's not really going to fit within the CBER mantra and there's no benefit to us to doing that at this point. So we're comfortable where we are with that one. With regard to MDRI, we like MDRI, but it is something very different.

Speaker 2

While we had it in our Mepsevii program and it was used and had helped support the program, it's still a methodology that's new for FDA. We've had a lot of meetings. I've presented

Speaker 5

a lot of

Speaker 2

conferences. I think there'll be growing support with it if we use it. So our plan rather than press our case is probably to put in a single primary validated type endpoint for them and then put our MDRI in as key secondary. Way we get the best of both. We manage what FDA may want or prefer and same time we get MDRI in there, which allows us to support the product.

Speaker 2

I do believe and my belief in the long run is that the MDRI will be a fundamentally new way and better way of doing particularly heterogeneous neurological disorder analysis. And once the FDA sees that in a large randomized trial, see how it performs and understand it, I think they'll start gaining more appreciation why it's a superior approach to analyzing clinical outcomes.

Speaker 1

Great. Thank you.

Operator

Thank you. Please standby for our next question. Our next question comes from the line of Joseph Schwartz with Leerink Partners. Your line is open.

Speaker 13

Great. Hi, all. This is Will on for Joe today. Thanks for taking our questions and congrats on the progress this quarter. So one for us on the DTX401 program.

Speaker 13

We recently saw the updated data in the ASGCT abstracts, which suggests that the cornstarch benefit rebounded favorably as compared to the data shared last year. So just wondering if you could provide some comments on how you're thinking about the durability of this treatment and how this may change your expectations, if at all, for the cornstarch reduction that we might see in the pivotal study later this quarter?

Speaker 2

Well, I don't think that's changed our opinion very much on that at all. I think the what we are noting over time is that the reduction starts happens very quickly, but to get all the way down takes time and there's some secondary factors. It does depend a little bit in the long run on how the doctor manages the starch. They have to get the starch down and get the glucose to come down so that the gene therapy actually expresses that the expression of the gene therapy is dependent on stimulating the promoter because we're using the normal GSCIa, a GSCIa Glucose 6 Phosphatase promoter. So there are some interesting features of how that operates, but we're comfortable with where we are.

Speaker 2

We haven't changed our expectations for the study. We think that we saw something like 50% reduction within a short period of time. But if you looked, it took a lot longer to get down. It was highly more dependent on how doctors were titrating in individual patients. But we're very comfortable with what we're seeing and we haven't we don't have concern yet on durability.

Speaker 2

We think it's been good over the long haul.

Operator

Thank you. Please stand by for our next question. It comes from the line of Yaron Weber with TD Cowen. Your line is open.

Speaker 12

Great. This is Brendan on for Yaron. Thanks for taking the question, guys. Just a quick one from us on the gene therapy pipeline. I think you

Speaker 2

correct me

Speaker 11

if I'm wrong, but I

Speaker 12

think you recently said that you might file for GSD1a around the end of this year or early next year. Totally understanding that this is somewhat in flux. But I guess in light of the transition to the manufacturing, should we expect kind of similar timing between top line data and filing for OTC? Or would you expect that to potentially go more quickly after the manufacturing is in house? And then kind of along the same line on pricing, is it fair to assume that both GSD1A and OTC would be priced similarly?

Speaker 12

And I guess if not, what might be dropping the differences? Thanks.

Speaker 2

Yes. Well, the BLA, I don't want to predict exactly the timing of filing. We have transitioned manufacturing internally. We're running those we're running those runs and we have to go meet with FDA to make sure, for example, whether they require of our manufacturing to be in the filing, right, at the time of filing versus can be submitted at, let's say, during the filing. So those are factors that will impact the exact timing of filing.

Speaker 2

And we need to get the data and season in a pre lay meeting and get that straight. So we'll put out a little bit more data. Our expectation though is probably going to end up being if it's late in the year, it would be actually more likely next year to get all the pieces early next year. But right now, we don't want to make a prediction because of some pieces we have to get straight. With regard to OTC timing, well, that's a bit further out.

Speaker 2

I'm not sure I want to predict whether we're going to how fast that's going to go. What I can say is that if you look at everything we have and we don't know that everything will be successful, but we have in front of us 6 delay filings over the next 3 years or so, so something like that. So we're going to be busy, including 3 within the next year or so, right? So we'll be busy and I'm sure OTC will have to be fit in once the Phase 3 is out. With regard to pricing, I don't think there's a big difference in how we price GSD1 OTC.

Speaker 2

They're very similar population sizes and severity of diseases. OTC happens to have very expensive drug like RAVICTI, which a lot of patients use. They probably could justify pricing easier with regard to the cost production assuming patients were getting off their other drugs. But right now, we haven't put any stake in the ground regarding pricing. We're listening and watching what's going on and we'll come up with a plan we get closer in.

Speaker 2

Thank you.

Speaker 12

All right, great. Thank you.

Operator

Please standby for our next question. Our next question comes from the line of Salveen Richter with Goldman Sachs. Your line is open.

Speaker 14

Hi. This is Lydia on for Salveen. Thanks so much for taking our question and congrats on the progress. Just another on the end of Phase 2 meeting with the FDA for Angelman. What would you view as a positive outcome here?

Speaker 14

And could you just remind us how you plan to message to The Street post this meeting and what details you plan to disclose? Thanks so much.

Speaker 2

So I think positive outcome is essentially finalize the endpoint, palette of endpoints and statistical approach we're taking, As well as what's the ability to put that forth and get it a fileable for approval, that would be the idea. So while we already have agreement on basic studies, I want to set some comfort on the duration as well as the dose dosing regimen and the endpoints. But I think the majority issue will be finalizing endpoints with them and that's what people are most interested in. With regard to messaging, if we complete the meeting and have a very clear solution, we'll put out a notice to the street on that fact. Sometimes the meeting can be pretty clear, but there's still a couple pieces to solve, in which case we'd finish that discussion until there's a final agreement between FDA and us, and then we would only announce at that point in time.

Speaker 14

Thanks so much.

Operator

Thank you. Please standby for our next question. Our next question comes from the line of Jack Allen with Baird. Your line is open.

Speaker 2

All right.

Speaker 11

Thanks so much for taking the question and congratulations to the team on the progress made over the course of the quarter. I know a few people have poked around this idea, but what are you thinking about as it relates to expectations for the annual fracture rate in the placebo on the Orbit? And I also wanted to ask, are you matching patients based on their seasonal enrollment in the study? I recently did some work with the KOL and they mentioned that seasonality can affect fracture rates as well. Any context you provide there would be very helpful.

Speaker 2

Yes. Well, we don't have any way to control the seasons, but if we did so there's a lot of things that affect fracture rate. And one thing I'll tell you is actually coming into a trial will increase the fracture rate simply coming into the trial because they're transporting, getting out of cards. And in fact, in the Phase 2 study, 25% of the fracture occurred between screening in the beginning. It was like a lot of the fractures in their last year were actually part of the process coming to a trial.

Speaker 2

So I would say to you there's fractures and fractures that are harder to predict. What we have assumed right now, I think is about 0.67 fractures. The threshold to be in the study is 1 fracture per year, but we're assuming and people ask me why we'd be assuming that. Well, you don't want to assume the middle ground of what you expect. You always assume on the boundary.

Speaker 2

You want to pick a safe boundary. Our expectation is it should be higher than 0.67. How much higher will be somewhat dependent on who's enrolled, what happens to them, how far are they traveling, how many potential risks are there and the type of OI they have. But at the boundary of 0.67% and the 50% reduction, we have ample power for the study. And if the fracture rate is higher and the reduction is higher, you synergize those 2, we could have substantially more power than required.

Speaker 2

So I think we're in a good place in what we're positioning. But we've said 0.67 with the criteria for entry though of having at least 1 a year.

Speaker 11

Got it. Got it. That's great color. I guess just as there was a seasonality component, I understand it's a global study, the patient is going to be distributed and matched across the geographies?

Speaker 2

Yes, they will be. But remember, they're always going to be in small, you randomize a little blocks, right? So within any period of time, the blocks are small enough that you should be creating evenness. We'll also be stratifying based on fracture rate, right. So the patients with high fracture, low fractures are even numbers between the two groups.

Speaker 2

I will also point out to you the way the trial enrolled, it actually enrolled the majority of the patient enrolled between November March, right, probably. So they're all really in a pretty tight window, I would say as syncretively enrolled as we've seen in terms of number of patients.

Speaker 5

Yes. And the randomization should help with seasonality too, because you're not randomizing exactly 1 to 1, but you are trying to keep that balance through randomization. So that could help there as well.

Speaker 11

Got it. Thanks so much for the color.

Operator

Thank you. Please standby for our next question. Our next question comes from the line of Luca Isef with RBC Capital. Your line is open.

Speaker 15

Great. Thanks so much for taking my question. Congrats on the progress. Maybe circling back on the prior questions and the first interim look for COSMIC, maybe just ask slightly differently. In a scenario where the Phase 2 data is replicated and the 57% reduction in fracture is actually rectificulated in the Phase 3, would that be sufficient to hit the staff by year end?

Speaker 15

Or do you need to see something better in order to hit the staff by year end? So that's question number 1. And question number 2 on OI, can you just remind us the latest thinking on the competitive landscape? It looks like Amgen is actually running a trial Phase 3 versus biphosphonate in 5 versus 17 years of age versus you're obviously running a Phase 3 versus placebo in 5 to 25 years of age. How should you reconcile that difference?

Speaker 15

Why is the FDA asking them to run a trial versus biphosphated 5 and older versus you running a trial versus placebo? Any thoughts there? Much appreciated. Thanks so much.

Speaker 2

Sure. Well, I'd reconcile that ours is better, but that would be the simple answer. Our trial will be 5 to 25 against placebo, but we're also running 2 to 7 which gets bisphosphonate. So we can you'll be able to look at both sides of the story. But I feel confident that we're in good position.

Speaker 2

The data that Amgen put out in BMD, at 6 months was about half what we achieved. That was at their highest dose that they tested in their dosing study. So right now our data will look stronger than theirs just based on that. So far, we're not right now, we're not concerned. With regard to the COSMIC, 60% is one of the factors, the real other important factor is how many fractures really are going.

Speaker 2

For example, if it was 1.5 fracture that would greatly help the ability in the control group to hit the endpoint. If it's 0.67 or less, then it might take more time. So 6% to 10% is enough to hit it, but you need to have enough fractures. So that's the other those two variables are synergistic and how they impact things. So, we couldn't say for sure.

Speaker 2

I think trying to handicap whether the first one is going to hit, it's stringent. I think it's a relatively lower possibility of hitting, but we wanted to open the door in case fractures were high and the reduction was high and we were already off scale, they wouldn't keep going with those kids on placebo. And you can imagine, there's people, children. So continuing placebo when they're when you've already gone way past what's required, I think that's smart. So and better for them, the right thing to do.

Speaker 2

Thank you. Thanks so much.

Operator

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

Speaker 1

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

Operator

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.

Powered by Quartr
Earnings Conference Call
Ultragenyx Pharmaceutical Q1 2024
00:00 / 00:00