Ultragenyx Pharmaceutical Q2 2023 Earnings Call Transcript

Quartr
Provided by Quartr
August 3, 2023

There are 14 speakers on the call.

Operator

Afternoon, and welcome to the Ultragenyx Second Quarter 2023 Financial Results Conference Call. At this time, all participants are in a listen only mode. At the end of the prepared remarks, you'll have the opportunity to ask a question during the Q and A portion of the call. It is now my pleasure to turn the call over 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 Kakas, Chief Executive Officer and President Eric Harris, Chief Commercial Officer Eric Cromdes, Chief Medical Officer Aaron Olson, Senior Vice President of Corporate Strategy and Finance and Ted Huizenga, Chief Accounting Officer.

Speaker 2

I'd like

Speaker 1

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

Speaker 3

Thanks, Josh, and good afternoon, everyone. It has been a year of increasing momentum marked by advances in our lead clinical programs, which we expect to result in multiple important data catalysts over the next few quarters. At the same time, our excellent commercial efforts continue to drive meaningful revenue growth across the portfolio, including Crysvita revenue in North America with our I'll spend a few minutes discussing the oxygenation imperfecta and Angelman syndrome programs Before turning the call over to Eric Harris to talk through our commercial update. Beginning with OI, In June, we reported exciting data from the Phase 2 dose finding portion of the pivotal ORBIT study showing statistic Significant increase in levels of serum P1NP, a sensitive marker bone formation. The bone production response to these patients This led to a rapid bone building effect following just 3 months of treatment with cetuzumab resulting in Nearly 10% increase in lumbar bone mineral density.

Speaker 3

At baseline, these patients had very limited bone marrow density with an average Z score In the 20 mid cohort of minus 2.12, which means the bone density was 2 standard deviations below the mean of normal patients for their age. After 3 months on therapy, the mean Z score increased by plus 0.65 points resolving nearly 1 third of the deficit from normal in a relatively short period of time. As we've said before, patients are showing meaningful improvements in bone health and we are highly encouraged with how they're doing. Improved bone health refers to the instance of fractures, bone pain and relative global health and activity to patients. In the ongoing Phase 2, we continue to collect data to compare fracture frequency during the CONFID study to show the impact of cetuzumab And increase the bone marrow density on fracture rates.

Speaker 3

We expect to share this data at an Analyst Day in mid October around the time of the ASBMR, The major phone focused meeting. In July, we announced that we initiated dosing patients in 2 Phase 3 studies evaluating cetuzumab in 2 different age groups. The Phase 3 portion of the pivotal ORBIT study is evaluating the effect of cetuzumab compared to placebo on analyzed clinical fracture rate in patients 5 to 25 years old. The newly initiated Phase III COSMIC study is an active controlled study evaluating sotuzumab compared to IV bisphosphonate therapy on annualized total fracture rate in patients aged 2 to 5 years old. Enrollment in both of these studies is going well so far in part because the Phase 2 data has generated a lot of excitement for the potential cotuzumab for both the clinical sites and from the patient community.

Speaker 3

Moving to our angiogram program. In May, we announced we received FDA agreement to expand the ongoing global Phase onetwo trial of GTX-one hundred and two to patients with Angelman syndrome in the U. S. The protocol amendment enabled us to harmonize the dosing range of use between the U. S.

Speaker 3

And ex U. S. Cohorts of the study. Since then, we've been working to activate U. S.

Speaker 3

Sites that have been on hold for a couple of years. We continue actively enrolling the expansion cohorts globally. Enrollment and expansion course is going well, particularly over the last couple of months. As of today, we've enrolled more than 20 patients. While we are on track to have 8 patients with a full 6 months data by the end of the year, we've noted that waiting just A few more months will enable us to report a more substantial update on well more than 20 patients with 6 months of clinical data plus safety data and all enrolled.

Speaker 3

So the trial is going well, it seems more prudent to wait for this larger set of expansion core data, which we expect to have in the middle of the first half We will also be providing the management program updated at Analyst Day event in mid October. This is an opportunity for us to provide more context for the clinical meaningfulness of the changes that have been observed in the study. Now I'll turn the call over to Eric Harris to provide an update on our commercial efforts for the Q1.

Speaker 4

Thank you, Emil, and good afternoon, everyone. On April 27, 2023, 5 years after we began Our highly successful Crysvita commercialization efforts, we transitioned the North America commercialization responsibilities To our partner, Kiowa Kirin, in the Q2 of 2023, the combined teams in the U. S. Continue to generate new start forms and have provided continuity of care for the existing patients. Our close collaboration and planning for the transition over the past 2 years has resulted in a seamless transition, continued revenue growth and importantly, minimized the impact on patients and their providers.

Speaker 4

As a reminder, a smaller Ultragenyx commercial team will remain in place supporting the Crysvita program in the U. S. Alongside their KKC counterparts through April 2024. Even beyond that time, Ultragenyx will continue to retain the responsibilities to promote Crysvita to medical geneticists in North America. We are thankful for the successful collaboration and expect to continue expanding penetration in the adult and pediatric markets.

Speaker 4

Shifting to Crysvita in Latin America. The team has continued to build impressive momentum in the region. As of June 30, There were approximately 410 patients on reimbursed therapy, which includes approximately 65 new patients who began commercial therapy in the quarter. Latin America is beginning to approach the same rate of commercial patient approval as we saw last year in the U. S, which bodes well for the long term potential in the region.

Speaker 4

Each country has its own process to obtain regulatory and reimbursement approval, but our team has been diligently working to facilitate broad access to Crysvita despite the hurdles. I expect the underlying demand for Crysvita in Latin America to continue growing at a steady rate and becoming an increasingly greater contributor To the Ultragenyx commercial story. Today, we are reaffirming the Crysvita guidance we issued at the beginning of the year. The range of $325,000,000 to $340,000,000 includes all regions and all forms of Perspeda revenue. More specifically, it includes Crysvita product revenue from Latin America and Turkey, the cash and non cash royalties from North America and Europe, And the collaboration profit share revenue prior to the transition.

Speaker 4

I'll now turn to do JOVI and begin in North America. In the Q2, we modestly expanded the U. S. Do JOVI commercial team With seasoned personnel from our Crysvita team to support continued growth and adoption of DEJOVY. During the first half of twenty twenty three, we added 61 completed start forms.

Speaker 4

We also increased reimbursements to 54 reimbursed patients in the first half of twenty twenty three. We continue to expand the number of treatise of Dajovy adding 18 new prescribers, including some healthcare professionals in centers for neuromuscular medicine. In Canada, We continue to make steady progress following the positive opinion we received from CADEV, completing pan CPA pricing negotiations and signing provisional listing agreements. In Latin America, we are continuing to leverage our existing infrastructure To commercialize Dajolviv. The patient find efforts have generated a growing number of patients with a confirmed diagnosis across Argentina, Brazil, Mexico and Colombia.

Speaker 4

We are continuing to work with the authorities across the region to ensure Dajovin is available for all patients

Speaker 2

who could benefit from this therapy.

Speaker 4

Across Europe, we continue to deepen awareness of LC FAOD with key stakeholders and address the high unmet need through named patient and early access programs. Requests are coming from all across all major European markets as well as Greece, Israel and the Middle East. We continue to expect 2023 global dojopy revenue To be between $65,000,000 $75,000,000 reaffirming the range we announced at the beginning of the year. Lastly, I'd like to touch on Efkeza. The team is focused on unlocking access across all markets In the EMEA region, deepening the awareness of HoFH and the urgency to treat and reinforcing FQESA's Unique profile among stakeholders.

Speaker 4

Across the region, a steadily growing number of patients are gaining access to Efkeza Through various early access programs, we are on track to launch in certain key EU markets over the next 6 months and the field teams are preparing the markets accordingly. Outside of the U. S, we are continuing to prepare for launches in Canada, Japan and other major markets around the world, further expanding global access to this important therapy. Across all regions, we have received overwhelmingly positive feedback for Akeza from KLLs and patients, and they have continued to highlight the significant unmet need for this treatment. Our teams will continue their efforts to bring this product to people living with HoFH as quickly as possible.

Speaker 4

In closing, we are reaffirming our 2023 total revenue guidance range Issued at the beginning of the year of $425,000,000

Speaker 3

to $450,000,000

Speaker 4

With that, I'll turn the call over to Aaron to share more details on the financial results for the quarter.

Speaker 2

Thanks, Eric. Earlier today, we issued a press release that included financial results for the quarter, which I'll briefly summarize. Company revenue for the quarter ended June 30, 2023 totaled 108,000,000 Crysvita revenue for the quarter was $83,000,000 which includes $61,000,000 from North America, dollars 16,000,000 from Latin America and $6,000,000 in European royalty and other product revenue. The Crysvita revenue figures for North America and Europe are inclusive of non cash components as a result of our previous royalty financings. As we typically remind you, ordering patterns in Latin America can fluctuate quarter to quarter.

Speaker 2

We are continuing to see significant growth in the underlying demand for Crysvita. The JOLBY revenue for the quarter was 16,000,000 Continued strong North America demand driving 22% growth versus the Q2 of 2022. Netsevi revenue at the same time period was $8,000,000 It's worth noting that sevi revenue maintained the same level we saw in the Q1, largely driven by new patients in Brazil and strong ordering from the U. S. Even 6 years after launch, this Ultra Rare product continues to grow in patient accrual and geographic reach.

Speaker 2

Our total operating expenses The quarter ended June 30, 2023 were $256,000,000 which includes R and D expenses of 165,000,000 SG and A expenses of $81,000,000 and cost of sales of $10,000,000 Operating expenses for the quarter include non cash stock based compensation of 35,000,000 And a one time milestone of $9,000,000 payable to Mireo upon initiation of the Phase 3 ORBIT study in OI. For the Q2 of 2023, Net loss was $160,000,000 or $2.25 per share. We ended the quarter with approximately $618,000,000 in cash, Cash equivalents and marketable securities. As expected through the first half of the year, cash used in operations was disproportionately greater than what we expect in the second half of the year. This is primarily driven by the timing of annual bonus payments and changes in certain working capital accounts.

Speaker 2

Additionally, we expect operating expenses to decrease in the second half The year driven by realized cost efficiencies and substantially reduced Crysvita North America commercial expenses with the conclusion of the profit share period in April. With the impact of these cost reductions, projected second half revenue growth and the timing of the working capital changes previously mentioned, We expect 2023 net cash using operations to be around $400,000,000 Now I'll turn the call to our CMO, Eric Crombez, We'll provide an update on our key clinical programs.

Speaker 5

Thank you, Aaron, and good afternoon, everyone. Emil has already discussed The progress in the quarter for the osteogenesis imperfecta and Angelman programs, so I will briefly touch on the latest progress in our gene therapy pipeline. Starting with UX701 for the potential treatment of Wilson disease. Earlier this week, we announced that we have begun dosing The 2nd dose escalation cohort in our pivotal study following completion of dosing and data review from the 1st cohort. In this first stage of the pivotal study, we are evaluating the safety and efficacy of up to 3 dose levels to determine the dose for the 2nd stage of the study that will support registration.

Speaker 5

In July, the Data Safety Monitoring Board agreed But it was safe to proceed with dosing patients with a higher dose of 1,000,000 and 13. The first patient in Cohort 2 has already been dosed and the other 4 patients have been identified. This gene therapy is designed to directly address the underlying cause of disease by establishing the normal trafficking of copper. This will address both the toxicity of free copper and the copper deficiency driving many of the signs and In the first dose score, UX701 has been well tolerated With no unexpected related treatment emergent adverse events observed as of July 11, and there are early signals of the establishment of normal Initially, study entry required well controlled signs and symptoms of Wilson disease on current standard of care, Which proved challenging and resulted in a large number of screen failures as many patients, for example, still had elevation And liver transaminases despite optimized chelator and zinc therapy. This tells us that even with current standard of care, There remains real unmet need for these patients.

Speaker 5

After additional discussions with regulatory authorities, we have Changed entry criteria, enrollment has accelerated. We are now on track to complete enrollment in Stage 1 around the end of the year and Expect to share initial data in the first half of twenty twenty four. Moving to DTX401 for the potential treatment of glycogen storage disease type 1a. It is important to remember that all patients in the Phase onetwo study responded and showed meaningful reductions in their dependence on oral glucose replacement therapy. These patients have demonstrated a durable response with patients moving into their 4th 5th year of follow-up with more detailed data presented at ASGCT in May.

Speaker 5

As we have previously disclosed, the Phase 3 study was fully enrolled earlier in the year. We expect data from the 48 week primary analysis period to read out in the first half of twenty twenty four. We look forward to sharing the 1st Phase 3 data generated by a gene therapy portfolio next year. Quickly on DTX301, For the potential treatment of OTC or ornithine transcarbamylase deficiency,

Speaker 1

enrollment in

Speaker 5

the Phase 3 study began earlier this year And this is a 64 week study that is designed to enroll approximately 50 patients. We are gaining meaningful traction with recruitment of this study, Especially as more healthcare providers and patients appreciate the Phase onetwo data with durable responses lasting more than 5.5 years with more detailed data also presented at ASGCT in May. Currently, there are 15 active global sites With additional site activations pending regulatory and IRB feedback in Italy, UK, Japan and Australia. We look forward to providing enrollment updates over the coming quarters as this program continues to build momentum. I'll now turn the call back to Emil to highlight the key upcoming milestones and provide some closing remarks.

Speaker 3

Thank you, Eric. I'll summarize the key upcoming clinical catalysts before we open up for Q and A. Starting with UX-one hundred and forty three for ossigens and Perfecta, Enrollment in both of Phase 3s is going well, supported by meaningful demand from patients. Our goal is to have both of these studies fully enrolled around the end of the year. We also plan to provide additional clinical data from the Phase 2 portion of the study including fracture data at Analyst Day in mid October.

Speaker 3

Next, GTX-one hundred and two Engagement Syndrome. We're planning to give an update on the program at the Analyst Day in mid October. That would include some information about the treatment effects we have observed so far in the earlier dose cohorts. We expect to share expansion data in the middle of the first half when we're able to share 6 month data on at least 20 patients. Closing with our gene therapy programs, UX701 We'll see these enrolling patients in the dose finding stage.

Speaker 3

We're excited about completing the first cohort and starting the second. We expect this dose finding stage to be completed around the end of the year Data on safety initial size of efficacy expected in the first half of twenty twenty four. CTX-four zero one for GSDIa dosed the last patient in pivotal study earlier this year. We're now in the 48 week window and expect to share this Phase 3 data in the first half of twenty twenty four. Through the first half of the year, we've made meaningful progress across all of our priority initiatives.

Speaker 3

We finished and opened our gene therapy manufacturing facility outside of Boston At just weeks successfully completed the 1st manufacturing run. This is not a modular assembled plant or refurbished clean rooms, For the true Grand Lift design and build state of the art GMP manufacturing plant. To build a great plant is hard, but To do it during the pandemic, to stay on time and on budget is exceptional. We give great kudos to our team on this accomplishment. In the Q2, the Corus team continued to deliver meaningful revenue growth with the LatAm Cresita franchise doing particularly well, becoming a larger contributor to the company's financials.

Speaker 3

Across the globe, our development teams are advancing one of the largest late stage rare disease clinical pipelines in the industry and we expect to generate a number of important data catalysts over the next few quarters. With that, let's move on to your questions. Operator, please provide the Q and A instructions.

Operator

Our first question comes from Gena Wang with Barclays. Your line is open.

Speaker 6

Thank you. One quick question regarding the AngiMend program. In mid October update, what clinical measurement will you be Presenting. And is Baileys your key measurement? And if so, what is your bar for efficacy to move forward?

Speaker 3

Yes. So our plan with when we will talk about there is folks only include means of the effects We're seeing and the information on the Baileys and that comparison was something we'll focus on with the expansion cohorts where we have a large number of patients Compared to a larger number of natural history patients to give you the kind of quantitation maybe you seek. So the October will focus more on the clinical meaningfulness And not so much on the detailed quantitative information. We'll reserve that for the expansion cohorts.

Speaker 6

Okay. Emil, so maybe follow-up quick follow-up questions. So based on the natural history, what would be the Bayley's, say, the change that you consider will

Speaker 3

Well, we've already Put forth that the size of change we've seen we thought were clinically meaningful. So the amount you've seen before is there. I think I'd rather not go deeper into it. I think we need to do it in a more deeper context with data at hand. I'd rather not go deep into that discussion at this moment.

Speaker 3

But When we put out the Bayley data and we put out the other data, we'll have the clinical meaningful thresholds, Quanti, it'd be the natural history data to look at. And I would not focus only on DAILIES. I see there's also other endpoints we're going to be looking at We're still working through the data from our expansion cohorts to help us really nail down what's the right answer. And so still in the mix is The global impression scale CGI scores, which FDA has accepted as primary, which would allow you to cover more domains essentially and be more Angelman specific. So we're still looking at a number of those particular endpoints, but the truth is we've had relatively small amounts of data from these escalating cohorts.

Speaker 3

Expansion data allows us to really get a large number of patients treated the same way and to give us kind of quantitation to really answer your questions in a robust way, which is not quite there yet. But I feel good about where we're at in the program and the fact that we have a drug that works and that we need to Figure out how to move to the Phase 3.

Speaker 6

Thank you.

Operator

One moment for our next question. Our next question comes from Lisa Baker with

Speaker 7

Hi, there. Can you just give us a sense of Have your level of confidence about, what you're seeing in, the OI program and how the changes And bone mineral density, relates to potential changes you might see in fracture?

Speaker 3

Yes. We have a high level of confidence that the magnitude of bone rod lift we saw at 3 months was already sufficient enough To improve the strength of bones and probably reduce fractures at that level we saw at 3 months in. So we have High confidence in fact that bone marrow density when improved by this mechanism, the antiscalculoskeletal mechanism where you're getting anabolism or production of new bone We'll translate into fracture improvements and we've talked about that on clinical data in the past, but we'll be able to talk more about this at the October Analyst Day to provide that support, but we have a high level of confidence that the BMD produced by Nantisk Glass Lexituzumab We'll translate into fracture reduction.

Speaker 7

Just as a follow-up on that, can you explain to me the Amount of sort of the bone marrow density levels of OI patients, how do they relate to those of Osteoporosis patient, because I'm just trying to kind of relate the two changes, the amount of changes you're seeing to what we outcomes we've seen in osteoporosis. It seems to me maybe the Bone marrow density levels are slightly different. Can you expand on that at all?

Speaker 3

Well, sure, Lisa. What we said from this Population in this study is that the mean bone marrow density was minus 2.12, which means 2 standard relationable to the mean of normal people. Now osteoporosis patients have reduced a bone marrow density. I don't have for you exact comparisons to put forth, but I would say The mean of minus 2 standard deviations is pretty low on the bone scale. And if you look at the range, we have patients as low as minus 4 And deviation, so these patients have I think a more severe on average bromal density problem than an average osteoporosis patient would and therefore have more need of bone production.

Speaker 3

What has been the misunderstanding is everyone thought that the defect in the Collagen was why the bones are fracturing. What we're kind of trying to say is actually while that may be a factor, it's in fact the effect of that mutation On bone production appears to be a bigger factor and that's something we can change with cetuzumab and that's why we think we're going to have an important effect on OI.

Speaker 7

Thanks.

Operator

Our next question comes from Maury Raycroft with Jefferies. Your line is open.

Speaker 8

Hi, thanks for taking my question. Based on the expansion data in first half of twenty twenty four, Is the timeline for the pivotal study start shifted out some? And have you received any preliminary feedback from regulators on your data so far and what And is this something we can learn more about in the mid October update?

Speaker 3

Yes. I don't think actually the timeline changes the timeline for what the Phase 3 is going to be, because we're going to be setting up the protocol and the plan and endpoints Even before the full data are available. So we'll already have understood what's going on. We'll have our discussions with the FDA Soon after that and have a full protocol ready to get kick in and get going in 2024. So it doesn't really change that timeline.

Speaker 3

It changes the time line of how much we know and when, but we're going to be gaining ground during the year and we expect to talk with the clinical outcome group at FDA, the coa group This year, we haven't talked further yet with FDA. We're looking at when we want to get to them. They said we could go to them. We'll look at When we want to start talking to them about endpoints, they appreciate that this will require a lot more discussion than an average program Being a first ever in a very complex developmental disorder, but with the first meeting with Koa, we'll get some ideas and feedback. We'll gain our data as we go along this year, but I would expect in late in the year, early next year, we'll have a What we think the endpoints will be, the data will then further finalize the decision on dose regimen and allow us to head to And then the Phase 2 meeting in the first half is our expectation and to think about Getting to a Phase 3 study then next year.

Speaker 4

Got it. That's helpful. Thanks

Speaker 8

for taking my questions.

Operator

Our next question comes from Joseph Schwartz with Leerink Partners. Your line is open.

Speaker 7

Hi. I'm Julie dialing in for Joe. Thank you I have 2 on UX701 for Wilson's disease. First, could you talk about your decision to move to an open label design and broadening Inclusion criteria in Stage 1, how do these two factors impact the efficacy results, if any, and If any that we're going to get for the data that we're going to get in the first half of twenty twenty four. And secondly, I believe in your opening remarks, you mentioned timelines around Cohort 2, But I'm curious about Cohort 3.

Speaker 7

When can we expect the Stage 1 Cohort 3 patients to be dosed and will the Cohort 3 data be included in the

Speaker 3

Sure. Well, I'll start with the last part. It's our expectation when Talk about first half is to talk include Cohort 3 patients and the point at that point would be to make a decision on dose And to then kick off enrollment of Phase 3, because it's a combination study, we go right to Phase 3, we make the call, make the decision and move. So the beauty of that is it will cut out any dead time. It's already agreed on the endpoints and moving forward.

Speaker 3

But let me let Eric Crombez Talk through the open label and the criteria changes and the reason for those and in the conduct of the study.

Speaker 5

Yes. No, I think in the context of a single site registration, it's always tempting at the beginning to kind of go to a double blind format there, but the truth is we do want to learn in that initial stage there and the blinding was really kind of hindering that. So that was In large part, the driver to moving Delta label, and I think it was absolutely the right decision, reviewing the data and really looking at those early signals after The readout from our first cohort. And as far as entry criteria, a gene therapy has never been studied in And certainly, it makes good sense to want to put any liver directed gene therapy into as healthy of a liver as possible. I think a lot of treaters out there would say their patients are very good, their team is good and does a very good job of managing the patients.

Speaker 5

The truth is, is once we started screening a large number of patients, we realized most of these patients do not have LFTs In the normal range, meaning that they're still really having effect on the liver from the toxicity of that free copper. But we needed to collect that data and have that discussion with the agency in order to adjust those entry criteria to allow more patients to enter the study.

Speaker 6

Okay, got it. Thank you.

Operator

Our next question comes from Ygal Nachosovitz with Citigroup. Your line is open.

Speaker 9

Yes. Hi, thanks. Another one on 701. I think you mentioned that you're seeing early signals of normal traffic of copper. Can you expand on that a little bit?

Speaker 9

Is the goal of this gene therapy to get patients back into the normal range of copper or just closer to normal range? Thank you.

Speaker 3

It's a little bit early. I'll let Eric comment, a little more on that, but it's a little bit early to go deep into the data since it's just the first cohort. But the goal of the program certainly was to try to improve copper distribution sufficiently to remove copper deficiency, which we believe It's occurring in not fully understood in many patients. And so, yes, we haven't set a threshold Requirement for how much that would be, but our goal is by having both detoxification and some improvement distribution, we think we can have a much bigger impact than you can with distillation. Today you want to talk about the early signals of copper.

Speaker 5

Right. And I think that's really the point here. I mean chelators have been great for this patient population, but chelators Buying copper that's freely in circulation, you're not pulling copper out of these hepatocytes where it's Accumulating, so again that the fact that you have elevated transaminases, it shows that you're not excreting copper into the bile And you're not loading copper onto ceruloplasm, which is how it traffics to cells for copper to act as an important cofactor for a lot of enzymes. So when you look at how you're measuring coppers for a chelator, it's different than how we're looking at Copper levels, whether it's urine, blood or from whatever capacity, once you establish normal trafficking patterns. And then importantly, we are still are looking at activity based assay, which shows the loading of copper on the ceruloplasm.

Speaker 5

So really a very direct measure of the effect of this gene therapy.

Speaker 3

Yes. So the trapping is, We have direct measures near what they're looking at to give us that sense, which is what the description of improving copper trafficking can come from. But it's early yet, it's cohort 1. We have more cohorts to go.

Speaker 9

Thanks, Amil and Eric. And then on Angelman, just operationally, can you comment So the update in October and then for the one next year, how many of the patients under the U. S. Protocol are going to be represented in each of those updates, just ballpark?

Speaker 3

Well, you see in October, most of The patients are in the program are ex U. S. There's only a small number that were on 2 mg that are now shifting to a higher dose as cohort E. So it's a relatively small number of U. S.

Speaker 3

Patients are involved in that exact number, I don't think it's worth knowing. We put in the data release how many patients we have, but I think what we What's probably most important, we talk about expansion, we're seeing well more than 20, it will be significantly more than 20 that we'll have 6 months of data. So that's why we can do a little more statistical analysis and have a group people all treated the same way, whereas in the Exhalation cohorts, they were treated different ways, different doses and it's not as easy to analyze. So there'll be a small number of U. S.

Speaker 3

Patients In the fall, but a larger number with loaded the correct way that will be represented in the First half update on the expansion cohorts.

Speaker 9

Okay. Thank you.

Operator

Our next question comes from Dave, Ganha, Ustifle, your line is open.

Speaker 10

2 from me as well. One, a commercial question. Just Wanted to clarify what the revenue numbers, it seems like there was a jump in the EU derived royalty. Can you maybe delve into what happened there and what the rest of the year may look like from the EU side of things? And then second, on the clinical side, So looking at the press release on GTX-one hundred and two, you mentioned the encouraging dose and time dependent clinical activity.

Speaker 10

I was wondering if you can speak to any inter patient variability here. Is there a certain duration of follow-up or certain doses that you're starting Convergent for deriving therapeutic benefit or is this still very much individualized? Thanks so much.

Speaker 3

Great. Well, I'll start with the second part and then Either Eric or Aaron can talk about the EU part. So what we said is that as we look through time and we even publish Some of that presents some of the day in July that the day 128 data is not as strong as it is at day 170 that going a little longer, particularly some patients have A significant improvement in that timeframe. There's no doubt there's some variation between patients and responsiveness. Some are responsive at very low doses, some need higher doses.

Speaker 3

And that will be true no matter what. Our goal in the expansion course is not to find the perfect dose for all patients, but to find A very good dose, it gives a good effect to a large number of patients. But our expectation in the long run is that there may be some need to be individualization and titration. And it's just hard to run that in a Phase 3 program. So the main goal of expansion is to find a dose that works The majority of patients that works well and we think we can do that.

Speaker 3

We see changes in all patients. All of them have improvements, but There's definitely some variation in the degrees of sensitivity and we're still learning more. And truth is we've treated relatively small numbers of patients now For a year, it's about I think it's more in the 13 that have a year or so. And with the expansion cohorts, it's going to allow us to get 40 patients on drug and really learn something about at 40 patients treated the same way, right, and get a better handle on the range and sensitivity. But our expectation is

Speaker 2

there will always be some

Speaker 3

variation and we'll manage it. But But our expectations will always be some variation and we'll manage it. But I think if we can get a majority of patients having a good Treatment effect, a significant transformative change of life, then we'll be able to manage an extension getting to the right optimal place. So let me leave that with that and let Aaron, I'm going to talk

Speaker 2

about the EU. On the EU, the non cash royalty did not jump in Q2, but as a reminder, there is a part of our North America royalty that is non cash now, and we can follow-up offline with any other questions.

Speaker 9

Thanks. Kevin, let's move on to the next question please.

Operator

Our next question is from Yaron Werber with TD Cowen. Your line is open.

Speaker 11

Great. Thanks for taking my question. So Emil, I got 2. 1, just on Angelman in the sense, how many patients do you think You want to have in Phase 2, nail down the power in for the Phase 3. And secondly, and potentially even nail down the schedule, the dosing schedule.

Speaker 11

And then secondly, on Sanfilippo, The program, the gene therapy program that you licensed in the based on that Phase 1, Phase 2 data, is there any way You can file for accelerated approval just given FDA's new overture on accelerated pathways, even though that data was Still early, not perfect, while you're doing a Phase 3 confirmatory. Thank you.

Speaker 3

Yes. Thank you, Yaron. So on the Asian program, We do have a lot of patients from the extension that are on drug for a long time. So that's a chunk of patients that help us in deciding the Phase 3. We'll announce in the mid part of first half data from at least 20, it will be well more than 20 of data.

Speaker 3

We'd expect to have 40 plus enrolled, maybe even closer to 50 enrolled. And so by towards Q2 or so, we'll have a lot of data on all those patients that will help contribute to the final decisions on dose and regimen that we'll be making. So hopefully that gives you kind of an outline of how much data we expect to have. We definitely think you need more than a handful to make this kind of decision and 20 or so, 20 plus will be a good number to make A handle on what we have, but before we actually pull the trigger on the Phase 3, we expect to have 40 patients worth of data or more To be confident that we've got the dose exactly right and we're picking the right things. So on Sanfilippo syndrome, a clover approval is near and dear to my heart.

Speaker 3

I've been Fighting for inborn areas for like nearly 30 years. Read my book, David Ryan. Anyways, The truth is that the FDA wants and particularly Peter Marks wants us to do XR approval, but it's hard to get reviewers Kind of agree. We are working with the FDA potentially on a workshop to talk about that. What I'd say to you is on our own sample program, it's Not exactly licensed, I guess it was licensed, but it was handed off to us.

Speaker 3

And we're excited to help these patients get forward. We did have to put into play some of the CMC part of the story, making the product has to get made. And a lot of the time line is driven more about getting CMC set up than the actual data part. So in the end of the day, Even if they said today they could we could file, we're still not ready because of the CMC part. So We're going to work on getting SLA approval.

Speaker 3

I do believe there's an appreciation, but now we need to get some degrees of science and start doing it. And we're setting up for the group of companies to go to the FDA and have a workshop and talk through that. And I've been advocating the FDA both in Editorials and in meetings about the need to start seeing the science differently and we hope we can get that to happen. I think if we can get that to happen for Sanfilippo and other MPS disorders, it opens the door to us actually getting the benefit of precision medicines that we have trouble Fully capturing today with a system that's just not designed for rare complex neurological diseases needing treatment.

Operator

Thank you. Our next question comes from Joon Lee with TD sorry, Churrus Securities. Your line is open. Thank

Speaker 8

you for taking our questions. I have a couple. On satrusumab, what's the value of doing an active comparator study against IV This is phosphonate, which is off label. Are you looking for non inferiority or superiority? And how did you power the study?

Speaker 8

And on GTX-one hundred and two, in light of the recent discontinuation of Rugo Nordson, what gives you confidence that 102 can succeed In Angelman, where Rubenerson with all the resources that Roche has to offer fail to advance? Thank you.

Speaker 3

Sure. So On cetuzumab, our original plan was to do the placebo controlled trial as the gold standard without an approved therapy. The truth is they're really young patients. There was more concern that those patients who have very high fracture rates couldn't go be on a placebo and there was resistance to that. At the same time, people are using off label bisphosphates and people have impression of them as being standard of care, those off label.

Speaker 3

And so Our view though is that the potential effects to TRUVV should be far better, far superior to bisphosphonates. But The best way to get that is to actually study it and prove it. With the bisphosphonates, 5 core randomized studies have been completed, 3 failed, 2 succeeded. The treatment effect size is a 20% reduction in fractures. So it's not very much.

Speaker 3

Patients do seem to feel better with it, which is why it's being used. In our trial, we're planning to do superiority of cetuzumab to bisphosphonates and we think the high fracture rate of that population and our expected effect on those fractures To generate a successful study that throughout the world, all global areas where there may be reimbursement questions It will show why strutsavab should be standard of care for OI and not just a second line treatment. And that's what that study will do. It also particularly important in Europe where comparison to drugs are being used is important part of Getting good reimbursement. So there's a number of factors on all that.

Speaker 3

Now on the GTS-one hundred and twelve and Roche, Rugenerys and Termination. We've been saying from the beginning that there are many ways to go after the Asian locus, but the locus specific Region that we are working on is more potent and it's because it's near the 5 prime end of the message. This is the work that Doctor. Dindo had Roche and Ios are working in Further downstream, when we've made those molecules, we do not feel they're as potent. The only data comparison was that Roche Required 24 milligrams to do what we were doing with 1 or 2 milligrams.

Speaker 3

I think whatever happened to the trial, we don't know. We only know it's public, but They weren't able to achieve a dose level applied safely that will allow them to get their knockdown they required to achieve what their particular goals were. But In my view that was somewhat expected because I think the potency was not enough and I don't think it speaks at all to the mechanism which We know from our data in our own hands that we're having a transformed effect on Angelin patients and One that I think will be extremely important to them and that's operating at the dose ranges of 5 milligrams to 14 milligrams. So that is what I think. I think it shows why the science matters and sometimes one really smart guy can beat a company With large amounts of money.

Speaker 8

Thanks, Emil.

Operator

Our next question comes from Salveen Richter with Goldman Sachs, your line is open.

Speaker 2

Thank you

Speaker 12

for taking our question. This is Tommy on for Salveen. Just trying to And maybe more the format of the Angelman release at the Analyst Day. Is it going to be in a similar kind of presentation as, for Since the update last year and any more detail you can provide on follow-up or patient numbers and just if you have any updates on how the OTC Phase 3 enrollment is progressing. Thank you.

Speaker 3

Sure. I'll start with Aungement and maybe Eric can comment on OTC enrollment. So it's interesting to ask about what the release is going to look like. You actually want the categories, the size of the treatment effects. We all want to know.

Speaker 3

It's not going to be the same as July, because in July we put out a lot of raw information, which we were personally quite excited about at the company and that We received we had a complex response from investors because it wasn't well digested. What we're talking about on Analyst Day is Not like that situation where there's a lot of granular data. It's going to be more high levels, going to talk about clinical meaningfulness information That will provide to help give people a better feel why we as a company are confident on the importance of this therapy, But it will not be focused on the quantitative data, which we said would be we'll let drive the expansion cohorts, the large amounts of data to be able to do what I Call the day driven statistical kind of look at what we're seeing, right. So it's a little bit more about political means for this and it will be higher level

Speaker 5

And then for OTC, like we commented, it's doing really well. Again, designed very similarly with a similar global footprint with clinical trial sites to GSDIa, so the truly global Phase So, really good enrollment rate, and really tracking well to finish up enrollment next year.

Speaker 9

Thanks. Next question please.

Operator

Our next question comes from Christopher Raymond with Piper Sandler. Your line is open.

Speaker 7

Hi. This is Nicole Gabreski on for Chris. Thanks for taking the question. So just going back to the Wilson program, and sorry if I missed this, I guess I was wondering if you could just expand on the changes you made for the patient inclusion criteria in the current study. And I guess Was this just primarily around baseline liver transaminase levels that were modified?

Speaker 7

And then I guess just beyond this, does this change your thinking at all about The potential addressable Wilson patient population for gene therapy?

Speaker 5

So, yes, so the 2 big Parts of entry criteria that changed were the LFTs. After initial conversations with the FDA really wanting these LFTs very close To the normal range, with patients not being able to achieve that in case we were able to have that conversation and allow patients and With somewhat, I would say, mildly elevated LFTs and that was important. And then also, stability of copper levels On chelators and zinc, I think most people would tell you that those are relatively stable and easy to control. It turns out they are not. So quite a bit of variability in copper levels regardless of where you're looking.

Speaker 5

So then again, really changing that criteria to allow enrollment to really accelerate. I would say we've always had high For this gene therapy, we do think with all of really kind of how we target these diseases, replacing what's missing is important here. Chelators have done a great job for these patients. But again, we want to affect both the toxicity free copper, which Chelators does A decent job of addressing. But then again, with these signs and symptoms of patients who are not well managed on chelators, We think it's really driven by the fact that copper is not able to traffic to cells and tissues that need copper DAC As a cofactor for some important enzymes, so again, addressing both parts of this disease and I think, yes, Really broadly applicable to all patients living with Wilson disease.

Speaker 3

I would add that I think our view of the addressable market has gone up. We used to say it was a fraction that might have severe disease not managed by chelators. The Alexion AZ chelator also has been pulled because it really wasn't helping that probably opens up The addressable market, because there's some view that maybe that chelator would be better, but it wasn't. Given our knowledge of how many people have transaminase and copper issues still a no feel right. I do think the addressable marker for Wilson could be higher.

Speaker 3

If we see a great effect in copper distribution and symptom improvement otherwise, I There's a possibility that turns out to be, a more important player, Wilson, a bigger fraction of the population. We still have more data to collect. We're not Not there yet, but I do think the possibility that this could become a more important and major that all the most For all patients who will listen to be addressable, I think it's a possibility, which I think makes this a really important program to push ahead as we are.

Speaker 7

Great. Thank you.

Operator

Our next question comes from Kristen Kluszko with Cantor Fitzgerald. Your line is open.

Speaker 13

Everyone, thanks for taking my question. Just one on manufacturing, given the size of your new facility, How much flexibility does this allow you to expand beyond the current pipeline? And maybe what are some of the mid- to longer

Speaker 3

Yes. The plant gives us a lot more flexibility because we can flip and switch What we do, we're still in the build up phase in terms of how many runs we can run, but that will accelerate quickly. And we also have a second suite that we can outfit and operate, which would get us to be running 32 runs a year. So I think we probably would have capacity to do for example, if we did partnerships or other deals, we could offer manufacturing plus the Piece of those type of deals is something we could do. But I would say to you, we have really one of the larger AAV Programs out there with 3 programs in Phase 3 Williston OTC GSD1a plus We also have potentially to put in the plant the UX-fifty five, the CDKL5 deficiency gene therapy, which is Heading to our 9D and it was actually the subject of the first run-in the plant.

Speaker 3

We also have a program we talked about too often as the Duchenne program, which is coming And potentially some others. So we have a great use for the plant, but I do think it gives us the capacity to be able to do some other manufacturing for other programs as needed. And I think the team will be a superb team. And given the challenges that CMOs, I think that it will become a valuable asset Broader than simply making our own products.

Speaker 6

Thank you.

Operator

Our next question comes from Anupam Rama with JPMorgan. Your line is open.

Speaker 7

Hi, everyone. This is Priyanka on for Anupam. We just have one quick question. Will the Analyst Day be only focused on the 143 and GTX-one hundred and two programs? Or will the overall pipeline also have other various updates?

Speaker 7

Thank you.

Speaker 3

Yes. Our expectation is to have several other programs highlighted there. Some you know about, maybe some you don't. Could be interesting. Don't miss it.

Speaker 3

So, we have A great pipeline. The hard part is that it's really hard for most people to handle more than 1 or 2 good things. But Olganix has Got half a dozen things and we will have more than GTH-four zero two zero I at the meeting. So I think it tended to be exciting. We tend to bring What we're learning and new things we've put together and hopefully give people a better breadth of understanding of the value we're creating And what we can do as a company is I think we will become the leading rare disease company out there.

Operator

Thank you. Our next question comes from Joel Beatty with Baird. Your line is open.

Speaker 3

Hi, this

Speaker 5

is Ben on for Joel. Thanks for taking the question. I'm sorry if I missed it, but what are next steps for dosing the remaining 4 patients in Cohort 2 for Wilson's disease? Yes. No.

Speaker 5

So we do have a 2 week dosing interval that was required by the FDA for Cohort 2, those additional 4 patients are lined up and ready to go?

Speaker 3

They're all screened and waiting. So it's just a time clock now.

Speaker 5

Yes. And then we will have another DSMB meeting and then we're only required to have a single week between dosing For the 3rd cohort, so the timeline will start to accelerate. Got it. Thank you so much.

Operator

And I'm not showing any further questions at this time. I'd like to turn the call back over to Joshua for any closing remarks.

Speaker 1

Thank you. This concludes today's call. If there are

Speaker 9

any additional questions, please contact us by phone

Speaker 1

or at irultragenyx.com. Thank you for joining us.

Operator

Ladies and gentlemen, this does conclude today's presentation. You may now disconnect and have a wonderful day.

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Earnings Conference Call
Ultragenyx Pharmaceutical Q2 2023
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