Ultragenyx Pharmaceutical Q3 2023 Earnings Call Transcript

Quartr
Provided by Quartr
November 2, 2023

There are 13 speakers on the call.

Operator

Good afternoon, and welcome to the Ultragenyx Third 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 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 over to Joshua Higa, Vice President of Investor Relations.

Speaker 1

Thank you. We've issued a press release detailing our financial results, which you can find on our website atulforganix.com. Joining me on this call are Emil Kakas, Chief Executive Officer and President Eric Harris, Chief Commercial Officer Howard Horn, Chief Financial Officer Eric Crombez, Chief Medical Officer Aaron Olson, Senior Vice President of Corporate Strategy and Finance and Ted Huizenga, Chief Accounting 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 Abel.

Speaker 2

Thanks, Josh, and good afternoon, everyone. Before we get started, I'd like to welcome our new CFO, Howard Horan, to the call.

Speaker 3

To say that he has hit

Speaker 2

the ground running is an understatement. He already has an Allgenics Analyst Day and a financing under his belt. We're happy to have him on board as we prepare for our catalyst for 2024. It's great to see many of you at our Analyst Day a few weeks We hope that the new data shared at the event along with the positive clinical impressions of the investigators on 2 of our programs Show you why we have confidence in our lead therapeutic candidates in their potential to transform debilitating disease with limited or no treatment options. We kicked off the day by sharing new data from the ORBIT study for cetuzumab in osteogenesis imperfecta It has been prevented a few days earlier at ASBMR, the Sverix and Cipher Bounds Mineral Research 2023 Annual Meeting.

Speaker 2

Interim data from the Phase 2 portion of the study demonstrated that zetrizumab significantly reduced the annualized fracture rate by 67% After at least 6 months of treatment, we continue to demonstrate ongoing substantial increases in lumbar spine bone marrow density reaching 19% in just 6 months in the younger patients. We also provided an update on our GTX-one hundred and two program in Angelman syndrome. The data we covered was longer term extension data from the dose escalation cohorts in the Phase onetwo study And it showed the treatment with GTX-twelve resulted in clinically meaningful improvements across multiple domains through both the loading and maintenance phase of treatment. The improvements we saw in Bayley and the agent severity assessments, formerly known as the CGI S severity scale, We're also supported by objective changes in EEG and comparisons to natural history. We also looked at the emerging first However, development changes from 3 of the original U.

Speaker 2

S. Patients. When these patients stopped receiving GTX-one hundred and two, they lost these first ever developmental gains. But we're able to gain these skills once they start treatment with new dose and regimen. Other patients also saw many first ever development gains, which gives us confidence in the potential transformative effect for this neurodevelopmental disease.

Speaker 2

These first areas are very important to the families and give clinical meaningful to the The 3rd program we highlighted was our UX701 AAV gene therapy for Wilson disease. We provide data on the 5 patients in the 1st lowest dose cohort. At 5e12gcper kilo, 4 of the 5 patients showed improvements in copper trafficking and had begun tapering off standard of care with key layers and or zinc therapy. This includes 2 of the earlier treated patients who are now completely off standard of care and doing well. Eric Ramiz will provide more detailed updates on these programs later in the call, but it's clear we have 3 large value programs, All generating data that meaningfully derisks the probabilities of their success.

Speaker 2

Now, I'll turn the call over to Eric Harris to provide an update on our commercial efforts

Speaker 4

Thank you, Emil, and good afternoon, everyone. After 5 years of successfully commercializing Crysvita in North America, This responsibility was transitioned to Kiowa Kirin on April 27, 2023. As part of the transition, A small Ultragenyx fill team and patient support services team was kept to help the Keaau Kirin fill team find and start With the combined field efforts, the demand for start forms throughout this year has remained strong and is greater than what we saw during the same period last year. In recent months, the majority of the stock forms have come from adult patients, which further supports our strategy of expanding the surgeon to community physicians to find these patients. The two teams are working hard to ensure patient and Shifting to Latin America.

Speaker 4

Shifting to PROCEDA in Latin America, as of Q3 2023, There are over 460 patients on reimbursed therapy, which includes approximately 50 new patients We began commercial therapy in this quarter. This year alone, we have converted approximately 150 new patients to the commercial drug in this region. The Latin America team has continued to build solid momentum, further strengthened by the recent reimbursement approval pediatric patients from the largest public payer in Mexico called IMSS. Crysvita is approved in 6 countries in Latin America, including Argentina, Brazil, Chile, Colombia, Mexico and Peru. Brazil continues to be the largest market in Latin America and we continue to see growing demand in this country.

Speaker 4

While the uneven ordering patterns in Brazil drive some quarter to quarter variability, The underlying demand remains strong. 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 Persueta revenue. More specifically, it includes Crysvita product revenue from Latin America and Turkey and the cash and non cash royalties from North America and Europe and the collaboration profit share revenue prior to the transition. For the Jovi in North America, the demand for start forms remains strong. In the U.

Speaker 4

S, we have added nearly 19 start forms and converted over 70 patients to reimburse throughout this year. We continue to expand the number of treaters of BIJOVI in the U. S, adding 30 new prescribers this year, including some healthcare professionals in the Centers for Neuromuscular Medicine. In Canada, we continue to make progress following a Outside of the U. S, there continues to be growing demand for XERJOVIN.

Speaker 4

In Latin America, our commercial teams are continuing to identify more patients, and we expect demand will continue to steadily increase over time. Across Europe, we continue to deepen the awareness for LC FAOD with key stakeholders and address the high unmet medical need through main patient Requests are coming from across all major European markets as well as Greece, Israel Today, we are reaffirming our 2023 global AJOVY revenue guidance range of $65,000,000 to $75,000,000 the range we announced at the beginning of the year. Lastly, on Efiza, we continue to make progress in major markets in Europe and the Middle East. Efkiza is now approved in Germany, where we have started to convert patients to commercial drug. In many other countries, the demand is steadily growing as patients gain access to FTEZA through various early access programs.

Speaker 4

In Canada, we received marketing approval We also continue to make steady progress in Japan, where we have meetings scheduled later this year with the Ministry of Health, Labor and Welfare to discuss pricing and reimbursement. Across all regions, We have received overwhelmingly positive feedback for our key data from KOLs and patients. They have continued to highlight the significant unmet need for this disease and the importance of this potent new treatment. We continue to respond to many urgent requests for early access, and our teams will continue their efforts to bring this product to people living with AQFH as quickly as possible. In closing, we are reaffirming our 2023 total revenue guidance range issued at the beginning of the year of $425,000,000 to $450,000,000 With that, I'll turn the call to Howard to share more details on the financial results for the quarter.

Speaker 5

Thanks, Eric. It's great to join the team for today's call. Before we get into the numbers, I'd like to thank Ted, Aaron and their teams for all of their contributions over the last year. They implemented a number of important initiatives around financial discipline, which have contributed to the strength of our current financial position. I will briefly summarize the financial results that were included in the press release we issued earlier today.

Speaker 5

Starting with revenue, Our total revenue for the Q3 was $98,000,000 Crysvita revenue for the Q3 was $75,000,000 which included $50,000,000 from North America, dollars 19,000,000 in product sales, primarily from Latin America and approximately $6,000,000 in European royalty and other product revenue. As we have previously disclosed, The Q3 U. S. Crysvita revenue was negatively impacted by a one time decrease in channel inventory related to chelakiran's change from Ultragenyx labeled product to chelakiran labeled product as part of the transition North America commercialization responsibilities. Again, this is a one time change and we expect Crysvita channel inventories to increase to more normal levels at the end of the year.

Speaker 5

The JOLVI revenue for the Q3 was $17,000,000 with North American demand driving 25% growth versus Q3 2022. Shifting to expenses, our total operating expenses for the Q3 were 243,000,000 which included R and D expenses of $157,000,000 SG and A expenses of $75,000,000 and cost of sales of 11,000,000 Operating expenses for the quarter included non cash stock based compensation of 35,000,000 For the Q3, net loss was $160,000,000 or $2.23 per share. As of September 30, 2023, we had $524,000,000 in cash, cash equivalents and marketable securities. After the end of the quarter, we raised an additional $326,000,000 from an underwritten public offering of common stock and prefunded warrants. Through the Q3, net cash used in operations was $391,000,000 We expect 4th quarter net cash used in operations to be around $35,000,000 driven by anticipated strong 4th quarter revenues and factoring in expected changes in working capital.

Speaker 5

As a result, we now expect full year net cash used in operations to be around 425,000,000 The team has worked hard over this past year to ensure we are in a strong financial position and we will continue to build on these efforts going forward. Now, I'll turn the call to our CMO, Eric Grumbez, who will provide an update on our key clinical programs.

Speaker 6

Thank you, Howard, and good afternoon, everyone. Emil mentioned the key clinical updates we shared at Analyst Day, and I'll provide Just a bit more detail on our priority programs, starting with UX-one hundred and forty three or sotrusumab for the potential treatment of osteogenesis and Perfecta. The data we presented at the Analyst Day supports our view That this is a disorder of inadequate bone production as much as it is about defects and collagen. Across the 24 patients Enrolled in the Phase 2 portion of the ORBIT study, we saw an improvement in bone mineral density Z score of 0.85 at 6 months. Importantly, a subset of 5 to 12 year olds saw nearly a 20% increase in bone mineral density with a z score change of 1.19.

Speaker 6

These improvements in bone mineral density across the 24 patients Treated in the Orbit Phase 2 translated to a 67% reduction and the annualized fracture rate following treatment with cetuzumab for at least 6 months. 20 of the 24 patients did not experience any new fractures in the 6 months following treatment with cetruzumab. For the 4 who did have a radiographically confirmed fracture, many of them occurred early on in treatment or had a traumatic precipitating event. The data is all the more compelling because many of the patients in the study were previously treated with bisphosphonates over the 2 years prior to dosing With cetirizumab. During this time, these patients continue to see a high annualized fracture rate with many fractures occurring with very minimal activity.

Speaker 6

These types of fractures are referred to as fragility fractures and examples include fractures occurring during sleep or when transferring out of a chair. What we heard from 2 principal investigators who joined us at Analyst Day is that they are not Seeing fragility fractures in these studies patients treated with cetruzumab and that many of these kids are now feeling strong enough to engage in more physical activities with friends and family. Next, turning to GTX-one hundred and two for the potential treatment of Angelman syndrome, where we showed Clinically meaningful improvements across multiple domains for the patients in the loading and maintenance phases of the dose escalation cohorts 4 With the long term extension data, we showed improvements compared to natural history data and supportive EEG data, providing further evidence that the changes we are seeing are meaningful and improving over time. We also shared data from 3 of the original U. S.

Speaker 6

Patients who stopped and restarted treatment. These patients gained, lost and regained a number of skills, including following complex directions, communicating needs and wants and improved behavior in sleep. These changes show the importance of GTX-one hundred and two to enable continued development in these patients with hope that they will continue to learn and develop new Doctor. Elizabeth Barry Kravis, who is a principal investigator for the study, took us through a few video examples What these developmental improvements translate to for her patients and their caregivers? Doctor.

Speaker 6

Barry Kravis has been working with Angelman patients in our clinic for decades and noted that it can take years for these patients to learn a single new skill. So the fact that these patients are learning multiple things in such a short amount of time is remarkable. Enrollment in the dose expansion cohorts, Cohorts A through E continues to go well and we anticipate Sharing data from at least 20 patients who have been on therapy for at least 6 months in the first half of twenty twenty four. Lastly, UX701 for the potential treatment of Wilson disease, which is a disorder of copper trafficking. As Emil mentioned, we are seeing a response in 4 of the 5 patients treated in the first dosing cohort With patients 23 completely discontinuing their chelators and or Xyng.

Speaker 6

At Analyst Day, we said that Cohort 2 Receiving a dose of 1813 has been fully enrolled. The DSMB is scheduled to meet soon to review the available data, which will enable initiation of dosing in the 3rd and final cohort in Stage 1. The 5 patients for this last dose escalation cohort have been identified and meet enrollment eligibility. We expect dosing in this cohort to complete around the end of the year. The improvement in caboviral markers and ability to reduce current standard of care are promising signs of the establishment of normal trafficking of copper in these patients, and we look forward to sharing additional progress with this important gene therapy program.

Speaker 6

I'll now turn the call back to Emil To close with the key upcoming milestones and provide some closing remarks.

Speaker 2

Thank you, Eric. I'll summarize the key upcoming clinical catalysts and before we open up to Q and A. Starting with UX143 for Osteos Imperfecta, Enrollment in both the Phase 3 studies is going well with strong support for the medical community following both of our data releases this year. We're enrolling at 50 sites around the world and are targeting complete enrollment in the Q1 next year. We also expect to provide another longer term data update The Phase 2 portion of the study next year.

Speaker 2

Next, GTX-two hundred and two in Angelin syndrome. Based on the patients who are Currently enrolled and dosed, we are on track to provide an update on the expansion course in the middle of the first half of twenty twenty four. As we have said, this will include at least 20 patients of data would have been on therapy for at least 6 months and include longer term efficacy data on early enrollees and a safety update on the total exposed population. Closing with our gene therapy program, GTX401 for GSDIa dosed the last Patient pivotal study earlier this year. We're now in the 48 week window and expect to unwind and share this Phase 3 data in the first half of twenty twenty four.

Speaker 2

US-one hundred and eleven for Sanfilippo syndrome, we are continuing to see meaningful clinical responses in these patients and we're working with the FDA around biomarker data to help CTX-three zero one for OTC is enrolling patients in the Phase 3 and we expect the last patient to be dosed in the first half of twenty twenty four. UX701 for WILTS disease should have all patients dosed in Stage 1 this year, and we expect to provide safety and efficacy data on all of these patients in the first half of twenty twenty four. We've worked This past year to ensure we are in a strong financial position heading into 2024 and beyond. We continue to see growing demand for our commercial products and completed It gives us the ability to advance our large value program through meaningful inflection points. We've been implementing more aggressive financial discipline, including realigning our headcount, Restructuring in places and doing the work we need to make sure we're putting the people and capital where we have the ability to generate the most value.

Speaker 2

Ultragenyx has come a long way since our humble beginnings. As I said at Analyst Day, we expect to have around 8 to 12 approvals in our 1st 15 years post IPO and these are in extremely debilitating disease with urgent need for treatment options. I think that really demonstrates possibly we feel to lead the future of rare disease medicine. With that, let's move on to your questions. Operator, please provide the Q and A instructions.

Operator

Thank you. Our first question comes from Manu Bhaum Rama with JPMorgan. You may proceed.

Speaker 1

Hey, guys. Thanks so much for taking the question and Welcome, Howard. Hope you're well, man. So I got a quick broader question here, which is What are you monitoring here for the Sarepta DMD gene therapy regulatory review process that could maybe potentially read through to your Broader gene therapy efforts and pipeline. And then on one of your gene therapy programs, specifically 401 and GSD1, We heard a little bit about that program at R and D Day, but maybe you could help us define a win scenario for

Speaker 2

that program when you flip the card and Very good. Thank you for questions. So As everyone knows, the Sarepta Phase 3 in blinding showed this is the primary endpoint of the NSAA, but hit strongly to other endpoints. I think it shows that the drug is working. I think the NSA is a terrible endpoint.

Speaker 2

And frankly, I've said people we would never want to work with that endpoint because it's just a clinician So it's not so surprising. I think the drug shows it's working and it will be up to Sarepta to manage that forward. I think What I would say in the broader context for our own program is that the ability to deliver micro dystrophin is having an important clinical benefit in these patients. It's still a first step in a path toward improved care for these patients. But we think I think in general, it says that these Mike and Stroughton, gene therapy programs can work, and we're still encouraged and still pressing our own program ahead in development.

Speaker 2

With regard to 401 GSE1A, the program we think there's something around 68,000 patients and about a fourth of that would be U. S. Patients. The majority of these patients, like 80 plus percent of the patients are null, Have no or are very essentially no enzyme. What that means is 80% of the patients are severe.

Speaker 2

That means 80% of the patients are at risk of dying if they miss a dose These are the patients that have essentially a gun to their head taking cornstarch every day. The driver for adoption There's a peace of mind in knowing I'm not going to die if I forget to take my cornstarch, and we think that's a big driver. We believe it's one of the reasons why the Phase 3 trial enrolls so quickly. People really wanted to get out of this treadmill that they're on with cornstarch and sugar control. And the fear of every night being a potential risk in death if something went wrong or if they go and exercise, they could collapse and be hypoglycemic.

Speaker 2

So we think there's a big demand and drive. Of course, cornstarch is not commercially costly, but I do think the peace of mind and Stability of people who can live a life instead of 1 in full of fear, I think it's big. And we have high hopes and that the adoption of the treatment We'll be more aggressive and brisk just as it was in the enrollment of the trial, which enrolled everywhere. In fact, We had a lot of people upset when we closed enrollment that couldn't get in the trial. So we think the demand is going to be there.

Speaker 2

And while it's not a huge program, it's We think 8,000 patients is a substantial one and we think that there will be early adoption for that program. And I do think that the clinical demand and need is important. I think we've seen it for that program. So I'm pretty encouraged so far.

Speaker 5

Thanks so much.

Operator

Thank you. One moment for questions. Our next question comes from Dae Gon with Stifel. You may proceed.

Speaker 7

Great. Good afternoon. Thanks for taking our questions. 2, maybe on GTX-one hundred and two and the satruzumab. Just wanted to clarify on satruzumab, AMOL, did you say enrollment completion in 1 Q24, is that for both Orbit as well as Cosmic?

Speaker 7

And are you placing any protocol restrictions on strenuous activity? I mean, it's encouraging there Being more active and fearless, but in terms of endpoints, I wonder if that could kind of create a confounder. For GTX-one hundred and two update in first half What kind of data should we be expecting? You had ASA, MDRI as well as Bayley-four, but if you could frame that for us, that would

Speaker 2

be great.

Speaker 3

Thanks so much.

Speaker 2

Very good, Dion. Thank you. So for cetuzumab, we're talking about both Orbit and COSMIC in terms of finishing enrollment. I think we're likely, but the main one we're talking about is Orbit, which is the main driver. But I believe both of them should get done in that timeframe.

Speaker 2

And in terms of this controlled exercise or the hazard risk, is someone feeling better at exercising? Well, that's already what's happening People were a lot more active than what was actually on the plus side is that they were active and a lot of them were wherever falls in, they didn't have fractures necessarily. So While there is some risk that they might be doing more, there was one person who played volleyball and they hadn't been playing. We're actually overall feeling that The pattern of having falls and fractures seems to be better. And so our net effect overall, as we think, even with increased activity, there'll be A reduction in fractures, which is really the best thing possible that if the kids are going to be active and to have a reduction of fractures while being active.

Speaker 2

So we're not so worried about the, let's say, the noise of having more fracture risk at this point. It looks like you still see the effect well even if there is some risk there. Now with regard to GTX-one hundred and twelve, I'd expect the day to be many of the same things you've seen, which is the Baileys, which will compare, of course, the natural history data for the main three endpoints we talked about and there were other 3 that we looked at for the ASA. There are other endpoints. We just described all the endpoints we had.

Speaker 2

We had said at the meeting that things like the Vineland and others Had a very similar pattern of response to those. So but I would look for data to be very similar to the package of data that you saw We're probably doing something very similar to what you saw before in terms of comparison in natural history and DSA. We'll try to including enough information to interpret the quantitative changes and the meaningfulness of those changes, which I think is one of the debates. And we're certainly going to look at Emerging skills as well in those patients, as best we can. So those are the things I think you'd expect to see.

Speaker 2

It should be 20 patients, 6 month data. There will be Probably 10 patients that have longer data out to 254 and more than 30 patients worth of data of any type. So It should be a pretty robust set of data, so I'm looking forward to that.

Speaker 1

Thanks. Next question?

Operator

Thank you. One moment for our next question. Our next question comes from Jeffrey Hung with Morgan Stanley. You may proceed.

Speaker 6

Hi. This is Michael Riata on for Jeff Hung. Thank you for taking our question. For cetuzumab, how do you think regulators will view the clinical benefit for younger Patients who are still developing versus adults who are more or less finished growing. Is there any appreciation for the ability to prevent fractures and Complications, potentially like bone deformations?

Speaker 6

Thanks so much.

Speaker 2

Well, I think you're hitting on a really Important thing, let's talk about what the FDA asked for. They wanted to have the major clinical fractures, excluding fingers, toes and skull as the endpoint because they feel those are most clinically meaningful. However, whatever they think is one thing. They're dealing with fractures from osteoporosis. The truth is what you talked about is really important that is the vertebral fractures and other types of fractures that would result in deformation of the bone are actually things that drive Very poor outcome.

Speaker 2

So our trial, which we have pediatrics and also has a very young group of patients, will look at not just clinical But also vertebral fractures and other fractures, which we think will benefit. So I think we'll be able to show the clinical fractures and hit the FDA's required endpoint, But we hope to be able to expand that to talk about other aspects of the disease, particularly in the very young patients in the COSMIC study degradation that leaves them all to be wheelchair bound as 5 or 6 year olds. I think that would be an amazing result. We're going to see what we do. But based on The very substantial lumbar spine bone marrow density improvement of 20% in some of the young kids, we kind of expect this line to be strong and Change the future of not deforming like they've had in the past.

Speaker 2

So I would say we can prove the FDA and get our approval, But the broader acceptance of achievement and its reimbursement will be supported by the rest of the body of data, which we are including in our plan.

Speaker 6

That's really, really helpful. Thank you so much for your response.

Operator

Thank you. One moment for questions. Our next question comes from Yigal Nochomovitz with Citi. You may proceed.

Speaker 8

Hi, team. This is Carly on for Yigal. Thanks for taking our questions. We had one commercial question. It looks like you're expecting a pretty significant reacceleration in revenues In the Q4, in order to meet the guidance range, I know you mentioned an inventory impact to Crysvita during the Q3, but can you talk a little bit more about Your assumptions driving that acceleration in revenue that you're expecting.

Speaker 8

Thank you.

Speaker 2

Sure. Let me I'll hand it over to Eric. The Q4 has a lot of differences in how things perform. There's always a lot of lumpiness as well. But Eric, if you Want to deal

Speaker 9

with what you think how revenue is going

Speaker 2

to go in the Q4?

Speaker 4

Yes. I think if you look at previous years, we've always had a strong Q4. So it's typical seasonality, which will also this year will entail some inventory rebuilding following the NDC swap out. And as I stated earlier, demand remains very strong. In fact, our demand And start forms is higher than it was at this point last year.

Speaker 4

So we remain confident that We'll see a strong Q4.

Speaker 2

Yes. I think if you go back and look, you'll see every Q4 has been an up quarter. So we're on track. We think pretty good about where we are in the business.

Speaker 8

Okay, great. That's helpful. And then maybe just one follow-up related to the Wilson Can you just how you're thinking about the size of the addressable population for a gene therapy approach in Wilsons? And maybe what you're hearing from KOLs about the proportion of patients not well managed on chelators and on the more severe end of the disease spectrum that could be addressable. Thank you.

Speaker 2

Yes. I think The Wilson market potential is an important question. The 50,000, 60,000 patients probably more because it's under diagnosed in my view. And you can look at it as maybe the 20% of patients that aren't well managed is the core indication. But I think with the Drop out of the Alexion AZ chelator as a competitor and showing that just chelation is not good enough to make patients better.

Speaker 2

The door is open to the idea that improving copper distribution could make patients feel better, do better than you can get just with a chelator, which means It might not be just 20 plus percent that have problems with their chelators. It could mean that more of the majority of the patients will listen. We're encouraged that the patients are getting off their yes, the chelators. But I think we're also really encouraged that the copper distribution seems to be improving even at the lowest doses and that patients seem to be feeling really good. My hope is if you restore copper distribution that the effect of copper deficiency, which is occurring in Wilson disease, Overlaid on top of copper toxicity is a real factor.

Speaker 2

And if we can make people feel a lot better and perform better, I actually think there's a potential for this to be An indication that becomes the majority of patients, because our ability to manufacture with the Pinnacle platform In our own plant, keeps the cost really low. It also means we can manage the pricing in a more intelligent way that would enable a larger fraction of these patients to get Put on therapy and actually build a bigger business model out of

Speaker 3

it,

Speaker 2

than one based on a $3,000,000 of patient kind of price point, which I think makes it more challenging. So We look at the opportunity here as potentially larger than the initial views if we can make patients feel better, do better, and I think there is a real chance for that

Speaker 8

Great. Very helpful. Thank you.

Operator

Thank you. One moment for our next question. Our next question comes from Tazeen Ahmad with Bank of America. You may proceed.

Speaker 8

Hi. Thank you so much for taking my question. Emil, I maybe just wanted to clarify one point. And then I'm sorry if it was already asked before. But When you talked to the FDA about downsizing the OI Phase 3 trial, you We're supposed to get specific feedback on that.

Speaker 8

Just wanted to hear your thoughts on what FDA's view on that particular

Speaker 2

Yes. We haven't really discussed the details of going through that. But The plan on the Phase 3 with the addition of the interim assessments, we think won't be a problem. But we haven't really disclosed any ongoing discussion with them, but we're comfortable with the ability to get the interim set. And The size of the study is really up to us.

Speaker 2

In terms of safety, the exact trial size is well above 100 patients is more than adequate in size. So We'll come up with a plan with them, but I'm not concerned about our ability to get that accepted.

Speaker 10

Okay. Thank you.

Operator

Thank you. One moment for questions. Our next question comes from Kristen Kuzco with Cantor Fitzgerald, you may proceed.

Speaker 8

Hi, everyone. Thanks for taking the question. Can you provide any more color or thoughts around the Timing of the interim analysis of the OI study?

Speaker 2

Yes. The way the interims will be done, we won't be disclosing when they're happening. We've said there, we'd expect a first one to happen this coming year. We want to make sure that patients had at least a certain amount of time of treatment before interim would be done. And the original plan for the program is to operate off of The fracture information, how many fractures there were, essentially event driven timing.

Speaker 2

So the precise timing is we haven't disclosed. It depends a little on fracture numbers, etcetera. But we said that one error will occur next year, but we won't disclose exactly when. It will happen in a controlled way, blinded unblinded assessment by the DMC. So we won't know, when it happens.

Speaker 2

So At this point, we'll all be waiting, but we're encouraged by what we're seeing and the potential the study could end early. But However, we feel we have a drug that works, so we're going to get through a positive Phase III. At least we're feeling very confident about the ability of the product to get us there.

Speaker 8

Thank you.

Operator

Thank you. One moment for questions. Our next question comes from Joon Lee with Truist Securities. You may proceed.

Speaker 3

Hi, everyone. This is Mehdi on for Joon. So on GTX-one hundred and two, for the 3 patients who whom regained some lost clinical benefits after redosing, So how do you best plan to highlight this significant observation for regulatory agencies? And is it at all possible that time to read those could explain some of these clinical benefits? And I have a follow-up question.

Speaker 2

Well, first of all, let's talk about what happened to those patients. Those patients got anywhere from 1 to 4 doses, 5 doses And had their clinical benefit effects of new or emerging findings, they had the safety event. And then they're off treatment for on the order of like 2 years in which they lost all this activity. So 2 years off, they're pretty much washed out completely. No drug, no benefit.

Speaker 2

So when they start up again, they're really Starting back from the beginning and regaining the same functions. In terms of the patient, there's one patient who really gained a lot of words who Had gained 9 to 12 words in the 1st period and now having been on consistent therapy for a longer period is actually up to 17 words. That's the patient also that's now swimming as well on their own without, float support. So We think that the washout period takes them back to the beginning. It's not really there's no relationship between What happened there and re dosing effect.

Speaker 2

If you looked at what happened with naive dosing patients, we showed a graph at Analyst Day that showed A large number of patients having similar first ever emerging skills the first time they went on treatment. So we think there's nothing Special going over those 3 that's any different from any of the naive treated patients.

Speaker 3

Thank you. The follow-up is on OI. So are there any specific reasons for preferential suitability of cetirizumab on AI versus other Antisclerotin antibodies like, EVENITY, SHR1222 or the others?

Speaker 2

Well, the only other one is Avententity or ROMO, I guess, we call it for short. Both target the same sclerotin. There are differences though. Remember, our program, fotuzumab, It's a fully human antibody, which we think is a better choice for a long term therapeutic because of the Risk of antidrug antibodies will be much lower at a fully human antibody. We haven't seen them.

Speaker 2

So we feel ours is a better choice for a chronic therapy. We will have chronic dosing in our label that is RX10. The promo is only 12 months. We think OI patients need continuous. And we've shown when you pull them off drug, as it was done in the AstraZeneca, they lose ground even with bisphosphonates on board, whereas ROMO is basically given for a year and then locked Supposedly, the effects are locked in, but with OI, that's not true.

Speaker 2

You need chronic dosing. So the product dosing story will be ours. And Finally, when we commercialize, we're going to provide the 1st rate patient support we do to our rare disease patients, which is not something that's going to happen for an osteoporosis drug. The last thing I'll mention is that the presentation of that drug is a 2 10 milligrams in a pre filled syringe. It's not very for different size patients and different amounts of drug dosing, whereas our presentation will allow week based dosing for each patient and optimization, which I think will be important in the ultimate care of these patients.

Speaker 2

So, ataxagolasa both Can work, but I think ours will be a better choice for long term use.

Speaker 3

Thank you very much. Thanks for taking our questions.

Operator

Thank you. One moment for questions. Our next question comes from Maury Raycroft with Jefferies, you may proceed.

Speaker 1

Hi. Thanks for taking my question. For 701 and Wilsons, What goes into the decision tree for decreasing standard of care and what is the target reduction in stage 1? And can you provide more perspective around patient baseline characteristics for the first two cohorts, including baseline serulo oxidase activity? Yes.

Speaker 2

Let me try a little top line and then Eric, if you want to provide a little bit more detail. The trial after they get the drug, there's a period of time where we watch and see how they're doing and then we start titrating down their standard of care. And the goal in the trial is to get them off standard of care completely, like the first two patients. The others, I think, are going to get there. I'll let Eric talk a little about what the criteria are.

Speaker 2

At baseline, we haven't put out all the information in great detail, but maybe Eric, you can provide a little bit A high level on a few things to help with Laurie's question. So standard of care, integration strategy and then the baseline.

Speaker 6

Yes, great. It's nice that we're able to do this in an open label fashion because it gives us the ability to work closely with these investigators. But the goal really is to give all patients a trial, of titration off of current standard of care. And what's nice about this disorder is you can monitor copper in a lot of very different ways and certainly with a very big focus on urinary copper, But we feel with all of the types of way we could measure copper, we really do have a good way to understand the effect of the gene therapy. Certainly, if any patients start Seeing any signs and symptoms or biomarkers start trending in the wrong way, we will rescue them back to Their original dose of chelators and things, but we really haven't seen the need to do that across the border or in a meaningful way.

Speaker 6

The ceruloplasm based activity assay is interesting and again important because chelators and zinc have no effect on that. So the only way for ceruboplasm to exist is to have copper bound to it. And then with this assay specifically measuring the loading of copper on the ceruboplasm, These patients are coming in really with an activity below the lower limit of detection. So again, measuring the rise from there. So Still early days, patients are definitely still increasing and benefiting from the transgene, but things seem to be really trending in the right direction for the great

Operator

Thank you. One moment for questions. Our next question comes from Salveen Richter with Goldman Sachs. You may proceed.

Speaker 11

Hi. This is Lydia on for Salveen. Thanks so much for taking our question. So just 2 on cetirizumab. So first, could you just provide a bit more detail on what exactly would trigger an early Phase 3 readout?

Speaker 11

And then also, do you have any idea on pricing and reimbursement given the availability of

Speaker 2

Sure. So the way the original trial was Done. It was an event driven that is the unwinding of the original final primary analysis is driven by having 100% of the fractures to achieve the information needed. So it would be event driven. And the original idea, certainly the Arabs, is to look at 60% 80% of that maximum.

Speaker 2

Assuming a large treatment effect, we think we could hit persuasive statistical significance at maybe just 60% of the fractions required. It's the separation of the 2 Is as high as 67% as noted. So it really depends on the number of fractures and the number of patients and the time of exposure. So it's a complex of those three points. So originally, the 100% expected to be somewhere between 12 24 months of the last of exposure to the last patient in and this would be less than that.

Speaker 2

But we expect that we would want to see at least 9 months of data of treatments for the last patient in is our expectation. So it will be fracture dependent, But we would expect to see at least 9 months of data from the last patient in. Last month, let me 9 months of exposure to the last patient in as a minimum.

Speaker 11

Thanks so much.

Speaker 2

Yes, the pricing reimbursement question. Well, obviously, Romo is out there labeled for osteoporosis has a certain price point. It's actually at a lower dose the way it's used. And what we're doing is actually at a much higher dose and will be optimized for OI. So you have to think about the dose differential For the 2 indications is one feature.

Speaker 2

The other, of course, is that Our treatment will be chronic. And so the question people will have with the shorter term treatment regimen is whether they should take Well, longer when it hasn't been given longer, right? I think that becomes more of a barrier to question about safety, and we'll have, in fact, the chronic data to show our drug We're going to sing hard about our pricing strategy. As you know, we've got a we're a company that looks at more moderated, Possible pricing as we did for Crysvita. We think that would make the differential between it and Ramo substantially less.

Speaker 2

And given the dose differential, We'd make it, I think, a not significant issue, for the program. And given our support systems, Our delivery home infusion, home delivery of drug, as we've done for Crysvita for like 85% of the patients, There are going to be a lot of features that will help make this a lot more approachable for our rare disease patients that I don't think they'll get support from. So those are all factors, I think, in how it will play out. But we're really knowledgeable about the space because Eric and his team has been Commercializing in 90% of those docs we commercialize Crysvita to are also treating OI, right? There's a 90% overlap.

Speaker 2

So we really know how they are. We have a strong relationship and that will put us in good position, I think, to compete. And in our view, we'll have the label, We'll have the best antibody, we'll have the right dosing, right regimen, the right team to commercialize.

Speaker 11

Thanks so much.

Operator

Thank you. One moment for questions. Our next question comes from Yaron Werber with TD Cowen. You may proceed.

Speaker 9

Great. Thanks guys for taking the question. First, just I think a quick one from us. Really kind of looking ahead to your first half of next year, obviously, you're going to have a pretty busy 6 months,

Speaker 2

it looks like. So,

Speaker 9

any sense that you can maybe give us on kind of the cadence of when to expect what even if it's Kind of relative one before the other would be super helpful. And then one quick one on GSD-1, sorry if I missed this, but Has FDA kind of given you any indication or do you already have a sense of how long after the top line readout you really need to continue to follow these patients? Really just trying to understand when you might be able or in a position to file and potentially launch with 401 if the data looks good. So thanks very much.

Speaker 2

Good. So, it came to the findings. We actually have a table that has some of it. I have to say, we've generally not provided extremely precise Target of catalysts for various reasons. It is a busy first half.

Speaker 2

We'll buckle your seat belt. It's going to be fun. We're going to have a lot of good work and coming out for you. But I don't think we I can give you a blow by blow of exactly when all is going to happen. But we'll have a table that will give you at least some ideas and it will be a fun quarter.

Speaker 2

I'm looking forward because we have So many working programs and we're in such a good position. It will be great to see how they're doing and be able to talk to you about them. Now the question on GSD1 is how long to file. The agreement with FDA is that we could file with 48 weeks of primary data and including then long term extension data from Phase III patients, which are now out like 5 years, so there's quite a bit of data there. So

Speaker 4

We think we have a

Speaker 2

lot of long term durability data in hand. But keep in mind that the trial enrolled over a period of a good part of a year or so. Even if we have 48 weeks From the last patient, they'll probably be up to couple of years of data, the very earliest patients by the time we file, right? So I think I would expect us to be able to file within a reasonable timeframe. There may be other factors that we'll have to discuss with regard to The rest of the package and filing, but we'll be working to try to file as promptly as we can once we get all the pieces together.

Speaker 9

All right, great. Thanks very much.

Operator

Thank you. One moment for questions. Our next question comes from Joel Beatty with Baird. You may proceed.

Speaker 5

Thanks for the update. For the Amelogenix spin out, what's the latest plan and timing and How much ownership does Ultragenyx plan to maintain?

Speaker 2

Well, we do have A term sheet signed and a group of investors put together that we're filling out that syndicate. I can't tell you more yet about the details, but Our expectation is for Ultragenyx to own the majority interest in the spin out, a majority interest in the spin out based on what we'd expect. But it's not been finalized, and I wouldn't want to provide any more details as we get closer. But it's moving along. We have a lot of interest.

Speaker 2

Analyst Day also brought out some new interest. I think there's a lot of belief that the mAbs monoclonal against amyloid Do work, but there's also a lot of room for improvement for something better. And we think this is one Good option for how you might do a better treatment. So we'll put out more information when we get there, but we don't have majority interest and We'll hopefully fill out that team and get that finance half much for the end of the year is our goal.

Speaker 3

Great. Thank you.

Operator

Thank you. One moment for questions. Our next question comes from Gena Wang with Barclays. You may proceed.

Speaker 10

Thank you for taking my questions. 2 very quick ones. The first one is regarding the Angioma program, the update next year. Amit, you say you will also have a 10 patient with a longer follow-up. Will you be able to share the Bayley's The domain, if I look through, it's a social emotional and also adaptive behavior.

Speaker 10

And regarding the Multi domain responder index, do you think that could be a possible index That you could discuss with the FDA about possible approvable endpoint in the future. And quickly regarding Crysvita, Vida, so regarding the in LATAM, now the territory will be much more important For the revenue contribution, any strategy you can think of can improve the penetration there.

Speaker 2

Okay. Well, good questions. Maybe I'll let but when I get to it, you can do the I'll let Eric do the Crysvita Penetration strategies question. All right. I'll start with first with the age of an data.

Speaker 2

You asked about Bayley, other domains of the Bayley. A lot of it means we're not I think the Adaptive and social emotional are not very well designed for intimate patients. They're designed for Normal people, so I think they're not very good. But we will have data on adaptive behavior. We'll have Vineland, which has adaptive behavior, but we'll also Another scale called ABC scale that will probably I didn't mention, but is an aberrant behavior scale, which I think is Maybe even more relevant to these patients are the most clinically important.

Speaker 2

We talked about social emotional or adaptive type things. So we'll have some things, but I don't think The Bayley is not the best test for some of those things. We're focusing on the ones where I think it's sensitive. With regard So that's 10 patients that we might have longer term data that is up to 254 or longer and 20 that would have day 170. So that's We're trying to give you a better sense.

Speaker 2

We'll give you what we have on all of them. Now for MDRI, We believe Inderide is a good strategy. We don't have FDA's agreement on that. They've ceded, I presented to them, including Multiple senior leaders in the multiple conferences, we published a good paper on it. It's a very powerful method.

Speaker 2

I think it's a very appropriate method. The key thing with the MDRI is that you really measure endpoints you can agree on anyways, endpoints that are meaningful, right? The only thing the MDRI is, is an analytical tool. How do you take 5 different endpoints and add up the results? And this says, look, I'm going to add up How many people responded in each of the endpoints to a clinically meaningful degree and add up those responses.

Speaker 2

So it's not conceptually that hard. You do get all the underlying data. So it's not like FDA is giving up anything by using that endpoint, right? They're actually getting all the underlying endpoints. So If they can get comfort around the daily scale for certain things, an ASA score, the parent behavior score, or violent or others, As representative of those functions, then I think we can get them comfortable with MBRI as an analysis tool and how to get to the result.

Speaker 2

So lastly, let's talk about Crysvita. Look, I think Crysvita should be majority of P's. In fact, I personally think every single kid who has XLA should be on Crysvita and not oral phosphate if they need treatment. And we still have room to go there. And we're working with our partners on it.

Speaker 2

I thought maybe Eric, maybe you could say anything we might be doing to try to help them maximize the penetration of Crysvita.

Speaker 4

Well, yes, just to reiterate, LATAM is doing great. It's been very successful thus far. We'll continue with our current commercial efforts. But really what's going to continue the strong demand there What's really going to drive the growth there is as we continue to get We've seen the significant uptake just recently in Brazil following the Formal reimbursement, public reimbursement, as we work our way through reimbursement through the other countries, we'll see Continue to grow

Speaker 2

in the Latin American region. Certainly, in countries that have started treating patients, they We like what they see and they start adding patients. So there is a drive for use of the drug and form reimbursement is definitely one of the pieces that will help get us there. It certainly has picked up a lot since Brazil got approved. So we're encouraged.

Speaker 2

I think there's still more room to grow in Cresita. It's

Operator

Thank you. One moment for questions. Our next question comes from Laura Chico with Wedbush. You may proceed.

Speaker 12

Good evening. Thanks very much for taking the question. I guess I wanted to circle back on the potential amylogenics spin out. You showed some intriguing data at the R and D day with Back to plaque reduction in the 5x FAD models, could you just remind us any data demonstrating effects on either Yes, any inflammatory or pro inflammatory markers there following treatment with the product. And just out of curiosity, will there be any further data updates Prior to the spin out, it sounds like things are moving along pretty quickly.

Speaker 12

Thanks very much.

Speaker 2

Yes. So we focus mostly on the pharmacology of lack rather than secondary markers of inflammation or etcetera. So I don't have more to offer you at this point. The one challenge I would say is when you're doing the way you do it in the mouth, injecting directly in the brain, there is an effect of putting a needle in the brain and how that affects things. To get to those models, I think you need to be doing real intrathecal treatment.

Speaker 2

And maybe in the rat model where you can do that, you can kind of look at those markers. But if you have to Through the brain, I think it makes it a little more complicated to get to look at those aspects of the neurologic disease. We won't likely put out more data until the spit out occurs. We are continuing to do some work. It's not a big burn factor, but there are some Experiment is going on to look at both the 2x FAD mouse and some other aspects of optimization, but we're really encouraged by the potential that we think is greater than the monoclonalized reducing amyloid in the worst model out there, which is the 5x FAD.

Speaker 2

And so We think there's enough interest. And with our systems and Pinnacle PCL manufacturing, it really puts us in a position to actually being able to approach a large market indication, which And I think it would be from a response we've seen from KOLs in our market where there is A great deal of interest in something that wouldn't cause area inflammation, but allow a single shot therapy for a treatment for a disease at this time. So we're excited about the spin out and we'll put more information out when we get it done as we progress.

Speaker 12

Thanks very much.

Operator

Thank you. One moment for questions. Our next question comes from Ed Arce with H. C. Wainwright.

Operator

You may proceed.

Speaker 3

Hi, good afternoon, everyone. This is Thomas Yip asking a couple of questions for Ed. I appreciate Thank you for taking our questions. First, perhaps for 111 for Santolipo Syndrome, Can you discuss some major topics that you plan to discuss with the FDA in upcoming meeting? And what do you plan to achieve coming out of the meeting?

Speaker 2

Yes. Well, in the MPS IIIA program, our main focus of these discussions is on how to qualify, epidermisulfate as a biomarker for accelerated approval. I'd point out to you, we're also measuring clinical data and we're encouraged by the clinical data as well. I mean, the patients are continuing to gain ground, gain development Skills over time and I think that this shows that the gene therapy is working. While we could potentially get approval by just following this patient clinically, Our hope is to be able to get the biomarker accepted.

Speaker 2

There's been a challenge for the agency. I think Peter Marks has publicly Support of the use of biomarker, including this biomarker at the recent NPS conference, but we have to get Through the details of how that's done, I think as a company we're as well versus anyone on how to explain the biomarker and how to analyze the results. But It is a situation where you have a neurodegenerative disorder with a relatively slower progression through multiple years. And therefore, the qualification takes a little more work to figure out and support. But I'd say everything I've seen in our program and multiple other Clinical programs from other parties shows that these markers are represent the underlying disease and their reduction through Either enzyme or gene therapy is showing a meaningful reduction that will have important clinical benefit.

Speaker 2

So we're confident about We value the treatment and we're continuing to work with them on what it takes to qualify and move ahead. I will say for the program, we're also working on the CMC side production. We had to take that over. That is going to take some time. So in any case, we wouldn't be ready to file until we're able to run the CMC side of the equation.

Speaker 2

This is not a priority program for the company, so we have managed it in a more capital efficient way as best we can given but our hope would get CMC straight as well, which will be part of the factor that will determine our ability to file it in addition to our discussion with the FDA.

Speaker 3

Understood. Perhaps just one more question from us, this one for GTS-one hundred and two for Angelman syndrome. As we expect the expansion cohort data in first half of twenty twenty four, what Do we expect the median treatment duration among these patients would be and What are your some initial thoughts on possible registrational endpoints?

Speaker 2

Well, the duration, Most of the patients, 20 will show, will have only day 170. We've shown you that in the most recent extension day, the day 254 looks Better than day 170. However, the dose loading, the average dose loading of expansion cohorts is Higher than what we just showed you before. So they're actually getting more drugs. So our expectation by day 1, we'll see more effect is our expectation.

Speaker 2

We will have 10 patients that should take us through 254. It will allow us at least a sense for how that's going and give us an idea. So our expectation for a pivotal study would be that it would be a Somewhere in the range of 7 to 9 month kind of study where we've loaded and gone through a few maintenance doses. We think that's the sweet spot for improvement and change without giving kids too many placebo intrathecal injections. These are people's kids and you're putting doing lumbar punctures in them.

Speaker 2

So I think that combination will give us enough time to separate And we think it would be long enough. I'm sure the FDA would always want a longer study, but I think we're getting close to the 1 year point. But I would hope That maybe it's going to be 8 to 9 months would be a reasonable place to show substantial separation. And look at day 254 as kind of A place where you could see a lot of movement in the development of these kids.

Speaker 3

Got it. Thank you again for taking the questions. Good.

Operator

Thank you. I'd now like to turn the call back over to Joshua Higa for any closing remarks.

Speaker 1

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

Operator

Thank you. This concludes today's conference call. Thank you for participating.

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Key Takeaways

  • Interim Phase 2 ORBIT data for UX143 (cetuzumab) in osteogenesis imperfecta showed a 67% reduction in annualized fracture rate and up to 19% increase in lumbar spine BMD after 6 months, with global Phase 3 enrollment on track to complete in Q1 2024 and an interim analysis expected next year.
  • Extended GTX-102 data in Angelman syndrome demonstrated clinically meaningful gains across multiple domains supported by EEG and natural history comparisons, with three patients losing and then regaining developmental milestones after treatment interruption; data from ≥20 patients in the expansion cohort are due mid-H1 2024.
  • In the first UX701 Wilson disease cohort (5 × 1012 gc/kg), 4 of 5 patients improved copper trafficking and began tapering off chelators, including two now fully off standard of care, and Stage 1 dosing is expected to complete by year-end with full safety and efficacy results in H1 2024.
  • Commercially, demand for Crysvita in Latin America and start forms for Jovi in North America remain strong, and the company reaffirmed its 2023 guidance of $325-340M for Crysvita, $65-75M for Jovi, and $425-450M total revenue across all products and regions.
  • Financially, Q3 revenue was $98M with a net loss of $160M, operating expenses of $243M, and a cash balance of $524M (plus $326M raised post-quarter), supporting an expected full-year net cash use of ~ $425M and runway into 2024.
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Earnings Conference Call
Ultragenyx Pharmaceutical Q3 2023
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