Ultragenyx Pharmaceutical Inc. ($RARE)

I'm one of the biotech analysts here at BofA. Our next presenting company is Ultragenyx. And here with me are Howard Horn, Chief Financial Officer; and Josh Higa, Head of IR. Thank you for joining us, guys.

So I think there's a lot going on at the company. I think most people are familiar with it, but maybe we can start with a quick overview of the company, kind of your commercial products, and you have a very busy second half of the year. So maybe you can highlight some of the key catalysts coming up.

Sure. Glad to, and thank you for having us. So Ultragenyx is a next-generation rare disease company on a pathway to profitability in 2027. We have 4 commercialized products, and we are estimating between $730 million and $760 million in revenue this year. We are hopeful to have 2 approvals and launches of 2 gene therapy programs this year. And the other data event people are waiting for is our Phase III data in Angelman that we talked about coming out in the second half of the year. So yes, it's a very busy year.

All right. Great. Maybe we can start with a quick question on the commercial side. So you recently reported earnings. I think there was a slight miss in the quarter, but you reaffirmed your guidance for the year. Maybe you can talk to us a little bit about 1Q dynamics and kind of what gives you confidence in the revenue guidance you provided earlier this year?

Yes. We've been asked about this a little bit today. So I think we and the Street are pretty well in lockstep for the full year. I think it's a question of how people were thinking about the quarters. I can tell you from my perspective, we actually beat our plan for the quarter. We may have been slightly under what the Street had, but the typical pattern for us is one of the sawtooth, right, a lower first quarter, higher second, lower third, higher fourth. We've seen that play out over the years. That is what is playing out again. We did go to pains at the end of the fourth quarter to talk about in our projections for this year, how Latin America might be an impactor to our Crysvita revenue. It's not an impactor from a demand perspective, but it is an impactor in terms of sales that can be lumpy because these are larger contracts. So those are things that are playing out. But overall, for our business, we feel like start forms and other underlying signals of demand are doing really well.

Great. How do you think about growth of Crysvita at this point? And I guess, how important is that to your goal of reaching profitability in 2027?

Yes. I think this year's Crysvita numbers of $500 million to $520 million top line imply single to double-digit growth, right, where in years past, it's been very healthy double-digit growth north of 20%. So I think we are seeing some leveling there. But again, it's with dynamics described for the year that I think will sort of reset again in '27. So I see it continuing to grow. The macro question about profitability and how we think about some assumptions there from the revenue point of view, what we see is that our 4 current programs will continue to grow double digits, and that top line will be augmented in some way by new launches. We have 3, as I was mentioning, that might be in the near term. Not all 3 of them need to hit for us to get to profitability, but that's how we think about the top line.

Okay. Great. So maybe we can move on to Angelman. Like you mentioned, I think this is highly expected readout later this year. You recently provided some long-term data at the earnings call. Can you maybe remind us what that was and kind of the relevance of that and how you think that has read through to the readout in later this year?

Yes. So last week on our earnings call, we talked about some sort of longer-term Phase I/II data. By the way, just stepping back, the philosophy of why we chose to put that out was that we wanted to help people understand the magnitude of the impact and the duration of the impact and to let people know that what we had used from the Phase I/II to power our Phase III, all those assumptions were still intact, right? So that was the main thinking. Now the details that we shared were 66 patients worth of data in our long-term extension, average of 3 years, some approaching 5. And these are patients 4 to 17 years old with full deletion of the UBE3A gene. And that we shared 2 things. We shared some efficacy points that I'll come back to, and we also shared on the safety side that we had no new cases of lower extremity weakness. And the 3 points that we shared on the efficacy side were, first, on Bayley-4 cognition, we talked about at 12 months approaching 10 points of improvement across the baseline against sort of a minimal threshold that you'd want to see at 6. We also said that in future time periods or later time periods, you saw that continuing to improve. So that's one of our endpoints that we're allocating alpha to it. The second endpoint we're allocating alpha to is what we call the MDRI. It's a mixture of 5 different endpoints, each of which have their own thresholds. But what we described there is that 1-year, 2-year and 3-year time points, the p-value was less than 0.0001, so compelling there. And then the last part was around expressive communication, which is another endpoint that we look at, and it followed a similar pattern to what I just mentioned for Bayley.

Okay. Great. How comparable are these data? Or I guess, how comparable are the patient populations that you're enrolled in the Phase I/II compared to the Phase III that would give us confidence that these results will translate to the Phase III data?

Yes. The Aspire trial and the Phase I/II are completely overlapping in who we enrolled, right? These are full deletion patients who are 4 to 17 years of age. So yes, it's a complete overlap.

Okay. And so you mentioned the split in the alpha for the readout for the Phase III. So you have the Bayley-4, you have the MDRI. Can you maybe talk or remind us the decision on using the Bayley-4 as the primary endpoint for the trial. I think the company has said in the future, they see the MDRI being kind of like the primary clinical outcome for Angelman. So why did you decide to make that decision and split the alpha between the 2 endpoints?

Yes. So stepping back, 0.04 of alpha is allocated to Bayley 4 and 0.01 is allocated to MDRI. I think, look, MDRI, this is not the first time it's been used. It's actually part of our Mepsevii label, but it is relatively new. And I think the agency has comfort with single endpoints. And so that is Bayley-4 was the one we put forward there. But at the MDRI, as you mentioned, I think that's the way people observe and experience and think about the disease, less so in a single endpoint, but more of what's the totality of impact for a patient. And so if you're a patient, if you're a caregiver or if you're a doc, I think that's the way you think about it. So that's why we thought MDRI is an important complement. And bluntly, it's also a hedge, right? It's a hedge. So we're not just putting all apples in one basket.

Okay. I guess from a clinical perspective and from a patient perspective, too, like what do you think families would see as more clinically relevant? Do you think they focus on benefit on the Bayley-4 or is the MDRI kind of more important for physicians and patients?

I guess in our discussions with patients and their families, well, families and caregivers, they don't just talk about one endpoint. They talk about many. And what you see when you look at our MDRI, not everything turns green, right? It's a heat map of the page. It's because not everybody has every issue, right? But what we're counting there is how many issues can improve for each patient. And again, I think that's how they view it.

And can you maybe discuss the kind of different scenarios where you hit on the Bayley-4, you miss on the MDRI or the other way around, what do you think would happen in those instances? And I guess, what's needed for commercial success?

Yes. Look, we -- because we have 2 endpoints, we could hit on one and not on the other and vice versa. We could hit on both or not on either, right? All the scenarios are possible. But from an agency perspective, right, they've allowed us to allocate out each. I think that means that each one is seen as valid to them. And my hope is -- well, my strong belief is we have a statistically significant trial and it gets labeled and we get it on market. I don't think there's a lot of time spent talking about what was that one number that you had in the trial. It's more about how the patients done, how are doctors observing their population.

Okay. Makes sense.

I think Howard's point is right. In order to have a statistically significant Phase III, we only need to hit on one. Both of them will be evaluated in parallel. But really -- and this is the case for every study. It's the totality of data that will be assessed, and that will be the case for us, too.

You mentioned something important. They are evaluated in parallel, not sequentially. So both are seen as having wait then.

What should we expect to see of the top line results? I guess how much data do you think you'll share? And are you planning to state some for later medical conferences or something like that?

I don't know that we've said that. I think we would share enough about our endpoints to make sure people understood that we'd had a success. But certainly, there would be more detail there. I mean this is an incredibly detailed data set where you're taking lots of measures even beyond the 5 that are in the MDRI. So there'll be a lot of rich data to plumb. But I think we would want to satisfy people's curiosity of did it really succeed, we would give enough on that.

That's right. Striking the right balance between giving people enough data to feel confident, but also wanting to do it in a timely fashion.

Yes.

Based on what we know from the natural history of the disease, what are your expectations for the Sham-Control in the trial? And what is the risk that, that might outperform and show more benefit than you would expect?

Yes. So natural history for full deletion patients is quite flat. You might get a percentage point on the Bayley for over the course of the year, right? And what I mentioned to you a minute ago is that we were seeing 10 percent -- 10 points on the Bayley-4 scale at a year. So I think the Sham arm, we believe it will follow that. There's other things we've done to try to make sort of the arms of the trial be comparable. Of course, we stratified by Bayley-4 cognition. We've also stratified by age. I think the other thing that we know is that folks who are in the 4 to 17 range who haven't been treated, they don't know that they're in the trial, right? So I don't think there's a bias that would be introduced by the patient themselves. So those are some of the things that we think about. Also, a hot topic recently has been that the Bayley-4 has caregiver input in the Phase II, not the case in Phase III. In our case, whether it's in or out of the Phase II data, doesn't change what we had shared with the community. But I do think that's an opportunity to potentially control for any bias in the Phase III, and this is a smart decision by the agency and one we expected.

Okay. Great. You mentioned safety and how the recent update highlighted there haven't been any new instances of lower extremity weakness. Do you think that's well managed at this point? I know you implemented a few different strategies to kind of deal with that during the dosing of patients. And if you do see some, what do you think would be like an acceptable rate for these patients given the high unmet need?

I think we have a well-understood safety profile at this point. What we're using to mitigate the things that we saw before is a Trendelenburg position where you put the patient head down at a certain degree of angle. Also you do a spinal fluid flush. Those things appear to be working. I think what's also very meaningful to me is that the agency at the end of Phase II and in our subsequent discussions doesn't spend a lot of time on this, right? So I think they probably also share our view. So yes, we -- I don't know that I have a comment on your last one. I think people understand it, which is important. I think everyone has resolved, which is also quite important. All those patients have remained in our trial. So were it to occur in the setting of a commercial situation, I don't think physicians would get frustrated by it, and I don't think it would affect adoption provided that it's in the realm of what we've seen in terms of a percentage basis of recurrence.

Okay. Great. And at the recent update, you also mentioned most patients are getting to the 14-milligram dose. How does that compare to your expectations? And can you remind us how the titration like process works?

Yes. Josh, maybe I'll ask you for help on this one. The 14-milligram dose, though, is what we have in Phase III, and that's what we would assume would be the commercial dose. But do you want to answer the other part?

And I think maybe one of the nuances between Phase II and Phase III is Phase II, there certainly was an element of dose finding. So we were working people up that titration ladder and trying to do it in a thoughtful manner. But once we figured out and established the safety profile that Howard mentioned, in Phase III, we have a very -- it's a much more sort of regimented titration pattern that all these patients will be on. And we would expect that the Phase III patients are all getting up to 14.

Okay. Great. And so I guess, assuming you have positive data later this year, what would be the next steps? And how do you view the opportunity in Angelman for your product?

Yes. I guess the next step is getting moving on BLA and get moving to be prepared to launch. We don't currently participate in a lot of competitive markets. This would be one. And so therefore, time is of the essence. I think to your second part of the question, it's quite a large market, right? We think about 60,000 patients globally in addressable markets that we could reach, maybe 20% to 25% of them in the United States. We haven't commented much on pricing, but I think given the unmet need and given the number of patients, this is quite a large market one that certainly is big enough for more than one player. And we're -- bluntly, we're just -- we're happy that we enrolled quickly, and we're happy that we're getting towards our Phase III data in the second half of the year.

How easy is it to find these patients? And I guess, how concentrated are they? Are they found around centers of excellence? Or I don't know how much of this is treated in the community setting?

Yes. So the patients -- I'd say it this way. They have extremely well-organized societies and groups. And so it's a very active community and one that we've been able to engage with throughout our clinical trials. So I think there are patients waiting for this for sure. We haven't said too much more about how we plan to do the launch and how many patients are identified. That will all come in the coming months once we put out the data. But it's a great market.

Okay. How big of a sales force do you think you would need for this launch? And is there any overlap with your existing commercial infrastructure?

So no overlap to our current infrastructure. But in a rare disease like this, you're not talking about hundreds of people for sure. You're talking about tens of people.

Okay. Got it. And maybe lastly, you're also running the Aurora study, which is expected to expand the addressable patient population. When do you expect to have data for that? And how meaningful would that expansion be?

Yes. So this is a trial that expands on our current Aspire trial, which is, again, in 4- to 17-year-olds that have full deletion. So this Aurora trial is the other age groups, older and younger that have full deletion as well as other deletion types or genomic types. That trial is going to finish enrolling at the end of this year. And I'd say 70% of the population is full deletion and roughly 30% is the remainder. So it's an important part of the overall pie and one that we wouldn't be blind.

Is there a reason to think that GTX-102 wouldn't work in these patients or you would see any difference in efficacy?

No.

Great. All right. So maybe we can move on to some of your gene therapy products. You mentioned you have 2 PDUFAs also coming up in the second half. Maybe we can start with GSDIa. What do you think is the unmet need in this indication? I think a lot of the pushback we get is like you can treat patients with cornstarch, which is pretty cheap. What is the need for a gene therapy product in this indication?

Yes. So this is our DTX401 program with the PDUFA date on August 23. Unmet need here is quite high. Let me describe, I think, what a patient today is like. They're taking cornstarch slurries every 2 to 4 hours around the clock. It's a nonstop, can't stop it. And if you do miss a dose of it, you could find yourself in a coma, seizures, death. So it's quite stressful day-to-day. And while people are using this as a mitigator of disease, it is not an impactor of disease and you still have the underlying metabolic issues in liver and kidney and other issues. So our hope with 401 is to actually address the underlying concern and get the liver functioning the way it should. So you don't find yourself in glycogen fallout as it were. So it's quite an urgent disease. It is maybe 6,000 patients globally. We have talked about price points in the $1 million to $2 million range. And given that our PDUFA date is coming up so soon, we are in sort of launch planning, right? And so what that means for us is we manufacture this one entirely at our gene therapy plant in Massachusetts, and we have been building up inventory. It will use the sales force we currently have for Mepsevii and Dojolvi today in the United States. So that's great leverage to have. We've been talking to payers and getting their opinions, and we're excited for that launch. 111 is shortly on its heels, and I know we'll talk about that. But our commercial team thought they were going to have these programs maybe a year ago. And so they're anxious to get them.

How do you use that additional time since you were expecting this last year, how have been using the additional time you had to prepare for the launch ahead of the PDUFA?

Yes. What I left unsaid is the reason we had the additional time is there was a CRL related to our 111 filing. So this is our Sanfilippo gene therapy filing. And so it had some observations at our plant in Bedford. So we've used the time in 2 ways, importantly, to address all those issues, right? We want to make sure all of that is great. And what I'd say is it also maybe opportunistically allowed the data to ripen. And so you have even longer time in this case for 301 and for 401 to show the improvements that people are getting as time goes on, right? So I think one of the worries with gene therapy is that things will abate. And that's not what we're seeing. In fact, it's quite the opposite.

Okay. What has been the feedback from the physician community to the data you've generated so far?

Strong. Yes, quite compelling. I don't know if we're still on 401 or 105. But in both cases, 111, maybe I'll pivot to that. While 401 is a potentially lethal disease, 111 is just surely so. And that's a place where there is really no solution. And I know the patient community is extremely well organized and waiting for this, and the physician community is really excited about the data.

Okay. Maybe going back to 401, given that that's the first PDUFA you have coming up, how confident are you in the filing now given kind of the roadblocks you face with 111? Do you feel like you've like fully fleshed out all the problems you had in terms of manufacturing?

Yes. So as I was mentioning, we spent the time since last spring working through the issues at our plant in Bedford. And so I'd say we feel good about that. And I described the interactions with the agency right now is just normal, right? There's back and forth questions being asked and answered. So I have comfort that we're on a normal path.

Okay. Got it. How easy is it to find these patents? You mentioned 6,000 globally, which is not a lot. But are these kind of well identified? Is there a potential to expand the patient population once you have a therapy approved?

Yes. So in the 401 population, they're identifiable because they're taking these slurries of cornstarch around the clock. And they wouldn't survive if they didn't. So possibility to expand like in rare diseases, there's almost always a way to expand. As we state like a 6,000 number, that's in the geographies that we know we can access. That is not an entirety of the globe type number. It's meant to be a pragmatic number people can use in a modeling.

Okay. You mentioned for the initial launch, you'll use the existing commercial sales force. Do you think there will be a need to expand that over time? Or do you think that will be enough?

So certainly, onesie, twosies, right, incremental expansion to make sure that and they have now 4 products in their bag that they can cover what they need to, but no more than that.

Yes. And I think maybe to add, certainly with a multimillion dollar single-dose gene therapy, you want to make sure that you have the right sort of support structure around that dosing to ensure that it goes well. So we will invest in just a small handful of individuals to make sure that each one of those individual doses goes exactly to protocol. But to Howard's point, it is meaningfully leveraging the existing field team, but we'll make small adds just to ensure for this particular type of therapy that it's done well.

Okay. Got it. And I just saw your price range of $1 million to $2 million. Is that based on your conversation with payers? How far have you got in that in order to get confident in guiding to that type of price for this product?

Yes. We're triangulating as we always do, to find a price point. I think it is emblematic of the need, and we have gotten feedback from payers. And so that's the range we're contemplating for launch.

Got it. Got it. And how do you see the kind of the ramp of this launch going just given the small number of patients?

Yes. I think in all of these diseases, there's a bit of a bolus that you'll work your way through. But importantly, once you're through that bolus, there is an incidence that occurs every year, right? It may be in the U.S., for example, 40, 50 patients for 111 and maybe slightly higher for 401. But when you add that in other geographies, this is still a franchise that's hundreds of millions of dollars. So I think it's an important part of the P&L of the future for us. I'd also note that because of these diseases and the way we've -- we're working to get approval that there are PRVs attached to both. And so monetizing those PRVs is an important way for us to keep our balance sheet strong.

Okay. Great. Maybe we can pivot then to 111 in Sanfilippo. What is the unmet need there? I think this is even a more rare indication than the GSDIa. So how big is that opportunity in your opinion?

Yes. So comparing to 6,000, this is maybe 3,000 to 5,000 and some of the variability in that window, as you described about diagnosis. Basically, these patients, you'll diagnose them young, right, in the first few years of life and life expectancy isn't much more than the teens. So this is -- I mean, this is as bad as it gets. It's a tough disease. So we're thinking the patient numbers that I mentioned from a price point perspective, maybe a bit higher than 401, so in the 2 million to 4 million range. And that our commercial preparedness is right on the heels of the 401 preparedness. As Josh mentioned, we'll leverage the sales force we have, talking with payers already. This is a program that does come through our plant in Boston or in Bedford, but that's still finishing off. The drug substance comes from elsewhere.

Okay. What do you think is the willingness of families to dose the kids with Sanfilippo at this point? And do you think there's been a change in the perception of like gene therapies among these like rare disease, given like recent setbacks that other gene therapies have faced in terms of unexpected safety events that have happened?

Yes. So I think the willingness is high, but I think it's supported by data, in fact. So we, in this trial, have patients who are out to 8 years, right? And they're still on the curve that we would hope they'd be on and showing improvements. So I completely acknowledge that there are other things going on in the gene therapy space that you have to be mindful of. I think the facts as they relate to our gene therapy programs are encouraging. And I think adoption will be strong.

How do you view this competitive landscape? I think there are other therapies in development. I think you're ahead, you're probably going to be first approved but there might be other approvals coming up, not for gene therapies, but enzyme replacement therapy. How do you see that playing out in this market?

Yes. I think you got to be mindful of it, right? We do have a lead in this case, and it will require us understanding what the data is from the other companies. Josh, I don't know if you have any other points to add.

No, I think you hit it well.

Great. And with these 2 gene therapy launches coming up, how are you preparing for both at the same time, given the PDUFA are so close to each other? How are you preparing for like having enough product to launch and then getting like all the commercial infrastructure ready?

Yes. So the commercial part, maybe we've hit on a bit already. So that team will have the augmentation of a few heads, but we'll be ready to roll with both programs. I did mention sort of how they're being manufactured, but I think I forgot to mention that we've been building inventory for quite a while now, right? We were already thinking about this because the launch could have been last summer for 111 and maybe later last year for 401. So I think we're ready from a manufacturing point of view, and I know we're certainly ready from a commercialization point of view.

And probably worth highlighting all of that inventory that's been building has been already expensed as part of R&D. And in those first quarters of launch when we're selling the previously expensed inventory, the margin benefit is meaningful. And you kind of get to steady state once you work through that. But it's one of those interesting P&L dynamics for everyone to be aware of.

Yes. Okay. Great. How are you thinking about the regulatory environment? We just learned today that Commissioner Makary signed. How have your interactions with FDA been over the past few months? And do you think there's any potential risk given uncertainty at the agency right now?

So yes, I did -- we were in a meeting earlier today when we heard about the resignation. We -- our interactions have been basically around the 3 programs we've been spending time talking about. So I think we characterized that those have been positive and reasonably normal. I think maybe the macro thought is that it would be nice for some continuity and consistency at the agency. We've seen a lot of change in the last year and a lot of uncertainty. And so I don't know the person who will be the interim lead. I hear he's a long-time FDA person from the food side, but just some level of stability, I think, would be welcomed.

Yes. And I do think we have had a historical precedent and would expect to continue to work well with whoever is at the agency for sure.

Great. And maybe on setrusumab, when should we expect to see any updates? Where are you on analyzing the data? And do you see a path forward for that?

Yes. Good question. I don't know that I have a great update for you. I think what we'd say is we've been analyzing the data from the 2 trials that -- 2 Phase IIIs that failed to try to determine if there's a path forward and if it warrants talking with agencies. I think our conclusion is it does warrant it. But to determine what that path forward would be and if we would file remains to be seen.

I expect that we would -- when we have come to a decision about what -- where we stand with that program, we'd give the Street a full update on that.

Makes sense. And then my last question, you touched on this earlier, but what do you think is needed to reach profitability in 2027? There's a lot of moving parts in second half things could go different ways. What is kind of your base case assumption to reach that point next year?

Yes. So what we've shared is the revenue assumptions that I noted earlier. We also, in the start of this year, began a cost program, cost savings program and had a reduction in force of roughly 10% of our workforce. And those will have impacts this year and next vis-a-vis the way we described it is R&D plus SG&A percentage declines versus where we were in '25. So if you take the growth on the top line and you take those set of assumptions, you can find your way to profitability. Relatedly, I also mentioned the PRVs, which on a GAAP P&L will hit the P&L, but also, I think they're more important from a cash flow perspective or from a balance sheet perspective. So that's the set of assumptions we start with. I will completely acknowledge that we don't have certainty about how the top line will grow. But I can say that under pretty much any set of scenarios, we have enough levers to control on the expense side to be able to get ourselves on our path to profitability. And our goal is, of course, not to just hang out at the razor's edge of profitability in '27, but to grow faster. And I think what will define the slope of our EPS line in those years will be how those launches do and how many of them and which ones.

Okay. Great. All right. I think with that, we're out of time. So thanks again for joining us.

Thanks. That was fun.