Ultragenyx Pharmaceutical Inc. ($RARE)

Hi, everyone. Good afternoon. Welcome to Miami. I'm Ellie Merle, one of the biotech analysts here at Barclays. Very happy to have Ultragenyx here with us for a fireside chat. And joining us from Ultragenyx is Dr. Eric Crombez, the Chief Medical Officer and EVP. Eric, thank you so much for joining us.

Well, it's an exciting year for the company heading into the Angelman Phase III. But before we dive into that, maybe just to start off with as a commercial stage rare disease biotech, could you provide a high-level overview of the story?

Yes. Great. And thanks for having me. Great to be here. So just very briefly, founded in 2010, public in 2014. Founded by our current CEO, Emil Kakkis, with a real focus on rare disease and focusing on patients and diseases where there still remains a high level of unmet medical need. And really with that focus on rare disease, trying to bring along enough platforms, whether it be enzyme replacement therapy, small molecule gene therapy, other modalities where we really have the diversity of platforms where we can focus on that unmet medical need and then figure out the best way to tackle these diseases.

Great. And before we dive into the pipeline, maybe just to touch on the global commercial footprint, which is less common for a biotech of your size. What led you to pursue the strategy rather than partnering ex-U.S.

Yes. So we do have and have built over the years a broad commercial footprint, it speaks to the strength of our commercialized products that is led by Crysvita and that is in partnership, but then also bringing along Dojolvi, Mepsevii and Evkeeza. And for us, really having control, direct control broadly across the various regions, certainly starting with North America, Europe, now with an office in Japan kind of as a jumping off basis for Asia and then also a deep and rather large team for South America. And I think what that allows us to do, in addition to maintaining control is really leveraging the expertise we have. It may be unusual, but also what we do is unusual and not relying on what some people may consider a very traditional large commercial footprint, but also relying very heavily on our medical affairs expertise and the team to really lead all of that work.

Great. And you're also approaching profitability in 2027, which is, again, less common for a biotech of your size. Could you highlight the factors getting you there? And maybe what profitability would mean for the company long term?

Yes. And I think that has kind of been our north star, if you will, for a while now and really focus on profitability in '27. Certainly, that has relied heavily on the base business, again, that is led by Crysvita but also really growing and growing in meaningful ways with Dojolvi, Mepsevii has been with us since the beginning, and then Evkeeza doing very well most recently. There is some dependence on approval and commercialization, launch of our late-stage programs. We do have a large and robust pipeline that has grown and progressed to late stage. And then looking also at PRVs. Our modeling currently has 2 PRVs originally focused on GSDIa and MPS III, but with its recent reauthorization also puts into play one for Angelman. And then again, with the advancement of our pipeline that I spoke about, the transition from late-stage rather large, rather expensive Phase III trials into approval into commercialization and launch and the cost reductions that's realized there even if there is some investment early on in the pipeline, those are much smaller scale Phase I/II, which are much less expensive than what we're investing in these Phase III programs.

Great. And before I jump into Angelman's, which I'm sure most people in this room and on the webcast are curious about, could you provide us a high-level overview of the pipeline and the programs in development?

Yes. So I guess, looking at kind of at our near-term approvals, so now being led by GSDIa recently received our PDUFA date in August that will be followed closely behind for our Sanfilippo program. So those 2 lead gene therapy programs kind of have traded spaces for which it was going to get approved first and be our first gene therapy approval. Importantly, followed behind that is the Angelman program and the Phase III data readout later this year. We have talked about the OI data readout at end of the year and our continued analysis of that data before making final decisions with that program. And then importantly, we do have our OTC program and Wilson also gene therapy. And then, again, a lot going on within our research group and a lot of potential to bring new things into the pipeline when appropriate.

Great. Yes, a lot going on. So maybe starting with Angelman, can you provide an overview of the program, the data we've seen so far and sort of expectations as we head into the Phase III?

Yes. So a big value driver for the organization this year, very important to us. We have been talking about the prioritization of this program for a long time. So it's really great to see that program heading into data readout this year. We did a relatively large Phase I/II study, and that was important to us because we always recognize the complexity and variability within neurology. We took the time to dose a total of 74 patients in that Phase I/II study that really allowed us to understand dosing, understand this, AO, understand the end points before we design and then launch that Phase III there. So two Phase III study Aspire and Aurora. Aspire leads that is our sham-controlled Phase III trial. We enrolled 129 patients between 4 and 17 years of age with full deletion. We like that approach and really continuing on with the same patient population we studied in Phase I to best understand how this drug will work in those patients. But importantly, in this case, focusing on patients with full deletions, meaning these patients are not making any UBE3A. That makes them a very consistent phenotype. And to me, that's the best way to have clear signal detection when you're reading out these Phase III studies. This does make patients also at the severe end of the spectrum. It is the majority of patients, but it is not the totality of the patients affected with disease. And that makes the importance of bringing along Aurora, our second Phase III study that is open label. It is a true basket study where we're looking at younger and older patients and then patients with other genotypes missense mutations, uniparental disomy and [ printing deuvex ], understanding that we really do need to bring this drug forward for all patients who could potentially benefit from it.

And in terms of the Phase III design, that's helpful context. But can you elaborate a bit more on sort of why the Bayley-4 cognitive score was chosen as the primary endpoint?

Yes. So cognition assessed by Bayley-4 is our primary endpoint. [ From -- 4 ] patients total in the Phase I/II, we had data to look at. And we're looking at across all of the key domains, cognition, gross motor behavior, speech and sleep, all of them are important. It really was what we were bringing forward as our primary endpoint in the basis of powering for that. So we did see a great response in cognition. Importantly, though, we like cognition because it is foundational to speech, walking, improving sleep, it's foundational to the gaining of all those additional skills, which we will look at as secondary endpoints. So really looking at a totality of really how these patients are affected.

And what would you need to see, I guess, to be statistically significant in Phase III as well as to be clinically meaningful on this cognition core?

Yes. So I think when we're talking about statistical significance, I think it's still most helpful to look at the data we presented at the fast meeting a couple of meetings ago. And that's where we looked at evaluation of cognition for Phase I/II that's changed from baseline, both by GSV scores, that's how you would traditionally assess this in a Bayley assessment but also by raw scores. And looking at raw scores is important because that is the FDA preference. They don't like modeling. They don't like adjustments to score. So the raw score is their preference, and I don't disagree with that. Looking at raw scores for cognition, we saw a 10.9 point difference improvement from baseline. That compares to natural history. And the way we were looking at natural history for powering is allowing for at least a time improvement over natural history, just accepting some things can happen in a Phase III trial that showed a change of 1.2. So looking at the difference between those two scores is how we power this, how we end up with originally needing 120 patients for statistical success there. We did over enroll to 129 patients because there was such demand and we had so many patients entering screening. We didn't want to leave them behind once they committed to the study, we wanted to allow them to dose there. So that's our basis for statistical significance. I think the best way to think about clinical significance is going back to what the FDA now is talking a lot about meaningful score differences that is the equivalent of clinical significance there, but the way we're talking about it now. And for the work we're doing on the MDRI, our second primary endpoint for Aspire and an important kind of hedge to cognition as a primary endpoint setting a MSD, a meaningful score difference, of plus 5.

Great. And what would you expect from the comparator arm? I know we have the natural history data, but sometimes you see patients perform differently under the guys of a clinical study. So how should we think about that?

Yes. And then the natural history for rare disease for Angelman, it is pretty robust. And I think we can rely on and we have dependent on it quite a bit as we are analyzing our data powering in the study. The truth is, is that developmental line, it really is very flat. These children by natural history aren't really growing, developing and learning new skills in a meaningful way as you would expect. It's not 0. And that's how we got to [ 1.2, 3x ] natural history to allow for things to happen. And that, to me, is being very generous when you're thinking about things that could happen in a Phase III trial. Importantly, what we've done is really think about the potential for placebo effect with Angelman. I think these parents are very motivated. These parents obviously understand there is no treatment available currently for this disease. And if they want to give their children a chance to develop and learn new skills, these ASOs are the best way to do this. So you could understand enrolling in a trial, you want to be randomized to the active treated. You want them to be doing better, when there's a potential for placebo effect there. And you could have seen that in the Bayley assessment because as you do a Bayley and neurotypical children as it was designed, you allow for caregiver input. So that means if a child is in front of you having an assessment on and they can't do something, but the parent says, they reliably and consistently do this at home, you can score that. We don't allow for a parental input. So it's really what can the child do in front of the evaluator, what are they demonstrating as new skills and then that controls for that placebo effect. So we do expect to see that control group run very consistent to what we've seen in natural history.

Great. That's helpful. So just going back to what you saw in Phase II, could you remind us in more detail of what was seen there on this Bayley-4 cognitive score? And in particular, just what the GSV is versus the raw score and what those 2 are meant to illustrate?

Yes. And GSV score was our original focus for the Phase I/II. It's how this was designed and validated and then that's your -- the score after adjustment. So you have -- so you can consistently follow neurotypical children as they develop, and it's a good way to do that there. Again, the FDA doesn't like any modeling or adjustments to those scores. So they just like the score as it is, as you purely add that off as you're doing there. And again, it was important for us to show that yes, the numbers do change marginally. But as we designed a results showed in those -- in that comparison from ways to, they are very comparable. And whether you're looking at GSV or raw scores, we still have greater than 90% power.

Okay. Great. And then maybe just to highlight a bit the Aspire trial and sort of the strategy there and the time line for that?

Sorry, just Aspire or Aurora?

Maybe let's just go over both, yes.

Okay. Yes. So again, Aspire leads that trial enrolled very, very quickly, yes, that speaks to the strength of the team, and it also speaks to the prioritization, we really did bring our best and brightest over to lead that study. I think it also importantly speaks to when you can enroll Phase III trial like this, that is intrathecal injection under anesthesia in roughly 7 months, the unmet medical need there and how these parents are really willing to move heaven and earth to get these children treated, and even just thinking about this as an intrathecal drug, there is a burden to participating in the clinical trial and all of those assessments. So again, I think they see this as their best chance for their children to develop, learn and grow and having a much more meaningful interaction with the parents and with the rest of the family there. So again, data readout, second half of the year, that study leads. Again, Aurora is important. It is open label that does help us with enrollment and burden for these children to participate. And really as a basket study, establishing comparable safety to Aspire. And then really a straightforward data extrapolation over to Aspire to show that this drug has the same benefit risk profile in all patients affected with Angelman.

And so the base case is, if successful, in the Phase III [ ARISE ] study that you'd potentially be filing for a broad label?

Yes. We -- again, to me, what can be very hard with rare disease where you often have subtypes is focusing on one subtype and then leaving a group of patients behind who are suffering from the same disease and really could clearly benefit. So we recognize the importance of having a full label and really bringing this drug forward for all patients with Angelman.

And when should we expect the next update from this open-label study?

So we talked a lot about whether we should do another broad analysis of that Phase I/II study. we really came to the conclusion that we did not need that data to help us as Phase IIIs were underway. And then really recognizing the amount of work it takes and it really is the same team working in Angelman, we need that understanding and expertise and not wanting to distract from the Phase III. We understand this is a competitive environment. We understand the importance of going fast but also with a high level of quality and integrity of that data set there. So we asked the team to focus there. We do not have plans for another update and just honestly really focus on that data readout in the second half of this year.

So you have another company in the space, Ionis developing a drug for Angelman's. What's your perspective on how your efficacy and safety compare relative to the Ionis program?

Yes. And I think from talking to investors, talking to treaters, both who are participating in either trial or both or physicians who are experts in Angelman, but not participating in the trials. I think a lot of them are waiting for the Phase III data where we can make a head-to-head comparison, both for efficacy and safety. But on the whole, seeing some level of equivalents there and, I think, also supported by both of us being granted breakthrough designation by the FDA, which is a very high bar. So to me, that's great. I think it's great validations for ASOs as the right way to approach this disease. It is large, where there are a lot of patients there. So I guess if the sentiment is roughly equality out there, then I guess all things being equal, I'm glad to be in the lead.

Great. Can you elaborate on the safety that you've seen?

Yes. So with the safety profile, and I think probably the focus there is on the lower extremity weakness that we've talked about. And a subset of those 74 patients, what we described as the dose expansion patients was we're really doing additional patients to make sure we truly understand dosing to go into Phase III because to me, if you can, you want to bring a single dose into Phase III, bringing multiple doses and just really drives up your patient numbers and just makes everything so much harder there. So with those dose expansion patients, we saw 2 events of lower extremity weakness. One was in retrospect. The PI saw elevated protein and a CSF sample went back to the family and asked if there was any possible challenges with walking and they said maybe, yes. So that's about as mild as I get. The second case was also mild and resolved on its own. So I think at this point, we're very confident in understanding. We understand the cause of this lower extremity weakness. We put in place a mitigation plan that did its job. And ultimately, I think we'll find with the phase -- full Phase III data readout. So this is the benefit risk profile for ASOs I don't think this is going to be something unique to all our ASO.

Okay. Interesting. Can you elaborate on the mitigation plan that you put in place?

Yes. So really, this is looking at the chemistry of any ASO, potential for irritation at site of injection. So really, that mitigation was not allowing that drug to pool at the site of injection. So that's really involved around a flush, and that's just moving it through into the CSF. And then Trendelenburg, while these children are not in anesthesia, in young children, when you're doing intrathecal, you do want to use anesthesia, so they don't develop this fear of going to the doctor fear of entering in the hospital there. So while the patients are recovering from anesthesia, we put them in a slight incline that's just using gravity again to get it away from the site of injection. So just really straightforward trying to avoid that concentrated localization.

Okay. That makes sense. Turning to like osteogenesis imperfecta. Maybe just -- can you give us an update, an overview of that program where it stands today and sort of next steps from here?

Yes. So we spoke about that Phase III data across the two studies at JPMorgan in January. And that's kind of where we are with conclusions we've drawn from those studies, and that was really based on how the studies were designed with the primary endpoint. Where we are today and truly trying to understand the totality of the Phase III data coming out of those two studies. And that's not just doing additional analysis, looking at subtypes, which includes types of osteogenesis imperfecta but different age groups. But also going back to the sites, talking to the PIs, asking the PIs to really talk to the patients and truly understand the effect this drug has had on the patients in these trials. And yes, we have measurements to do that in a controlled way as part of our end point but it still doesn't really truly capture the full picture of what's happening, how are they really feeling? How has this changed their life on a day-to-day basis, what type of activities they are doing? What type of risk they're doing and truly what is the full picture around any fractures they may be having. And that's really what takes time here, is going back really on a patient-by-patient level in addition to all the additional analysis we're doing. So we can really understand is this driving towards a no-go decision with this program? Or is there something there in a subset of patients that we think is clearly showing benefit risk. And if we come to that conclusion, if we get to that point, then obviously, the next step would be go back to the FDA or back to regulators have that conversation and make sure there is a path forward. But today, we are still really truly trying to interrogate data set and really understanding it to the fullest success.

That makes sense. And what are the time lines in terms of this data analysis?

Yes. So we haven't really given time lines, so you don't want to rush this process. We understand that we need to go fast. We are not going to take forever, if you will. But again, when we failed to meet our two primary endpoints. We need to make sure we thoroughly analyze this, make sure we truly understand this. So we wanted to give ourselves that time before we put an external time line on that. So more to come.

Makes sense. And then for your gene therapy program, kind of remind us of the time lines there and the submissions.

Yes. So GSDIa, I guess, now is our lead gene therapy program with PDUFA in August is great. Sanfilippo, we had that IRL that is all really just requiring additional paperwork and written response. So we'll do that quickly. that's a 2-week validation period, not the normal 2-month validation period. So do you expect to get a PDUFA date for Sanfilippo not too far behind GSDIa, both within this year. So more to come on that. And then OTC in Phase III, that study has always remained a little bit in the background for the prioritization of how we've been talking about it, but OTC remains on track for that Phase III data readout. And then also for our Wilson program, still with that additional cohort, making sure we understand that we are able to get the majority of patients off of standard of care doing well before we make that final dose selection to invest in Phase III.

So a lot of programs, maybe if you could just high level kind of the size of each indication and how you think about kind of the unmet need in those?

Yes. So Angelman leads both by size, we're talking 60,000 patients in the territories we cover. A lot of people have talked larger numbers than I think 60,000 is probably modest, but still very big, rare. That also has arguably very high unmet need, but nothing available for these patients. . Sanfilippo very similar situation. These patients have absolutely nothing available to them, and they once they become symptomatic between their first and second birthday really deteriorate to the point by 5 years of age. They have a lot of accumulated neurodevelopmental damage and don't live beyond their teens traditionally. GSDIa, these episodes of hypoglycemia can be life-threatening, particularly in pediatric patients. So again, that is our focus where there is true high, high unmet medical needs in these patient populations.

Makes sense. Maybe just in terms of the submissions, given broadly some of the changes at the FDA, how are you thinking about the approvability here of your gene therapy programs?

Yes. So I think if there's any benefit from going through the CRL and now with the IRL is we are clear what the FDA inspections are. And the findings with the CRL were really based on things with our manufacturing facility, things that we are absolutely able to do and to fix and respond to. The FDA has always been complementary of the data coming out of that Sanfilippo program. And they have remained complementary. We recently did a data update at the World meeting and showing really the strength that's held up over time. So a lot of confidence there. And then also with GSDIa, we learned a lot from that Sanfilippo experience. Again, very strong Phase III data that's held up over time, hitting statistical significance for a primary endpoint. So again, with our PDUFA date in August, a lot of confidence there. And then obviously, working again with the importance place on that Angelman readout in the second half of the year.

Great. Welcome. Well, Eric, thank you so much for joining us, and thank you, everyone, in the room and talk to you all soon.

Thank you.