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. 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. Before we dive into that, maybe just to start off with, you know, as a commercial stage rare disease biotech, could you provide a high-level overview of the story?
Yeah, great. Thanks for having me. Great to be here. 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. 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. 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 this strategy rather than partnering ex-U.S.?
Yeah. 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. For us, really having control, direct control broadly across various regions, certainly starting with North America, Europe, now with an office in Japan, kind of as our jumping-off basis for Asia, and then also a deep, and rather large team for South America. 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, you know, 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. 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?
I think, you know, that has kind of been our North Star, if you will, for a while now and really focus on profitability in 2027. Certainly, that has relied heavily on the base business, again, that is led by Crysvita, but also really 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 then 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. Looking also at PRVs, our modeling currently has two PRVs originally focused on GSD1A and MPS III, but with its recent reauthorization also puts into play one for Angelman.
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 scales, phase I/ II, which are much, much less expensive than what we're investing in these phase III programs.
Great. Before I jump into Angelman, 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?
Yeah. I guess looking at our near-term approval, now being led by GSD1A, recently received our PDUFA date in August that will be followed closely behind for our Sanfilippo program. Those two lead gene therapy programs kinda have traded spaces for which was gonna get approved first and be our first gene therapy approval. You know, importantly followed behind that is the Angelman program and the phase III data readout later this year. You know, we have talked about the OI data readout at end of year and our continued analysis of that data before making final decisions with that program. Importantly, we do have our OTC program and Wilson also gene therapy.
A lot going on within our research group and a lot of potential to bring new things into the pipeline when appropriate.
Great. Yeah, a lot going on. 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?
Yeah. You know, 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. 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 ASO, understand the endpoints, before we designed and then launched that phase III there. Two phase III study, Aspire and Aurora. Aspire leads, that is our sham-controlled phase III trial. We enrolled 129 patients between four 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. 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. 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 patients affected with disease. 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, imprinting defects, understanding, you know, that we really do need to bring this drug forward for all patients who could potentially benefit from it.
You know, in terms of the phase III design, that's helpful context, but can you elaborate a bit more on sort of why the Bayley-IV cognitive score was chosen as the primary endpoint?
Cognition assessed by Bayley-IV is our primary endpoint. From four 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 and the basis of powering for that. 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. Really looking at a totality of really how these patients are affected.
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 score?
Yeah. 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. Looking at raw scores is important because that is the FDA preference. They don't like modeling. They don't like adjustments to scores. 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.
The way we were looking at natural history for powering is, allowing for at least a 3-time improvement over natural history, just accepting some things can happen in a phase III trial. That showed a change of 1.2. 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. 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. 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 +5.
Great. 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 guise of a clinical study. How should we think about that?
Yeah. Then the natural history for rare disease, for Angelman, it is pretty robust, and I think we can rely on it, and we have depended it on it quite a bit as we are analyzing our data powering this study. The truth is that developmental line, it really is very flat. These children by natural history aren't really growing, developing, learning new skills in a meaningful way as you would expect. It's not zero, and that's how we got to 1.2x-3 x natural history to allow for things to happen. That's 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. You know, I think, you know, these parents are very motivated.
These parents obviously understand there is no treatment available currently for this disease. If they wanna give their children a chance to develop, learn new skills, these ASOs are the best way to do this. You can understand enrolling in a trial, you want to be randomized to the active treated. You want them to be doing better. There's a potential for a placebo effect there, and you could have seen that in the Bayley assessment because as you do a Bayley in neurotypical children as it was designed, you allow for caregiver input. That means if a child's in front of you having an assessment done 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 parental input.
It's really what can the child do in front of the evaluator? What are they demonstrating as new skills? That controls for that placebo effect. We do expect to see that control group run very consistent to what we've seen in natural history.
Mm-hmm. Great. That's helpful. Just going back to sort of what you saw in phase II, could you remind us in more detail of what was seen there on this Bayley-IV cognitive score and in particular just what the GSV is versus the raw score and what those two are meant to illustrate?
Yeah. GSV score was our original focus for the phase I/II. It's how this was designed and validated, and then that's your S-score after adjustment, 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. They just like the score as it is, as you purely add that up as you're doing there. Again, it was important for us to show that, yes, the numbers do change marginally. As we designed, the results showed in those, in that comparison from Wave 2, they are very comparable. Whether you're looking at GSV or raw scores, we still have greater than 90% power.
Mm-hmm. Okay, great. Maybe just to highlight a bit the Aspire trial and sort of, you know, the strategy there and the timelines for that.
Sorry, just Aspire or Aurora?
Maybe let's just go over both. Yeah.
Okay. Yeah. Again, you know, 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 a phase III trial like this that is intrathecal injection under anesthesia in roughly seven months beyond that medical need there, and how these parents are really willing to move heaven and earth to get these children treated. Even just thinking about this, you know, as an intrathecal drug, there is a burden to participating in the clinical trial and all of those assessments.
Again, I think they see this as their best chance for their children to develop, learn, and grow and, you know, have a much more meaningful interaction with the parents and the rest of the family there. 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. 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.
The base case is, if successful in the phase III Aspire study, that you'd potentially be filing for a broad label.
Yeah. Again, you know, 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. We recognize the importance of having a full label and really bringing this drug forward for all patients with Angelman.
Mm-hmm. When should we expect the next update from this open label study?
Yeah. We talked a lot about, you know, whether we should do another broad analysis of that phase I/II study. We really came to the conclusion that we did not need this, that data to help us as phase IIIs were underway. 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. You know, 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. We asked the team to focus there. We do not have plans for another update, and just honestly really focused on that data readout in the second half of this year.
Makes sense. You have another company in the space, Ionis, developing a drug for Angelman syndrome. What's your perspective on how your efficacy and safety compare relative to the Ionis program?
Yes. I think, you know, from talking to investors, talking to treaters, both who are participating in either trial or both, or, you know, 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. On the whole, seeing some level of equivalence there, and I think also supported by both of us being granted breakthrough designation by the FDA, which is a very high bar. You know, to me, that's great. I think it's great validations for ASOs as the right way to approach this disease. It is large, rare. There are a lot of patients there.
I guess, you know, if the sentiment is roughly equal out there, then I guess all things being equal, I'll be glad to be in the lead.
Mm-hmm. Great. Can you elaborate on the safety that you've seen?
With the safety profile, and I think probably the focus there is on the lower extremity weakness that we've talked about, and in 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 wanna bring a single dose into phase III, bringing multiple doses in just really drives up your patient numbers and just makes everything so much harder there. With those dose expansion patients, we saw two events of lower extremity weakness. One was in retrospect.
The PI saw elevated protein in a CSF sample, went back to the family, and asked if there was any possible challenges with walking, and they said, "Maybe, yeah." That's about as mild as it gets. The second case was also mild and resolved on its own. You know, 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, you know, with the full phase III data readouts, that this is a benefit risk profile for ASOs, not. I don't think this is gonna be something unique to our ASO.
Okay. Interesting. Can you elaborate on the mitigation plan that you put in place?
Yeah. Really, you know, this is looking at the chemistry of any ASO potential for irritation at site of injection. Really that mitigation was not allowing that drug to pool at the site of injection. That's really involved around a flush, and that's just moving it through into the CSF. Trendelenburg, why these children are in anesthesia. In young children, when you're doing intrathecal, you do wanna use anesthesia, so they don't develop this fear of going to the doctor, fear of entering in the hospital there. 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. You know, 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?
Yeah. We spoke about that phase III data across the two studies at JP Morgan in January. 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 in 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.
Yes, we have measurements to do that in a controlled way as part of our endpoints, 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're doing, what type of risks they're doing, and truly what is the full picture around any fractures they may be having. That's really what takes time here, is going back really on a patient-by-patient level in addition to all the additional analyses we're doing, so we can really understand, you know, 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.
If we come to that conclusion, if we get to that point, then obviously the next step would be to go back to the FDA or go back to regulators, have that conversation, and make sure there is a path forward. Today we are still really, truly trying to interrogate the data and the dataset and really understanding it to the fullest extent.
Mm-hmm. That makes sense. What are the timelines in terms of this data analysis?
Yeah. We haven't really given timelines 'cause we don't wanna rush this process. We understand that we need to go fast. We are not gonna take forever, if you will. Again, when we fail to meet our two primary endpoints, we need to make sure we thoroughly analyze this, make sure we truly understand this. We wanted to give ourselves that time before we put, you know, an external timeline on that.
Mm-hmm.
More to come.
Mm-hmm. Makes sense. For your gene therapy programs, kind of remind us of the timelines there and the submissions.
Yeah. GSDIa, I guess now is our lead gene therapy program with the PDUFA date in August, is great. Sanfilippo, we had that CRL that is all really just requiring additional paperwork and written response. We'll do that quickly. That's a two-week validation period, not the normal two-month validation period. Do expect to get a PDUFA date for Sanfilippo, not too far behind GSDIa, both within this year. More to come on that. Then OTC, in phase III, that study's always remained a little bit in the background for the prioritization of how we've been talking about it. OTC remains on track for that phase III data readout.
You know, for our Wilson program, you know, 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.
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.
Yeah. Angelman leads both by size. You know, 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 with nothing available for these patients. Sanfilippo, very similar situation. You know, these patients have absolutely nothing available to them, and they, you know, once they become symptomatic between their first and second birthday, really deteriorate to the point by five years of age, they are, you know, they have a lot of accumulated neurodevelopmental damage and don't live beyond their teens traditionally. GSD1A, these episodes of hypoglycemia can be life-threatening, particularly in pediatric patients. Again, that is our focus where, you know, there is true high unmet medical needs in these patient populations.
Makes sense. Maybe just in terms of the submissions, you know, given broadly some of the changes at the FDA, how are you thinking about the approvability here of your gene therapy programs?
Yeah. I think, you know, if there's any benefit from going through the CRL and now with the BLA is, you know, we are clear what the FDA inspections are, and the findings with the CRL, you know, were really based on, you know, things with our manufacturing facility, things that we are absolutely able to do and to fix and respond to. The FDA has always been complimentary of the data coming out of that Sanfilippo program, and they have remained complimentary. We recently did a data update at the world meeting, and showing really the strength has held up over time. A lot of confidence there. Then also with GSD, GSD1A, 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.
Again, with our PDUFA date in August, a lot of confidence there and then, you know, obviously, you know, working again with the importance placed on that Angelman readout in the second half of the year.
Great. Awesome. Well, Eric, thank you so much for joining us, and thank you everyone in the room, and talk to you all soon.
Thanks.
Thank you.