Right. Good morning. Thank you for joining us at the fifth Annual Guggenheim Genomic Medicines and Rare Disease Day. I'm Debjit, and my privilege to host Emil Kakkis, the CEO of Ultragenyx.
Thank you.
Thank you, Emil, for being here. It's gonna be a pretty interesting second half for you guys. Maybe we can start with the upcoming catalysts and where the pipeline currently stands.
Sure. We will have a lot of data this year. We've been working on a number of programs. We have probably more late-stage programs than I think anyone in the rare disease world. Our first update probably coming ahead will be the data from the phase 2 portion of the phase 2-3 study for setrusumab in osteogenesis imperfecta, that should come mid-year. We'll have data on 24 patients of one or two months of worth of data on their biomarker P1P, which is a measure of how much bone they're producing. We'll also have some data on bone mineral density for those who've been in the trial a little bit longer, beginning last year. Combination of the P1P, the bone mineral density data, plus the pharmacokinetic data will allow us to optimize dosing for the pediatric portion of the study.
We believe the 20-milligram dose is a fine dose for everyone, but from our experiences and other experiences, the children often need a little bit more antibody to get the same exposure, and so we'll help fine-tune that dosing exposure. What you'll learn then is, does the drug have an important impact on children? You know, how much impact on P1P and bone mineral density are we seeing, and how does that compare to the adults treated before? You'll hear more about where we are set on moving into phase 3. We have set up all the sites in multiple countries and are getting patients lined up for the phase 3. We feel good about the potential for setrusumab in osteogenesis imperfecta. That's the big first date. The second thing is for GTX-102 would be late in the year, expansion study.
We'll look at larger number of patients loaded at higher doses, and we'll look at their outcome at 6 months, and some of the patients may be at shorter than that. But the idea would be to get enough patients loaded at higher doses to give us a read on where we're going in phase 3 in terms of endpoints and efficacy. After that would be our GSD I phase 3 data, which would be in early 2024, plus Wilson phase 1 data as well.
Awesome. Let's start at a high level and, focus on the Angelman asset first. There have been some interesting approvals of the FDA recently at the Neurology Division, right, FA and Rett. Given sort of degree of flexibility that we see at the agency, what do you need to see from them, or what do they need to see from you on the Angelman asset?
Well, I think it's been interesting to see neurology in the last year because it's not only that, it's also the Amylyx ALS drug. I think there's been some evolution at neurology regarding the way they're approaching things. Of course, Billy Dunn has left. There's a new acting chair who's of that group, the neuroscience group. I think they've made good decisions on those drugs, and I think there's a sense of need for these neurology diseases that I think do set us up for Angelman. We've had good interaction with the FDA more recently on our program, and I think that the fact we've collected a fair amount of good data now from ex U.S., both safety and efficacy, I think it puts us in a good position to negotiate with FDA to get the U.S. open as well.
I think that neurology is an area where there's been a lot of failures in the past, right? A lot of challenges, I think we're seeing some opening up to the reality that some of these diseases are very difficult and that we're gonna have to accommodate what it takes to get to a good outcome, to a great outcome, which might be a good outcome to start with. For the Angelman program, the kind of data we're seeing, which is multiple domains of improvement in areas where you've never seen a drug improve anyone before. I'm talking about language function or motor function, fine motor behavior.
These are very unusual areas for drugs, and to see those kind of multi-main improvements in the same patients, I think is a meaningful thing, and I feel like we'll be able to move ahead and get that going in the U.S. I feel like the day we'll get this year from the expansion, put us in position to negotiating a reasonable phase 3 and get that started next year.
Do you think the FDA still matter to CGI as the primary endpoint? Given the Bayley data that you have, which is pretty remarkable, there is room to move within those two?
Well, I've never really thought that CGI Angelman syndrome was really a good primary endpoint because it's a relative scale, and it's not an absolute scale. It was allowed for Ovid, but I don't think it's actually an optimal choice. We're doing the scale, and we're using it primarily to help in an individual patient basis look at titration of dosing. To really look at clinical benefit, you have to look at quantitative scales that you can calibrate against what does this amount of improvement mean for a patient, right? Whereas CGI scales don't quite anchor that well enough. We think that a multi-domain assessment is the best, but I think the Bayley score, particularly expressive receptive communication, which are having very meaningful improvements, which is very unusual because I've never seen anything affect language function before in a drug, right?
That's very special. If you add that to-Substantial improvement in sleep disorder, sleep problems, and the abnormal behavior problems. In addition, some fine motor and gross motor improvements. I think you're talking about a number of different scales that could feed into that, and the exact structure of the endpoints, we'll have a discussion with FDA. My preference is to use a multi-domain type analysis to capture it all. If they don't go for that, probably language will be the most likely one because it's the top complaint for parents with Angelman syndrome.
If you imagine being able to call your child's name, they don't listen to the name, or they don't follow instructions, and then they are able now to hear their name and respond to you and follow instructions without being shown, it's a fundamental change of life at home, right? These are the reasons why people are lining up to get in the study. These are things that are really important to people, and I think we could certainly anchor on that as a primary. I think all the domains happening in the same kid are a powerful result. We feel good we have efficacy that could take us to phase III. Now we're just trying to optimize the amount of efficacy we get, and the expansion will allow us to get enough data to help gain comfort on that.
Got it. The expansion cohorts, are you trying to sort of harmonize the dose across all the three regions before you get it up and running? You get agreement from the FDA, I don't know, 7.5 milligram dose is the starting dose across the board.
No, we already initiated dosing ex-U.S., and we've added a number of countries. Now it's not just 2 countries. We're gonna be something like 8 countries where the trial will be open. That's already started. Dosing's started. Site initiation's started. That's all happening. The U.S. will propose an approach, and either it will match or it'll be a variant. We'll be able to get the U.S. started. If the regimens are slightly different for the U.S., we'll just have 2 different regimens to watch, and between the 2, we'll choose if we end up with 2 slightly different regimens. There's a lot of variables here. It's not just drug dose. It's the frequency of dosing. It's the maintenance period, all these other variables. I don't look at...
Whatever comes out of the U.S. will give us another shot at understanding what the optimal outcome is. If we need to treat more patients to get enough data, then we'll do that because it's important to get it right. The 40 patients is what we've been talking about, but if we had another regimen, we could add another group of patients to make sure we test out that regimen. The FDA has been communicative with us, and we've had good engagement. Hopefully we'll figure out soon about opening the U.S.
Got it. Is FDA still married to a randomized study for approval, or depending upon the quality of the data from the expansion cohorts, is there a room for an accelerated approval given the recent flexibility?
I don't think there's gonna be room for accelerated approval in this situation. The reason being that a lot of the endpoints are much more subjective, and I think that we're gonna need a larger number of patients given the size of these populations. We're not expecting to be able to move ahead. We've had some exciting data, but I'm expecting us to need a randomized study. I would also point out to you that it's not just getting through the reg pathway. Ultimately, you have to get reimbursement. These days, reimbursement, having a randomized study is far more powerful type one data, right?
This will be important, you wouldn't wanna hamper the long-term outcome of the product by not having the optimal type of data to get reimbursement, not just U.S., but globally for a disease this prevalent and for a drug this important.
Got it. The lower extremity weakness that you initially had, you've sort of largely navigated through that, except that you had one weird case who wasn't as severe. What did you learn from that? I mean, scoliosis?
Yeah
...being a major impediment and won't be reflected going forward.
Yeah, I think I'm saying that that exception proved the rule, which is when we looked at his MRI, he had a localized spot of inflammation right where the drug was given. That was what we were avoiding with tralokinumab. The fact he had it means the tralokinumab didn't get applied well enough for him and his scoliosis situation. I feel pretty comfortable that the method of mixing and distributing the drug will keep us safe and keep patients safe. We just have to make sure people adhere to that carefully. I don't think his case is a new risk. It's just something manageable. I would say he also reversed, and if you look at the patients who had the...
We have 3 patients who had the event before, more severe version of it, who are back on treatment and not having a problem. It does tell you that even if you have that event, it doesn't mean it's a block to treatment. It just means you have to manage their regimen correctly. I think, what we learned about the event, it's actually, I think, a lot more manageable, rather than an end to treatment.
There seems to be a dichotomy between how the treating physician sees these events versus the rest of us on the street, because when we talk to the docs, they don't think if you get those improvements, functional improvements in communication and behavior, this is a manageable event from their perspective.
Yeah, I think that's true. Well, they're also seeing the patients trying to get in the study. I mean, I'm getting like People find out I'm on Facebook, so I get a lot of patients on Facebook contacting me like I was in line for the study, and I didn't get in what happened? There's a lot of emotional energy here this stuff is really important to families. Yeah, I think You know, the first time, this is not something I would agree with, one of the parents said, "I'd rather have my kid in a wheelchair behaving well and talking than being the way he was before." That's kind of telling you how important it was to be able to communicate with your child and be able to interact.
It tells you the benefit-risk, the way people see it, is different, right, from the FDA. The doctors are impressed with things, and so I think that's why you're hearing that. It's manageable. We don't have to accept that compromise. We'll have to watch out for it, but I feel good about us being able to navigate around it, particularly because we've been dosing patients, a number of patients, for a long time now at, you know, up to 10 to 14 in maintenance, not seeing the problem, right? If that tells you can repeatedly do this, it's not like everyone gets it eventually, right, at any dose, right? That's not true. You can dose and avoid the problem. To me, it means it's just a question of managing it well.
If the expansion cohort comes out clean, and you don't see the problem, do you have flexibility to take the dose higher? I mean, obviously, you had gone up to 20 mgs single dose before.
Well, certainly. We certainly do. We could go a bit higher. The question is, you know, how much efficacy, you know, how much safety, and how much time? I think our view is we want a good result right now, but we don't wanna cause continued delays trying to get perfect, right? Because I think you could easily titrate people individually over time, but we wanna get a good result that's a meaningful clinical result, get the drug out on the market, and titrating further is something well within the range of acceptance, right? We could continue to work that. I just wouldn't wanna drag out this process for a very long time.
Our hope this year is to essentially end the discussion about what's an adequate dose, and you get a good effect, and to get approved, and then continue to work from there.
You did mention that the expansion cohorts have already started dosing patients ex U.S.
Yeah.
Where did you start, from a dosing perspective?
We haven't put out the details of it. We've decided to be more contained on how much disclosure we're providing. We are dosing higher than we did in the original cohorts last year of 4 and 5. We've been seeing effect, as we talked about last year in the middle of the year, between the 5 and 10 range, we're seeing a good effect. We're comfortable there, and we've said we've had 10 to 14 during maintenance phase, right? Those are dose ranges that are effective. We're feeling good about where we are in the dosing, but we haven't put through the details at this point.
Got it. Switching to the OI program, those data will come in first. Do you think there's gonna be a ask for a comparative study versus bisphosphonates, or?
There wasn't an ask. The agency didn't ask for us that was an option, but we decided to do it. The reason was, is that in the really youngest patients, the doctors are uncomfortable not giving them any treatment. Even though bisphosphonates are off-label, they don't wanna treat them. In our view, treating those really young ones is, like, where we can change the future for OI. Those are the ones where the fractures are very frequent and deform their bones and their life. I don't want us to wait too long, and so we're gonna do a randomized control, open-label, randomized against bisphosphonates so that everyone gets treated, and therefore we can put in the most sickest patients in that group. Because it's open-label, we'll be able to see what's happening.
Our expectation, though, is setrusumab will be substantially better than bisphosphonates because of its effect on improving bone mass and bone strength that are more powerful. I think that that study will also show then, even if bisphosphonates are an off-label standard of care, that we can show head-to-head what it looks like and answer that question, right, from, you know, regulators as well as reimbursers. The two studies together I think give us a complete picture, and our expectation is to beat bisphosphonates readily and to show the improvements on symptoms and fractures as well in the randomized placebo-controlled study.
When you talk about kids needing slightly higher doses, is that because of the sclerostin expression? Is that differential between younger and older, you know, individuals?
No, the difference is primarily in the metabolic rate for antibodies, how long they circulate, and how long they get cleared. If you look at all the antibody drugs, they tend to need higher doses in the younger ones. In the XLH Crysvita case, for example, the optimized dosing for kids was 1.6x the dosing for adults. We already have experience in that. It's been seen like that for multiple products. It's more about monoclonal antibody, you know, clearance distribution than it is about sclerostin. We don't know about sclerostin, but the trial is why we'll figure that out, right? We'll figure out what a block gives you and how much anti-sclerostin effect and how much pharmacodynamic effect. 'Cause what matters is pharmacodynamic effect. The actual concentration is irrelevant to what the pharmacodynamic effect is.
We'll look at concentration, look at pharmacodynamic effect, and then calculate from modeling what's the best dose-response combination that we can look for.
For insights into fracture rates, how long does the study have to be, even in the current pediatric setting?
Well, in the current study we're expecting between 12 and 24 months of time. It depends on the rate of fractures, but the way the study will be enrolled is we'll have an interim assessment while the study is enrolling to look at the fracture rate and the differential, which will tell us how long the last patient needs to be dosed in order to end the primary analysis. If the groups separate more rapidly, and the fracture rate is high enough, then we may be able to end after 1 year. If the fracture rate is lower or the separation not as great, we'll have to go a little longer. That flexibility allows us to make sure we have a study that will demonstrate the difference. In osteoporosis, the fracture rate separated within 6 months, which is pretty fast.
I think in pediatrics, the fracture rate will separate within a few months, that the patients will respond metabolically very quickly, and their bone strength improve very fast. If they separate very quickly and there's enough fractures in the population, that'll help separate the groups very quickly. We've assumed a 50% reduction in the powering in fracture rate, and that placebo or leftover bisphosphonate activity is about 20%. That's the separation rate, right, between the two.
Is there a threshold of P1P activity which correlates with fracture rates?
There is the P1P seems to predict bone mineral density improvement. If you look at the 90 patients worth of data at 2, 8, and 20, and you look at P1P, and you can correlate it with BMD. P1P at 1 month correlated with BMD at 12 months. The BMD production with setrusumab is, like, steady. It's like a straight line for the entire year. Whatever you turn on in that first month is happening consistently all year long. We can use the P1P at 1 month to help predict what we think BMD will look like at 1 year. When you look at the data we have, it's in our deck as well, we can show that the BMD improvement correlates with an estimated strength of bone as well, and it's dose dependent.
It's one of the tables in our in our deck. Look at that. That method uses the wrist and the micro-CT to look at the structure and estimate the strength of the bone based on the structure. It says it's not just the amount of bone, but where the bone is, and it showed statistically significant improvements in bone strength correlate with BMD and correlate with P1 P. They all tie together very well.
Got it. Let's wrap up with your two gene therapy programs, GSD and Wilson's. Gene therapy seems to have just completely fallen off people's radar over the last, call it two years. What are you seeing that's gonna sort of drive interest in that?
It has slowed up. I think, you know, remember Zolgensma really galvanized community. They got approved very quickly and had a profound effect. We think a lot of these other drugs are having a profound effect. Maybe it's not children who can't walk that are walking, but it's a profound change of life to be able to greatly reduce the amount of starch you need so your glucose control is now endogenous or to change your copper metabolism or the other program changed your ammonia metabolism. We think it's maybe it's faded because of some safety events in some of the other programs, in Duchenne programs, right? In the MTM program. I think the place we're at, we've had a excellent safety profile in liver-targeted therapy, and we think we're seeing good results.
We also have the MPS III gene therapy, which we acquired from Abeona Therapeutics, which is a little bit more Zolgensma-like in terms of an IV dosing of AAV9, which also has shown a good effect on the biomarker as well as clinical. I think the challenge right now is what is it gonna take to get AAV products approved, right? I think, we're doing randomized studies right now because that's what was asked. That creates a higher burden, right? I think that's created some of the issue. The GSD I trial is enrolled. Timeline for data is in early 2024. We're I think we're on track with an important result for GSD Ia.
Wilson stage one is enrolling this year, our hope would be early 2024 to have data on the dosing stage of that program and head to phase 3. OTC is starting to enroll its phase 3 as well. We have a few kids now who essentially have been clear of ammonia control problems for several years now, 4 or 5 years now. I also think durability has been one of those issues. I think the OTC data we have, which is the first program we got, has had 4 or 5 years of people not needing drugs or diet control. I think those are real cures.
I just think it's AAV gene therapy is working, and I think there are always going to be challenges, but I do think that we're in good position among any company to be able to put forth a number of product approvals in the next while.
Well, wishing you the very best for the upcoming data events, and thank you so much for your time today, Emil.
Thank you, Debjit.
Appreciate it.