Operator: One moment for our next question. And that will come from the line of Joseph Schwartz with Leerink.
Will Raphael: This is Will on for Joe today. So just to quickly from us both on Angelman. So previously, it was noted that you expect to see more of an effect as compared to the prior data cut, given the higher doses in the expansion cohort. I just want to make sure that this is still the expectation, and then also for Angelman, we often hear that these patients are constantly gaining skills and there may be some increased hope in the community, which could lead to a placebo response. So just wondering what strategies can help mitigate a potential response in a pivotal trial?
Emil Kakkis: Thank you. So our expectation that loading at higher doses that the improvement should be accelerated relative to what we’ve seen. We haven’t changed our view on that. The thing I would say is, remember that in the Phase II data we showed you from extension, we went all the way out to 500 days of treatment, right? So the magnitude effect you see at 500 days is not going to be the same that you’re going to see at 170 days. But we do expect that the higher load dose and should — and the large number of patients that should make us allow us to verify that we’re seeing a real effect. Now with regard to the placebo response, I think the longer-term data already show you that there’s — it’s not a placebo response because they continue to gain ground.
The placebo effect doesn’t go on forever. It goes on for a while then people eventually recognize something is not happening. But be able to see linear continued gain of ground over time is clearly beyond what you would see with the placebo effect. In the Phase III, though, you have to worry what you’re thinking, well, what if people are optimistic. What we are doing and a lot of the key endpoints, use third-party psychologist evaluators like for the Bailey, the third-party value are is looking at the kid doing things. While the patient report may have some impact, they are looking for the kid to do things. So that helps provide some objectivity that we’re seeing the kid actually do things and it’s not just wishful thinking. That said, our expectation is to have a large enough effect and the large enough population of patients to be able to power past a placebo effect.
In addition, the longer time frame we’re talking about, which is maybe 250 days or 230 days should be well past the normal window of what placebo would be. I think when you look at how many domains are improving in patients, two to five domains improvement in most of the patients it will become evident to people who’s responding and who’s not responding. And so the issue raised is certainly one of importance and we’ve been thinking a lot about it. But I do think the negative effect, the length of time are factors, which will help reduce the risk of a placebo response clipping or impairing the results of that study.
Operator: One moment for our next question. And that will come from the line of Jack Allen with Baird.
Jack Allen: I have two quick ones. The first of all, as the commercial products, namely Dojolvi and Crysvita. I know there’s some seasonality in the fourth quarter numbers. But when you analyze out the fourth quarter numbers, it seems like you’re already at the lower end of guidance. So I was hoping you could provide some more color as it relates to how we should think about the growth of those two products over the course of 2024? And then on GSD1a, any thoughts on your early market research here. Is there a subset of patients that are more severe that could be asked to really adopt a gene therapy here?
Emil Kakkis: That’s for GSD1a?
Jack Allen: Yes.
Emil Kakkis: Okay. So with Dojolvi and Crysvita, guidance is always an art form, but our view is that we’re continuing to see something close to 20% growth. Dojolvi may be a little slower because some of the territories we just have — we’re responding to named patient sales, but I think Eric made that clear. We’re in the territories that we’re commercializing, we’re continue to see the 20% growth rate I don’t think there is any issue with this. We’re trying our best to navigate guidance and give the Street numbers we feel confident in achieving. And I think looking at 20% growth rate, I think, is I think, still excellent growth rate. So the lumpiness, Q4s in these patterns with Latin America have been a recurring theme. It is what it is.
I think, ultimately, it’s just — it swings up and down. I think Fourth quarter tends to be higher. Is there some buying before the winter months and before the new year? But — and it’s just something that we’re always going to have to manage overall. So you have to — we have to smooth it out with guidance that makes sense, but I feel good about the guidance we have and 20% growth rate should be excellent. With regard to GSD1a, 81% of the patients have severe genotype or no like genotype, right, 81%. So the vast majority of patients are severe. There are some milder but majority are severe. And so we’d look at the population being more homogeneous in that regard than many of our gene therapy disease that we study. So at this point, I would look at most of the patients being highly dependent on starch, having very severe phenotype and probably in the greatest need and the most danger from that disease in terms of crashing and dying suddenly.
Operator: And one moment for our next question. And that will come from the line of Ed Arce with H.C. Wainwright.
Thomas Hoffmann: Good afternoon. This is Thomas here asking a couple of questions for Ed. So just for GTX-102 and Angelman, amount patients in the expansion cohort. Can you tell us what are some of the longest current duration that these patients have in the Phase III study? And also, what are some additional endpoints that investors can focus on compared to the previous days.
Emil Kakkis: I heard the extension cohort. You’re asking from the ones we presented how long they go out. The — by the time we get to end of Phase II, we’ll have patients who have had two years of treatment probably, but it will be somewhere between a year to two years of treatment of exposure for all those patients. So quite a long time and we have patients — a good chunk of patients who are already beyond age day 504 at the Analyst Day meeting. So I think actually that’s a good — shows you that chronically exposed accumulating drug doses are not going to cause the safety problem in this disease. So I think that’s an important part of the safety profile that we can doing these treatments and I have an issue. Reestate your second question because I didn’t quite catch that.
Joshua Higa: I think the second question was about additional endpoints that they should be considering. Beyond perhaps what we’ve already discussed at Analyst Day.
Emil Kakkis: I see. Well, we have a lot of different ones we’re looking at. The ones we talked about, the Bailey or the core, the either the Angelman severity assessment for behavior or sleep or an alternative behavior or sleep scale could be used — those are two alternatives their scales the scale we’ve used before. We’ve seen them before. We haven’t didn’t include — we didn’t have them in the most recent extension data. So we’ll get a little more information on those alternative ways of doing it. I would say to you in our discussion with the FDA, they were highly flexible to us calling out questions and just pulling up like a few key questions but endpoints and relying on those for the endpoint. They were I think showed great collaborative flexibility and not rigidity with regard to choosing those endpoints.
And so within our existing data set, we can even just pull out questions, for example, and hone in on those questions and use those for particular for behavior sleep. So our goal would be not to go with new things we haven’t seen before, but to look at what we have and pull out the best data sources that are sensitive to the change and are clinically meaningful for patients in coming up with those agent, but there won’t be brand new things you’ve never seen or that we don’t have any data on.
Operator: I’m showing no further questions in the queue at this time. I would now like to turn the call back over to Joshua Higa for any closing remarks.
Joshua Higa: Thank you. This concludes today’s call. If there are additional questions, please contact us by phone or at ir@ultragenyx.com. Thank you for joining us.
Operator: Thank you all for participating. This concludes today’s program. You may now disconnect.
