Emil Kakkis: Well, I think our Phase II data kind of lay down what I think we’re going to expect. I would expect it to be better reduction would be very similar to what we’ve seen, if not better. So, we found there with only a minimum of six months, an average of nine months exposure, right, 67% reduction. The patients we’re enrolling are very comparable with that. If anything, enrolled patients might have a higher fracture rate, I think. And so, we would expect that reduction to be something what you’d expect to see. Those are I don’t know if you consider — when you enroll patients with fractures, it’s not exactly controllable. They are who they are. But because we have the threshold requirement to get in the trial, we’re essentially eliminating patients who would have very low factor rates and wouldn’t necessarily be able to demonstrate benefit in that period of time.
I think with the type of patients enrolled, the number of which type, I think we’ve set ourselves up to replicate what we saw before. And I really don’t see any uncontrolled factors. I don’t know, Eric, if you have anything.
Eric Crombez: Yes, definitely. I mean, I think the biggest controllable factor was really enrollment rate and the studies are fully enrolled. Yes, we know the types of patients and it was good to get a good mix of one, three and four in there. I would say, yes, I would agree. The uncontrollable factor may be, especially when you’re first initiating treatment in the 1st couple of months, you may have some patients who are having fractures before setrusumab really takes effect there. But, there is a degree of unpredictability with fractures.
Emil Kakkis: There’s probably also the fact that some people some of the kids like feel really good and start being more active. People were worried maybe that caused more fractures, but it didn’t look like that was true. Or that as they fell, they didn’t fracture. So, we actually are not concerned about the fact that his might feel good and start being more active. It doesn’t look like it’s going to cause a problem that looks like their bones are stronger, they’re doing great. So, the truth is the more activity probably strengthens the bone faster because the action actually puts strain in the bones. The bones actually are strengthened by that actual action. So, thank you for the question.
Operator: Our next question comes from the line of Maurice Raycroft with Jefferies. Your line is open.
Maurice Raycroft: Hi. Thanks for taking my question. Maybe I will ask one on Wilson’s disease. Just wondering how you are assessing changes in global copper metabolism and what drives the time point of the endpoint or the timeframe for when you can measure benefit and get adequate insight into benefit?
Emil Kakkis: Well, the two main ways we’re looking at copper is how much free copper is coming out in the urine, right? The urinate copper, which is a sign of how much is sort of oozing out of the tissues and coming out with a chelator. So, if you get rid of the detoxifying, if you detoxify copper through the bile, then you should have less coming out in your urine. So, that’s the detox side of the equation. On the other side of the question is loading copper on the ceruloplasmin oxidase activity. So, we’ll be measuring the ceruloplasmin oxidase activity, which is a very sensitive way of looking at copper loaded correctly on ceruloplasmin. So those two biomarker assays will give us a sense of the overall copper metabolism. I wasn’t sure Eric, was there anything else to add?
Eric Crombez: Yeah, we’re doing a liver biopsy study, so it’ll be great. This is really the first time we’ve been able to do liver biopsies. We made it optional, but the majority of patients did opt in for that. So, it will be interesting to look at copper concentration and histopathology in those samples.
Maurice Raycroft: Got it. Maybe just a quick question on setrusumab. We see that you’ve got a title at ENDO and you’re guiding to which is I think scheduled for June 1st and you’re guiding to having a longer-term Phase II data in the second half of this year. Just wanted to clarify, will that presentation at ENDO be an ENCORE or should we expect what should we expect in that update?
Eric Crombez: Yes, that will be a Pura ENCORE presentation.
Maurice Raycroft: Got it. Okay. Thanks for taking my questions.
Emil Kakkis: We’d like to see good news again, frankly, if it’s okay.
Operator: Our next question comes from the line of Jeffery Hung with Morgan Stanley. Your line is open.
Jeffery Hung: Thanks for taking my questions. For the setrusumab Orbit study, if you go to the second interim, what would the bar be for stopping the study at that point? And in that scenario, would you have greater confidence for stopping the study early with the second interim? And then for the COSMIC study, what would it take for you to stop the study early in that?
Emil Kakkis: Yes. So, the second interim as we’ve planned it right now would be at 0.01. So that’s much less stringent, right? That’s 10-fold larger P value. And then the final is 0.04. So, I think the reason the second is less stringent is that at that point everyone would have at least a year of treatment. So, we felt there was less regulatory issue there. And then 18 months would be the 0.04, it’s just sort of the backstop if we have to go that long. For COSMIC, remember, it’s an open label study, randomized, but open label. And so, we’ll be looking at the x-rays of the DMC. And our DMC will be looking, since these are little kids, one of the questions will be is if there is a stark separation in the fracture rates in that study, the DMC will probably be obligated to end the study and not keep kids on an inferior treatment.
And so, while we haven’t set criteria for that, they will be looking at the study during the year. And if they were to hit a strong separation of the groups that they felt was below expectation they could stop. Our expectation is that the younger patient will respond faster and since they finish enrollment, we think by the time we’re doing the first interim of the one study, the other study should be pretty far along. And if the one hits, I think the other one will be should be ready. So we’ll probably be pretty closely coordinated with the two. But the DMC will be all along have the opportunity to look at the data and determine is there a reason to stop that study. And remember going another year is a big deal if you’re two years old and you have a bone issue, right?
So, it’s a lot different in that study. But fortunately, being open label, DMC has a chance to take action at each time they take a look.
Operator: Our next question comes from the line of Joon Lee with Truist. Your line is open.
