Yatin Suneja: Let me ask the question, Chuck, do your best in translating. So with regard to 043, I think you mentioned that you have confirmed target engagement. Can you characterize that for us? Was there a dose response? And how do you feel about 0.5 dose? Is that sufficient to elect either a clinical or a biological activity? That’s one. And maybe a similar question for the other one because I don’t think you said for 1326, anything on the target engagement.
Charles Williams: Yes. So Craig, can you hear me?
Craig Parker: Yes.
Charles Williams: Question is we mentioned that we’ve confirmed target engagement and there was a dose response. So I think for — Yatin is asking actually for both programs, for 043 specifically, how do we feel about 0.5 and the biological activity that we might see? And a similar question as it relates to 1326?
Craig Parker: And Yatin, I can’t hear you, so make sure you let Chuck or others know that you can hear me. So as you noted — you can hear me, okay. As you’ve noted, we’ve confirmed target engagement with 043, at least targeting ASGR1 receptor through ALP elevation. So these are not adversities. These are ALP elevation that results from blocking ASGR1, which is a scavenger receptor in the liver that takes ALP out of the circulation. I think your question is really about what kind of doses have we seen activity in animal models? And are we in the range with 0.5? And while we’ve typically employed higher doses in animal models, we think we’re in a range that could be a therapeutically active dose, and then I’ll just also make the observation that obviously, given that we had not seen any of these adversities in other species, other species may not be that translatable for predicting a dose response.
So we’re in the range, and I wouldn’t be overly concerned or focused on the exact dose in the mouse translating to humans since the translatability for tox has not been there. For 1326, we do not have a target engagement assay, so we’ll take getting into UC patients and biopsying the tissue to identify whether we’ve activated Wnt signaling. So in that situation, in that setting, we have an assay for a Wnt target gene called Axin2 which we’ll look for to confirm that we’ve activated the pathway.
Yatin Suneja: Got it. Maybe one more question, Chuck, if you can translate. This is — so I think it seems like at this point, we cannot rule out whether this is the phenomenon that you’re seeing at least on the liver-related AEs, is it target-specific? We cannot rule that out. However, you are saying that these damaged tissues might be more sensitive. So can you help us understand is there any threshold effect at certain doses you might not see. I’m just curious like what gives you confidence…
Craig Parker: Chuck, I can’t hear anyone still.
Yatin Suneja: Yes, these damaged tissues are more sensitive.
Charles Williams: Craig, can you hear me?
Craig Parker: Yes.
Charles Williams: Okay. So he — Yatin’s question has to do with — we can’t — at this point, you can’t really rule out the liver issues are target-specific, and seeing that the damage might be more sensitive, is there any threshold effect at certain doses that we’ve seen or might see based on the data we’ve collected?
