Kelly Shi: Thank you for taking my questions. I also have a question on IRAK4 program. We see the clinical development is expanding in this space, and oral agents like JAK inhibitor and BTK inhibitor are showing interesting efficacy signal. I’m now curious, how should IRAK4 degrader be positioned to other oral therapeutic candidates? What would be the differentiator clinical features to be anticipated based on targeting strategy and also the MOA of degrader design?
Nello Mainolfi: So it was a bit — the sound was not great, but maybe if I understood correctly, you were talking about how does IRAK4 compare to, like, other small molecules like JAK or BTK inhibitors in immunology. Jared, do you want to take some of that?
Jared Gollob: Yes, I mean, I think certainly the differentiation is there potentially both for efficacy based on the mechanism as well as on safety. We know that 474 IRAK4 degrader, because it’s impacting the IL-1 receptor pathway as well as the toll-like receptor pathway, has the ability to impact multiple different pro-inflammatory cytokines essentially with a single compound, whereas many other agents in the I&I space, targeted agents in particular, have a more restricted effect on all of these pro-inflammatory cytokines. And so, the broader effect on multiple different cytokines, we think, can give us broader development opportunities within autoimmune and auto-inflammatory diseases. I think that is one important differentiating factor.
I think the safety factor is something which also can’t be overlooked. We’ve presented before or summarized before the fact that there are adult human IRAK4 genetic knockouts who in adulthood do not have any phenotype or any susceptibility to infection. And so, I think being able to potentially maximize knockdown of IRAK4 chronically to essentially optimize efficacy without compromising safety, I think, is a real central game changer in differentiating factors from other drugs, like JAK inhibitors, for example. JAK inhibitors do have broad anti-inflammatory effects, but they have significant safety liabilities in terms of risk of infection, risk of cytokines, risk of malignancies. That is not something that has been seen in either human IRAK4 knockout individuals or even in preclinical studies.
And so, I think this ability to potentially really strongly degrade and knockdown IRAK4 chronically to maximize efficacy while not having any safety issues could really allow this drug to be broadly developed across multiple different indications, also not just in moderate to severe patients but also in milder patients. I think this really provides an optimality that really can’t be seen or challenged by other modalities. And so, we think that this is one of the real value propositions of 474, both the differentiation potentially on the efficacy standpoint as well as on the safety standpoint.
Kelly Shi: Terrific. Thank you.
Nello Mainolfi: Next question.
Operator: Thank you. The next question is from the line of Jeff Jones from Oppenheimer. Please go ahead.
Jeff Jones: Good morning, guys, and thanks for taking the question. Just two quick ones from us, there’s some evidence of improved efficacy in targeting IL-17A and F versus just IL-17A [a la Bimekizumab] (ph) versus Ustekinumab. And could you comment on whether targeting IRAK4 would be expected to impact the pathway for both forms, just a technical question. And then, on the financial side, how should we be thinking about the Sanofi collaboration revenues going forward versus milestone payments? Thanks.
Nello Mainolfi: All right. So, Jared will take this first. And then, —
Jared Gollob: Yes, I think the question around the activity of, say, IL-17A/F targeting versus A, especially in like diseases like HS where there may be an advantage, I think sort of more broadly speaking further, I think, speaks to the advantage of having a broader anti-inflammatory effect versus a more restricted one. I mean, here it’s still restricted to IL-17, but being able to hit the A and F isoforms rather than just A is already showing you that if you broaden out the impact, you potentially can increase efficacy. Now, even though IRAK4 does not specifically target the IL-17 pathway, we know that by impacting the IL-1 family cytokine pathways as well as the folate receptor pathways, we do impact IL-17 production. And while we haven’t looked specifically at A versus F isoforms, we would assume that, that impact is probably broad across multiple different IL-17 isoforms.
And so, I think it comes back to the point I was making earlier, which is that having a drug that has a broader anti-inflammatory effect within these autoimmune diseases that have very pleiotropic inflammation, and that includes both HS and AD and many others, is an advantage. And I think the 17-A/F versus A, which is just another way to sort of highlight the advantage of going broader and having more efficacy versus being more restricted and narrow.
Bruce Jacobs: And, Jeff, just to answer your question on revenues, while we don’t obviously guide to collaboration revenues, you can see in our balance sheet the deferred revenue number, it’s just over $46 million. That’s the amount of revenue we expect to recognize over the near term as we fulfill our performance obligation. The inclusion, though, of additional milestones, there’s no additional milestones are included in that number. So, anything that is achieved with respect to future milestones, those would be largely recognized at that point in time. So, that’s what I can tell you on that.
Jeff Jones: Great. Appreciate it, guys. Thank you.
Operator: Thank you. This concludes our question-and-answer session. I would like to turn the conference back over to Justine Koenigsberg for closing remarks.
Justine Koenigsberg: Okay, thank you. We’d like to thank everyone for joining us this morning and look forward to keeping you updated on our progress. Later this month, we’ll be participating at the BofA Conference and hope to see many of you there. In the meantime, please don’t hesitate to reach out if there are additional questions following today’s call. Thank you. This concludes today’s call.
Operator: Thank you. The conference has now concluded. Thank you for attending today’s presentation. You may now disconnect.
Justine Koenigsberg: Goodbye.
