Taylor Schreiber: So it was driven by a few factors. First of all, on both the CD40 and CD47 binding sides of the molecule, we were looking to find a dose where full receptor occupancy and receptor saturation was achieved. And that was achieved by that 3 mg/kilogram dose and that was visible both in terms of the receptor occupancy data and observation of non-linearity in the PK profile. Beyond that, we were looking for a dose that led to maximal induction of the pharmacodynamic effects driven by CD40. So many folks are aware that with others €“ with CD47 inhibitors, the only pharmacodynamic effect you see in a study like this is receptor occupancy. So the observation of rapid margination of CD40 expressing cells from the peripheral blood post dose is a unique effect for 154 relative to any other agent in the space.
That was maximal by the 3 mg/kg dose and maintained that maximal plateau up through the 10 mg per kg dose. The other primary pharmacodynamic effects were rapid induction of multiple cytokines, including interleukin-12, IP-10, CCL2, CCL4, CCL22 and a number of others. And those cytokines also achieved a €“ what appear to be a maximal plateau by that 3 mg/kg dose, which did not escalate appreciably by the 10 mg/kg dose, but also importantly didn’t decline. And so on all of those markers, 154 was differentiated both from single-acting CD47 inhibitors and lacked any of the toxicity or bell-shaped dose response effects that characterize prior CD40 agonist and so all of that gave us confidence about this being the right dose to bring in the combos.
Yigal Nochomovitz: Great. Thank you.
Operator: Thank you. We will take our last question today from Zhiqiang Shu of Berenberg.
Zhiqiang Shu: Good afternoon. Thanks for taking the questions. My question is related to your 252 program. Obviously, it’s not surprising to see the discontinuation there, but I was wondering if you can talk about the learnings from this program, particularly around the PK/PD aspect to 154, what the PK/PD from 252 is consistent with what you are observing in 154? Thanks very much.
Taylor Schreiber: Sure, thank you. Zhi. So the trial cross comparisons here are, I think, quite valuable. And with the 252 program, we completed dose escalation through that 24 mg/kg dose compound continued to be extremely well tolerated. And across that dose escalation, we saw dose dependent binding to CD4 cells expressing OX40 and migration of those cells out of the peripheral blood post dose. And so again, from a TNF receptor agonist perspective, the tolerability and lack of any evidence of a bell-shaped dose response curve and the pharmacodynamic effects with both 252 and 154 are helpful in terms of validating one of the central hypotheses of the ARC platform that if you engage TNF receptors with a hexameric drug, you will not observe some of the toxicities and pharmacodynamic €“ abnormal pharmacodynamic effects that prior antibody-based regimens have seen.
So that’s an important finding from a platform expansion standpoint, again both from the safety and the pharmacodynamic side. And we’re also learning some important lessons I think in terms of what OX40 and what CD40 stimulation achieve in human cancer patients. And when you look at the 252 data and you note that there really are €“ there were no appreciable serum cytokine changes. The only cells that were migrating were the specific CD4 positive, OX40 positive cells. It was a much more immunologically quiet molecule, so to speak, in this patient population, whereas the CD40 agonist clearly all across the dose escalation led to very clear escalations in a number of cytokines, infusion-related reactions have been much more common with that agent.
And so the differentiation in biology between the two constructs paints a very clear picture that this is target-mediated activity that we’re seeing here. So always hard to close down a program like this, but I think we’ve learned what we needed to learn from this molecule and those learnings will benefit other compounds moving forward.
