We know that in the mucosa Tregs have a completely different cytokine environment that they’re exposed to, very low IL-2 in those kind of environments, because need a different kind of a signal. So ulcerative colitis and indications that impact both the lower or the upper mucosa are ones that we’re prioritizing. And then we also know that in the setting of CNS, particularly around the role of myelin and demyelination and the role that TNFR2 plays in controlling some of that biology, which has been really nicely shown in animal preclinical models in mice. That’s also the reason why multiple sclerosis also is a high indication for us. So that’s just a flavor of how we’re thinking about the program. Certainly, the two really go together and they’re highly complementary and they — between REZPEG an NKTR-0165, they kind of hit the two main biological axes of Treg biology.
Operator: Our next question will come from Roger Song from Jefferies.
Roger Song: Great. Thanks for the update and taking our questions. Maybe just a quick one regarding the REZPEG — [Technical Difficulty] next steps after the Phase 2b. Understanding you need to follow them over longer, but at the top line, what will be your next step plan for those two indications? Thank you.
Howard Robin: Okay, I’ll let Mary answer that. But clearly, we said we’d have data from the the initial 16-week induction period by first half of next year. And then of course, we’ll go into looking at the durability of the response. ButI will let Mary expand on that.
Mary Tagliaferri: Yeah. Thank you, Howard, and thank you, Roger. So lucky for us, the pathway to approval for an agent that you’re developing for atopic dermatitis as well as alopecia is very clear. So for atopic dermatitis, should our Phase 2b trial readout is positive, and we show a statistically significant benefit on the EASI score, then we would start planning for the Phase 3 program. And in the Phase 3 program, typically you have either one or two doses of your drug versus placebo. Also the primary efficacy endpoint in these two monotherapy trials versus placebo is the 16 week. Some other agents look at a 24-week induction period. And for the FDA, the primary efficacy endpoint is the vIGA. And in Europe, it’s a co-primary endpoint of the vIGA plus the EASI 75.
In addition to those two Phase 3 monotherapy trials, we typically do a combination trial with topical corticosteroids versus the topical corticosteroids alone, and that is the Phase 3 program for atopic dermatitis. These trials are pretty easy to enroll to and it generally takes about a year to enroll to those studies. In addition to the efficacy, you need roughly about 600 patients that have been exposed to REZPEG at your highest dose for 12 months. And then in terms of alopecia areata, it would be two Phase 3 trials and at the REZPEG versus placebo, again, the induction period is a little bit longer than you see in atopic dermatitis because it takes longer to grow hair. So the induction period tends to be about 36 weeks. There’s obviously not a combination trial that would be run.
So in contrast to atopic dermatitis that requires two Phase 3 trials, in alopecia areata, it would be two.
Roger Song: Great. Thanks for the detail. And then maybe you can comment on your ongoing litigation with Lilly for your REZPEG? Any kind of updates from Diane? Thank you.
Howard Robin: Sure. Look, there is, as you know, the court ordered us to go to mediation with Lilly, and that’s actually scheduled for next week. We’re not going to comment on the results of this. We’ll comment when we reach a solution with Lilly. But we will be mediating with them. They were clearly responsible for an egregious error that changed the dynamics of REZPEG. And clearly, if you look at the original data and then you look at the corrected data, REZPEG seems to function very, very well in atopic dermatitis. It appears to be highly competitive, very different from their initial calculations. So they filed — Lilly filed a counterclaim which of course has very little merits behind it. And certainly we certainly don’t expect that to be valued by the court, nor do we expect that we will owe Lilly any money, not at all.
And I think this will sort itself out over the coming year. I can only tell you that the judge did not dismiss our case against Lilly and ordered us into mediation. We’ll see how that goes.
Operator: Our next question will come from Jessica Fye from JPMorgan.
Unidentified Analyst: Hey, this is Nick on for Jess. Thanks for taking our questions. Maybe just a quick one in revisiting the design REZPEG. I understand the PEG conjugation parts differential bias for IL-2 or alpha versus beta, but can you remind me exactly where on the IL-2 molecule the PEG is placed to impart that bias mining?
Howard Robin: JZ, do you want to take that?
Jonathan Zalevsky: Yeah. Hey, Nick. Yeah. So we’ve not shared that level of detail. We have published in our first manuscript in the Journal of Translational Autoimmunity a lot of information about the design of REZPEG, but we’ve not shared which amino acids, for example, are pegulated. What I can tell you is that we have a lot of experience in designing these kind of molecules. And this kind of a molecule in REZPEG is very similar to some of the original foundational molecules like Pegasus or Neulasta that we made with many of our partners over the decades. And then in regards to how it works, those biological effects from the PEGylation, they impart the right kind of receptor occupancy. They part the right kind of duration of signaling.
And that’s what gives REZPEG this continuous ability to renewed regulatory T cells as you continuously dose it. And we have data in our dosing people for three months or six months with the maintenance of that pharmacodynamic effect. That’s the goal of that treatment.
Unidentified Analyst: Yeah, that makes sense. And maybe just a quick follow-up to building on that. I know there’s obviously clinical data, there’s in-human data, but just understanding a bit more. I know there there’s some observations of NK cell activation, higher doses in the earlier models. Have you seen any instances of that happening in the clinic and in the dosed you’re testing? And how would that manifest itself in either AD or alopecia areata trial?
Jonathan Zalevsky: Yes. Well, we’ve published that as well. So in our our second publication, which captured the results of our Phase 1a and Phase 1b studies, we presented those results. So we do see that in some people — not in all people, but in some people have an NK elevation. It seems to build up with time. So REZPEG, for example, cause — Tregs are instantly elevated from the very first dose. NK cells are sporadic, and you don’t see them in all people and when you do see them, they seem to take longer to present themselves. And then one thing that’s very curious is we changed the skewing of the NK profile. So as you know, there are 56 bright, 56 dim NK cells and those differ in the expression of Fc Gamma R3A CD16. And in normal situation or — I guess in the in one kind of immunological state, you typically have primarily a CD 56 dim, 16 high.
