REZPEG doesn’t induce those cells, it induces that CD 56 bright, 16 negative NK cells, which many people have postulated actually have regulatory functions. So it does induce in case of in the sporadically and when it does it skews that into that other possibly more regulatory phenotype, and we publish those results.
Operator: Our next question will come from Andy Hsieh from William Blair.
Andy Hsieh: Great. Thanks for taking my questions. Appreciate the update. just two quick ones. One on the TNFR2 validation that you mentioned, JZ. Just to clarify, are you referring to a human genetic validation on a population basis to derisk the mechanism? And secondarily, for 255 — so the Phase II JAVELIN Bladder Medley study, I think the last time you mentioned that there could be a second half update. So curious about first, the timing for that, and also the disclosure. So would that be in conjunction with a partner or would that be kind of Nektar disclosure? Just trying to get a sense of the logistics there. Thank you.
Howard Robin: Let me answer the second part of it first, and then I’ll let JZ go on. Look, we do expect the data from the Medley Bladder cancer study in the second half of this year. We don’t have an exact date yet, and I certainly — we will certainly disclose it once we — the data’s been cleaned up and Merck KGaA has looked at the data, cleaned it up, discuss it with us, and we go through a normal process. But I would expect that to all happen in the second half of this year. JZ, you have any comments?
Jonathan Zalevsky: Sure. Andy, thanks for asking a human genetics question. That’s super cool. So TNFR2 validation comes from a number of different sources. And before actually touching on human, let me touch on a few of the critical preclinical findings that have made. So TNFR2 has both been overexpressed and it’s been knocked out, and you see that corollary phenotypes. Like when it’s gone, animals have a hard time maintaining Tregs populations. They also have a hard time mounting any kind of first of Tregs or Treg control like in the setting of a model like the , for example. If you run E80 in the knock-out, the disease is extremely exacerbated, right? And it’s much, much worse than it is — whether you use , similar kinds of results.
Likewise, when you drive its expression, you could reduce the ability to even insult using various inflammatory agonists. Also studies that have made transmembrane TNF mice, some of the studies that Jonathan Cedric did in the early 2000s, since that’s the primary ligand, you really get TNFR2 [Technical Difficulty] as a primary signal model, and again, you have very similar kinds of effect where those animals were driving R2 and they remain highly immunoregulatory. It is very hard to create an inflammatory model in that background. And then in people we see a kind of cluster of steps and other kind of polymorphisms go together. So first, like most canonical Tregs dysfunction is IPEX. And IPEX in humans is when you have a FOXP3 loss of function.
Very severe autoimmune skin type of disease. And actually TNFR2 snips and things are modified. TNFR2 expression and signaling actually can resemble IPEX. This not be as severe, because obviously knocking out FOXP3 is much more severe than losing TNFR2. So I hope that answers your question. There are many, many streams of validation of TNFR2 and probably I guess that one more is actually just coming from the field that uses TNF in addition to reg. So we know that if you treat with a pan-TNF inhibitor like Humira or Remicade, or Adalimumab — pick your favorite one, right — they knockout transmembrane and soluble. And you see that that’s contraindicated in a number of indications. And the removal of that transmembrane that takes away the TNFR2 signal that short circuits what you’re trying to achieve therapeutically.
So all of those roads kind of lead to Rome, and they have really led the field come to understand that the two receptors, R2 and R1, they share very differentiating functions in that R2 is like the natural antagonist to R1, and it seems to turn off that inflammatory pathway the TNFR1 drives. It’s highly tissue protective. So to create an agonist to capture that kind of biology could be really, really therapeutically ideal. And that’s what we’re trying to do.
Operator: [Operator Instructions]. Our next question will come from Arthur He from H.C. Wainwright.
Arthur He: Hey, good afternoon, Howard and team. This is Arthur from H.C. Wain, thanks for taking my question. Just to maybe — first question for Mary. So are you guys open to a very REZPEG in the patient with biologic experience either within a single agent or in combination with a biologic through collaboration or ISP?
Mary Tagliaferri: Yeah, hi, Arthur. It’s a good question. So we talk a lot about this internally. And generally speaking, the FDA requires you to ensure that patients who are biologically experienced have a washout period of 5.5 half-lives. And so patients who have previously been exposed to another biologic agent have to be off treatment for about 12 weeks. So some clinical trials have permitted these patients to be enrolled. But because of the very long washout period on their prior agent, it ends up being pretty difficult, to actually enroll these patients, even though scores of patients have been exposed to say, Dupixent. So it is something that we’re considering for the Phase 3 program, how or potentially if we would include those patients into our study.
And then we always — JZ and I and Jennifer spoken many times about whether or not we would ever do a combination trial, say, REZPEG with an IL-13 inhibitor. And so we’ve also spoken about that a lot internally, and it’s certainly on our list of clinical trials to consider. For us, though, the primary goal is excellent execution of the Phase 2b, seeing the data and should that be positive to move very quickly to a program that would allow REZPEG to get to patients as quickly as possible.
