Walter Liszewski, MD, talks with Matthew Zirwas, MD, about the potential therapeutic applications, based on the article “Targeting the OX40-OX40L pathway: A new era in atopic dermatitis management by T-cell rebalancing,”1 as well as the risks of therapies targeting the OX40 pathway.
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A Closer Look at OX40 Pathway Modulation
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Dr. Walter Liszewski:
Hi, everyone. My name is Walter Liszewski. I'm a dermatologist in Chicago, and today for our Type 2 Inflammation Journal Club, I'm excited to have my colleague, Dr. Matt Zirwas, who will be joining me to discuss a paper about OX40inhibition and the role of OX40 drugs in dermatology, and the paper we'll be discussing was published in the journal, BioDrugs. So Matt, thank you for joining me today.
Dr. Matt Zirwas:
Thank you. And I already learned something amazing on this podcast, that it's Liszewski.
Dr. Walter Liszewski:
Yes.
Dr. Matt Zirwas:
I've always, in my head, it's Liszewski.
Dr. Walter Liszewski:
Yes. I'm sure you're one of those people who's used to people saying your name, sometimes not always correct, sometimes not even close to being correct.
Dr. Matt Zirwas:
Yeah, yeah, exactly right.
Dr. Walter Liszewski:
Yes, but enough about that. One thing that's easy to pronounce is OX40, and can you tell me a little bit more about OX40 and how does it work?
Dr. Matt Zirwas:
Yeah, so it's a fascinating pathway, and it's really disappointing that these drugs cause Kaposi sarcoma. In all functionality, we're not going to use them except for somebody who has failed every other possible therapy. But it'sfascinating, and when we use it, we're going to be impressed by how well it works. The OX40 pathway, so this is very distinct from cytokine blockers. So OX40, and I can never remember which one is on the T-cell and which one's onthe antigen-presenting cell, but basically one of them has OX40, one of them has the OX40 ligand, and it's a costimulatory molecule. So, whenever the OX40 cell and the OX40 ligand cell touch, it makes the memory T-cells live longerand keeps them active and all this kind of stuff.
And what people really need to understand, it's a really simple concept, that if we affect the memory T-cells, we affect all the cytokines. It's not like IL-13, IL-31, TSLP, TARC, where we're trying to get one and, oh, we got bifunction, nowwe'll get two. This is you get all of the cytokines, and that's what made this such an exciting therapy, and the idea that if you could deplete the memory T-cells or at least reduce their activity over time, you might retrain someone'simmune system and actually have long-term disease modification, AKA cure.
Dr. Walter Liszewski:
Remission, whatever you want to define it as.
Dr. Matt Zirwas:
Yes.
Dr. Walter Liszewski:
Yeah.
Dr. Matt Zirwas:
Yes, so they were super, super exciting drugs. I did both the ... Amlitelimab is the Sanofi product and then rocatinlimab is the Amgen product, in both the trials. I didn't have enough patients in them to be able to say one's better thanthe other, but when you look at their data, they're both similar. They are probably a little less effective than dupi at 16 weeks, but I saw them be very reliably effective. And it was interesting. The rocatinlimab, the Amgen one that isnow no longer being developed, I saw a number of people who, on your first dose, you get bad fever, chills in a substantial number of people. And I had two of them would get pretty significant oral ulcers, so apoptosis. They had someissues with GI ulcers, so it seems like that was not just your mouth, you could also get it in your intestinal tract. All of that was manageable and not a big deal.
But then six months or so ago, safety reports started to come across my desk, because when you're an investigator, you get letters.
Dr. Walter Liszewski:
A lot of them.
Dr. Matt Zirwas:
Yes, you get a lot of ... Every time there's a side effect anywhere in the world, you get a freaking letter, and so the first one came in-
Dr. Walter Liszewski:
I have a stack of FedEx letters from Sanofi right behind me. Yeah.
Dr. Matt Zirwas:
And so, I started to get ... I got the first one that said "Kaposi's." The day I got the first one that said "Kaposi's," I said, "Oh, my God, both these drugs are dead." I thought that the next day I was going to get an email saying, "We'restopping the trial, because commercially there is no future." Crazy.
Dr. Walter Liszewski:
A couple things about that I want to kind of tease out for our audience. So the cool thing potentially about OX40s is that instead of being very targeted to a cytokine downstream inflammation, we're targeting really early, and we'relooking at helper T-cells. So not only the TH2 type, but potentially also TH1 or TH17, because one of the complicated things about atopic derm is that it's heterogeneous. And acute AD, we think of it as Th2, but there are some patientsthat have a lot of Th17 or potentially even a TH1 overlap with the TH2, and that's where having something that's a little bit broader...
One of the limitations that you mentioned is that at week 16, data doesn't look that good. And the phase two data for both these drugs was incredible. The phase three has been a little bit more modest, but with the ability of thesedrugs to potentially rebalance the immune system, to increase things like Tregs, to decrease memory T-cells, that we're able to rebalance the immune system, it's a very similar concept to, say, phototherapy, which does somethingvery similar, increases Tregs, decreases memory T-cells, and helps to rebalance. Now this happens-
Dr. Matt Zirwas:
Can I first ... I just got to tell you, I'm so stunned and impressed right now. Had not occurred to me to draw the analogy to phototherapy. That is brilliant, brilliant.
Dr. Walter Liszewski:
But it's the same thing, because why does phototherapy work in cutaneous lymphoma? It doesn't kill the lymphoma cells. It rebalances the T-cell population, and that's what the OX40s are trying to do, but anytime you tinker with theimmune system, weird stuff can happen.
Dr. Matt Zirwas:
Yeah, and one of the other things that was promising about these drugs, and phototherapy is such a good analogy for it, right, phototherapy works for AD, it works for psoriasis, it works for CTCL, it works for GA, it works for lichenplanus. It even works for alopecia areata and vitiligo. These drugs, just like phototherapy, had this incredible ... like, if they were drugs that we could use, they could have worked for almost everything, just like phototherapy.
Dr. Walter Liszewski:
Yeah. And Sanofi is actually trying to leverage it, because there are other disease states where there are T-cell dysregulations, so things like vitiligo or alopecia areata. Now, the big thing is that both rocatinlimab and amlitelimab havehad reported cases of Kaposi sarcoma.
Dr. Matt Zirwas:
Yeah.
Dr. Walter Liszewski:
The good news is that these were predominantly skin-related. Now, I did learn something very interesting recently at AAD. I'm going to drop a bomb on you here, OK?
Dr. Matt Zirwas:
Yes.
Dr. Walter Liszewski:
Just see what your reaction is, OK? In the rocatinlimab trials, the Kaposi sarcoma was apparently only seen in older white men who are HIV negative who have sex with other men. There's a thought that it's a subpopulation that'sprobably HHV-8 positive. What if we could screen for HHV-8 serostatus? Or if we know certain populations are more prone to getting this, is there still a risk of Kaposi's across the entire group?
Now, I don't know what was reported in the Sanofi amlitelimab. I don't know if it's the same patient population, but one other thing I want you to be aware of is, in our clinics here at Northwestern Chicago, we have been seeing anincrease in Kaposi's in HIV negative men. And Sloan Kettering recently described that there's type one, two, three, four Kaposi's, don't ask me to tell you what they are, but they created a fifth type of Kaposi's, which is for MSM menwho are HIV negative.
Dr. Matt Zirwas:
Huh.
Dr. Walter Liszewski:
Maybe it's just a subpopulation.
Dr. Matt Zirwas:
Yeah. So first, the idea of screening for HHV-8, it does change the calculus some. I think that it'd be ... And so for our listeners, by the way, you got to know that it was a well-known thing that OX40 pathway has a unique role insuppressing HHV-8, so that was a known thing. When I did the SIVs for these trials, I said to both companies, "You know this is going to cause Kaposi's, right?" And they were like, "No, our basic scientists have assured us there's nosignal. It'll all be fine." And I was like, "OK." I think the challenge is still going to be, even with the HHV-8 screening, we know how much derms love a drug where they don't have to check any labs. You're going to have to do HHV atbaseline in every patient, and then you'd have to do it annually, because somebody could catch HHV-8.
Dr. Walter Liszewski:
Absolutely.
Dr. Matt Zirwas:
And then the second thing is going to be just literally saying the words when you're like, "Well, we've got all these great drugs and this one's really good. It might rebalance your immune system, but it causes cancer." Derms are notgoing to ... We're not going to use it.
Dr. Walter Liszewski:
A tough sell. It's a tough sell, and it's slow.
Dr. Matt Zirwas:
Yes. And you'll use it, I'll use it. Every city, there'll probably be ... A city like Columbus, I'll be the only guy. In Chicago, there'll probably be five people who use it. There'll be people who use it, but from a commercial perspective, there'szero chance of there being enough people prescribing it to make it a winner. I do hope they bring it to market, because it's going to be something that we can have in our back pocket for that person who's failed dupi and Adbry and lebri and JAKs and nemo, and you're like, "I've tried everything," it'd be nice to have another option.
Dr. Walter Liszewski:
And those patients are out there though. That's the thing.
Dr. Matt Zirwas:
Yeah, they are. They are.
Dr. Walter Liszewski:
People aren't, because people think, "Oh, you just put someone on dupi and they're good." No, no, no, no. I'm going to steal from what Jonathan Silverberg says. He practices in the twilight zone, and I think you and I are both in verysimilar practices, where you get the people who've come and who've failed multiple drugs and you biopsy them. It's not lymphoma. We've done patch testing. There's nothing there. They just have a really recalcitrant form. We still doneed new drugs in atopic dermatitis. It is not a sealed case. And whether or not OX40 is able to deliver on that, more to come.
Dr. Matt Zirwas:
Yeah. One last, last thing. I'm curious of your experience.
Dr. Walter Liszewski:
Yeah.
Dr. Matt Zirwas:
The times when I've had somebody who didn't do great on dupi, didn't do great on a JAK, and then I'm like, "Ooh, I'll put them together," I have been very underwhelmed by that. It has been, the best of the two, we didn't really getmuch better whenever we put them together. Has that been your experience, or have you had good success combining dupi and a JAK?
Dr. Walter Liszewski:
I have not. It's been challenging. And I've definitely done that where you're like, hey, if I take upadacitinib, 30 milligrams, probably the best AD drug we have, plus one of our good biologics, you would think that since there are differentmechanisms of actions, they would work. But there's some sort of weird phenotype about some AD patients that it just somehow doesn't work, and maybe OX40 is the key? We're going to find out.
Dr. Matt Zirwas:
Yeah. Yeah.
Dr. Walter Liszewski:
All right. Well, thank you so much for having time to chat with us today, and I really appreciate it.
Dr. Matt Zirwas:
It was a great time. I really enjoyed it, Dr. Liszewski.
Dr. Walter Liszewski:
Yes, that is correct, Dr. Zirwas.
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Walter Liszewski, MD, talks with Matthew Zirwas, MD, about the potential therapeutic applications, based on the article “Targeting the OX40-OX40L pathway: A new era in atopic dermatitis management by T-cell rebalancing,”1 as well as the risks of therapies targeting the OX40 pathway.
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