Transcript
Dr. Neal Bhatia (16:01):
I do like the idea of, again, reemphasizing the crosstalk between the barrier and inflammation, especially... And like you said about keratinocytes. Keratinocytes are dendritic cells, right? They secrete the different interleukins, especially two and one, or more one, if you will. But also, again, the ones that we are now most familiar with, again, what we learned from biologics and JAK inhibitor pathways, four and five mast cells and eosinophils work. Obviously, 31 is a big itch cytokine which we know about.
But again, if you think about the components of a topical, putting those at bay, clinically, where does that fit into a conversation? Obviously we're not going to have that with patients because they're not going to know the numbers, but we're thinking more across the board, we can control inflammation that way. So, are there any talking points to be had with not just other clinicians but other patients? Where do we have those discussions?
Dr. Joshua Grosshandler (16:59):
Yeah, I mean, I think that to take it on both sides, I think for me, it's really helped us open up windows of opportunity into, hey, you see it every day, I see it every day. You got people that you maybe just don't know, right? Hands are tough, feet are tough. And I think it gives us the ability to say, "Well, we have this mechanism where it kind of works on both sides of the fence." And in addition to that, again, back to the barrier, we know it's impacting that.
One thing we haven't talked about yet is also it works as a great antioxidant. We know oxidative stress plays a role in both of these conditions, amongst other things. And we know, interestingly enough, aryl hydrocarbon receptors or tapinarof also is a scavenger. It goes and it scavenges reactive oxygen species. And in addition to that, again, it's shutting down oxidative stress in a different pathway.
So, it's able to really be this almost like multimodal approach, so it's kind of helping us. So I think there's these patients all the time where we're stuck. And the beauty in what I usually tell people is, "Listen, I'm kind of between two things, right? I'm between atopic dermatitis, I'm between psoriasis. Sometimes it's really hard on certain locations to tell the difference between them, but we've got these beautiful treatments that can work on both." And so I think that's been one of the, I think, nice things.
Ultimately, yes, people say, "Well, you have that with a steroid, too." Sure, no doubt. But I think one of the things that steroids have always done, although maybe we really haven't talked enough about it or understood enough about it, is it's impacting the barrier, right? So maybe for that short-term, it's really helpful, but most of these conditions are very chronic conditions and they come and go.
And so I think the other beautiful thing, and maybe that brings us into this discussion of potential remittive effect, right? We have these medications, tapinarof being one, that has data showing, both in psoriasis and in atopic dermatitis that, hey, you use this medicine, you get them to clear, you stop the medicine, and then it takes a certain amount of time for them to get back to mild. And that was seen in the trials.
In atopic dermatitis, it was around 80 days on, I think the median or the average, or the mean, excuse me. And then within psoriasis, we saw that I think their median time was 115 days for the people who have gotten completely clear. But still, even people who had been not completely clear at the time they switched over into this long-term extension, they eventually got there, and then they still had about the similar time.
So I think talking about trying to maybe impact disease greater than just acutely, I think this pathway may give us some of that. I think it does based on some of the data that exist. And I think that that gets into hitting these different mechanisms beyond just inflammation.
Dr. Neal Bhatia (19:43):
Yeah. And the concept of making things go away, making them stay away are conversations we never used to have, because obviously steroids will rebound. And everything else we might've tried, whether they be calcineurin inhibitors or anything in that class, I mean, there were more bandages than actually thinking about a remedy.
And it's funny because certain people we know who will remain nameless on this discussion, I've had arguments with them about the difference between remission and relapse. And it's like, OK, relapse is actually your disease coming back and remission is the concept of keeping things away once they're gone.
And the idea of a remittive effect is exactly that, right? Is there something in the pathway that says, "OK, we're going to see that this may not even come back, or at least in the same place"? But again, that concept, again, is it something that patients should buy into and we say, "OK, well, you've had atopic dermatitis your whole life, or as you're aging, psoriasis may evolve from there"?
And even that old tagline of psoriasiform dermatitis, when we can't make a decision, it's all part of the same. And we take label almost for granted and say, "OK, well, here's the template. Can we use this in areas of maybe recalcitrant cutaneous T-cell lymphoma or some other eczematous process?" I mean, where does that thinking fit in? Because obviously, getting label is one thing, but getting the process done is another.
Dr. Joshua Grosshandler (21:17):
Yeah, I mean, I think all really good points, and I agree with you. I mean, I think this whole remittive relapse, all of the conversation is really hard, but I think a couple of things. First, when we talk about patients, and we really think about taking care of patients, they're looking, I think, for a few things, right? They're looking for, "Hey, I want more acutely my disease to be better. I want that itch to be better. I want the spots that are there to look better."
Ultimately, I think all of them will take, "Hey, you're not going to have a spot," or, "You're not going to have to use your medicine over a really long period of time." Now, why is that happening? I think there's a lot of theory, and I think getting back to relapse versus remittive. But one interesting concept that I've been noodling on a little bit more lately is the concept of these T regulatory or T memory cells.
And so, I think a lot of us are starting to focus a little bit more on that, because to your point, why does it come back in the same spot? Why is this thing continuing to happen in the same spot? And I think that the story really is going to hopefully probably play out, and already is, that these play a big role. And one interesting thing within the aryl hydrocarbon receptor is it actually impacts them. It actually helps decrease, suppress them. It decreases their maintenance. We have, again, back to signals, the signaling pathways that keep them around.
And there was this trial that was done looking at some of this and looking at betamethasone and calcipotriene or calcipotriol, and these different medicines, and seeing, "OK, what's the impact on these T regulatory cells?" And what we're actually seeing is, hey, with them, some of these medicines don't do as great of a job. With others, maybe they do. And so, maybe that's something that's going to help us.
And I think, ultimately, getting back to the patient and when we're talking about it, I think giving them perspective. I never love to promise anybody anything because we just don't know, right? When we're looking at these data points and these studies, we're talking about averages and medians and all these data points, which I think help us and it helps give them perspective.
But I think at the end of the day, usually how I break it down for people is like, "Listen, this medicine can work fairly quickly, but we know it's going to take some time overall to probably work on your entire disease. Maybe it's going to help with the itch fairly quickly to make your spots, let's call them, improve. We know that's going to take a little bit of longer time, but we've got this opportunity where, hey, if you use this and you get to completely clear, you may have where you don't have to use very much medicine moving forward. You may not have as many flares throughout the year."
And I think for them, that's an easy way to conceptualize it versus saying, at least in my clinic, it's like, "OK, you can expect to get 115 days." Right? And I think that just sets us up for failure, which none of us want. We want to be heroes. Right?
Dr. Neal Bhatia (23:57):
Yeah.
Dr. Joshua Grosshandler (23:58):
And so that's how I've played within it. But I agree with you, on one last point, as far as whether it's psoriasiform or whether it's this or that, I think sometimes patients don't care as much, right? They want to know that you're giving them something that is going to help them, and that you have the confidence that it's going to help them. Again, not in that short-term, but that middle and a little bit of the long-term. And that's where, again, I think utilizing some of these things and understanding conceptually how it works, I think it gives us some of that opportunity.
Dr. Neal Bhatia (24:29):
As you're saying that, I'm just thinking about how recipe-driven we are in the clinic, right? We give something for cleansing and moisturizing, typically give something for itch, in addition to the prescription. Even though, like you said, there may be good itch data with the topical that we're giving, but I think if we don't give the patients the idea that, "Okay, look, this is a one-stop shop, you're going to take care of everything with just this," then we're basically fooling them and ourselves, right?
But by the same token, if we can get by with, "OK, your itching is starting to go down, you may not rely on these." Or these other adjuncts to itching and just say, "Look, use them at the first sign of flare or the first sign of itch, but maintain yourself with this active ingredient that goes after the process," I think then we actually can gain some traction on compliance. So I think that's an important observation you made there.
