Simon Burns: I wanted to introduce our esteemed host today Dr. Lebwohl and Dr. Kim. Thank you so much for joining us. Before we jump in, I wanted to just give a quick introduction on Vial. We’re a next generation CRO. We work closely with leading principal Investigators across the country and help scale their research businesses. And that also ends up powering the CRO.
On top of being a CRO, we also wanna host great conversations about the future of research and these two esteemed luminaries are a great example of attempts of conversations we wanna host. So Dr. Lebwohl, Dr. Kim, very excited to hear the conversation today about each research. I’ll leave it to the two of you to take it away and look forward to the conversation here.
Mark Lebwohl: Great. Thank you very much. Since Brian is the real brain power behind itch. I will serve as the moderator and ask Brian some questions, some of which he suggested to me, others of which I have certainly had myself and I will start out by saying that there isn’t a day where itch is not a significant part of interaction with a patient, not one day ever. With that in mind I wanted to start with some basic background Brian, because, we use the term, itch, but how many different kinds of itch are there?
Brian Kim: Yeah, I think that’s the million dollar question. I appreciate Vial giving us the opportunity to kinda co-host and talk about this I wanna start with some of the misunderstandings about itch. And I think there’s been this historical assumption that itch is really just one symptom and it’s a trivial symptom and it can be solved if you can just solve one itch. The problem, I think, has been that we haven’t been able to solve many itches at all. It turns out it’s probably not one inch, and that’s why it’s taken so long to solve. The problem’s not trivial, as you said, it’s probably the most common symptom in dermatology. Not the symptom that’s most addressed but the most common. And fortunately now, and I think partly why we’re having this kind of conversation is that people are recognizing this, and this is becoming a real thing. And it’s attractable thing that can be addressed therapeutically diagnostically, and we can start to unveil what’s probably actually more like hundreds of different inches.
Mark Lebwohl: Yeah. I must say when we get referrals from non-dermatologists in particular, every patient who has complained of itch is treated with antihistamines.
Brian Kim: [laughs]. Yeah.
Mark Lebwohl: Regardless of the cause. And I’m glad you laughed because elaborate on why that will work for some but not others.
Brian Kim: I was hoping you’d say that, right? I think that goes directly in the line with what I said, is that because we thought it was one itch, that’s all it could be. And really what you’re saying is essentially the first itch that we came to really recognize was histamine-mediated or histaminergic itch. And the belief that it’s one itch and that it’s all histamine-mediated is so strong that you still have a $2 billion market for a drug that doesn’t work for 99% of the itches out there. And yet we are still prescribing it for itch in that fashion. And, literally that’s the IMS health data.
So that’s quite remarkable. And in fact, it bleeds into the biology too. There’s this idea that there’s histaminergic itch and that’s non histaminergic itch and that’s true, but the fact that is the classification is quite astounding to me because the vast majority of itch is non- histaminergic. And so that- that’s like the bifurcation, even in the biology end. Tells you how biased we’ve been towards using antihistamines, believing that antihistamines will work. And that is the basis of most itch.
Mark Lebwohl: Yeah. I, I will say the other comment that I have regarding what you said that there are many diseases characterized by different kinds of itch. We, Bruce Strober and I years ago developed a patient’s symptom diary for psoriasis and we distributed questionnaires to enormous number of patients. I don’t even remember the number, but also to physicians. And it turns out when you ask physicians, if itch is important in psoriasis, it becomes a trivial symptom as you called it. Dermatologists saying that. But when you ask patients, it was the number one complaint they had, was itching.
Brian Kim: Yeah.
Mark Lebwohl: So I think the reason for that it has to do with how bad the itch is in atopic dermatitis compared to psoriasis where clearly in atopic dermatitis, the itch is intolerable. It is what causes, it, patients, if you don’t control the itch, you’re not winning the disease. Whereas in psoriasis, once you control the skin lesions, you do see the itch go away. Although, often you see the itch go away first.
Brian Kim: Yeah. But I think there are similar themes even in atopic dermatitis yet because there are a lot of patients who actually improve in terms of the lesions, but the itch actually persists. But I think the providers don’t necessarily want to talk about that cause now we’re reentering the world of the mysterious itch, not the itch that we know. And I think it starts to become more in the realm of idiopathic. And I think… [00:05:00] also, I know that you are very fond of these patients with chronic pruritus mainly because you probably see them a lot like I do. Those patients aren’t well recognized either. It’s, what I see the most of, but I don’t think most providers really believe that is necessarily an attractable thing that they would actually want to devote say a chapter and a textbook of dermatology on.
So I think there’s a long ways to go. And I think that I like your contrast between psoriatic itch and atopic itch, and I agree with you, there are differences in the way we perceive that. But I also think that kind of context dependency in terms of how we perceive itch is true across the whole spectrum. And there are so many chronic itch disorders, with your kind of, legendary background in psoriasis, just look at what happened with the psoriasis’ boom in dermatology. But now look at itch where we’re going into an area where there are so many diseases, prurigo nodularis, notalgia paraesthetica, brachiordial pruritus, scalp pruritus, lichen planus, the list goes on and on. That’s just a handful. Uraemic Pruritus.
This is potentially the biggest thing, in some ways, for dermatology, and the fact that as we’re saying this isn’t just one itch and the provider notion of the itch, I think you’re right, is very discordant depending on what we’re talking about. It’s not all gonna be the same and we’re gonna land on different pages with the patient. Another example is itch associated with checkpoint inhibitors is actually not rare. It’s actually fairly common. It’s a fairly common side effect.
Mark Lebwohl: Yeah.
Brian Kim: But the oncologist, when I talk about it, say how come we never saw this in the trials? To your point, I’m not so sure they were looking for it or asking about it. And the primary focus of those trials for checkpoint inhibitors is survival of metastatic cancer. So I don’t think there was any oxygen to have itch come into the room as a part of a site visit or a discussion or, the follow up visits for these patients. So anyway, there’s a lot we can unravel here.
Mark Lebwohl: Yeah. So you open up a lot of doors and I wanna get back to talking about some of the treatments you mentioned and treatments that are coming. But before we do that I’m gonna just say one of the reasons I was so excited about getting you to Mount Sinai is I heard a lecture that you gave on a diagnostic approach to itch. And we had done a study here, actually, one of our residents, Roselyn Stanger, who’s a superstar did a study where we took the first 100 patients of what we said were itch of unknown origin.
And we used our definition, not formally published definitions. There are several very surprising findings. Many of our patients were elderly and something like one out of 10 ended up having subclinical bullous pemphigoid at least by some parameter, whether it be BP180 or BP 230, or direct immunofluorescence that showed linear staining, even though there were no skin lesions. And- by the way, most of them had that. And of that 10%.
We also found, surprisingly many of the organized approaches don’t pay any attention to the drugs the patients are on. So if you’re on an ACE inhibitor, that’s no matter what’s causing you itch, the ACE inhibitor by its mechanism is making it worse.
And many of our patients were able to just stop the ACE inhibitor and have the itch go away. And then the third surprise, I’ve been practicing long enough to see, I don’t like testifying in court, but I’ve been approached many times for physicians who allegedly missed a diagnosis of Scabies and the patient itched for years.
And to me, that’s such an easy condition to treat, one day of Ivermectin or before resistance developed, one day of Permethrin, and you’d know in a couple of days that they were so dramatically better, that something was going on. Now, when Rosalyn submitted her manuscript, it was rejected by one of the major journals because, they said that’s ridiculous. You can always identify Scabies. I’m around long enough to know that’s simply untrue.
And they had other similar comments and ultimately it was accepted in a good journal. All of us see these patients, often they’re elderly, they have pruritus nobody’s been able to handle. What’s your approach first, to diagnosing it. And then when you get to the diagnosis, we’ll talk about treatment.
Brian Kim: Yeah. Essentially you just take a very systematic approach. I think there’s so many things that can cause itch that if you just go down one path and say, I think it’s this, you get into trouble. Initially I try to turn my brain off and just rule out systematically, things that could be obvious, make sure there isn’t some kind of hematologic arrangement, which is an obvious thing and you don’t wanna miss that do a good physical exam, make sure they don’t have lymphadenopathy. They don’t have lymphoma.
Of course though, it’s been low yield for me in my clinic I always get a comprehensive metabolic panel, make sure there isn’t some kind of metabolic arrangement. I’m pretty liberal with the chest x-ray cause we’ve caught enough things with the chest x-ray particularly not commonly, but we’ve caught it enough [00:10:00] times, mediastinal lymphomas. And then after that, it’s really directed by the history.
People always talk about cancer and itch. Do we need to do a head to toe whole body scan? I don’t think so. I think we could just be very comprehensive with the history and if they have particular risk factors, go after that again. Is there a platelet elevation? Do you see their hemoglobin go up? Those are rare things.
At the end of the day, we arrive at a fairly comfortable diagnosis that we don’t know what’s really causing their itch but it’s a pattern that we see. And I think to your point, I think bullous pemphigoid is still rare. I think that you probably have a bit of an enriched population of patients, [laughs]… and I do too.
They’ve seen 6, 7, 8 dermatologists, and that’s a unique population. I’ve caught all sorts of crazy things. But I don’t think that’s gonna be the general experience. I’ve thought about in bullous pemphigoid and we’ve caught it many times. I’ve almost thought to the point where, you know, do a lot of people just have kind of this intermediate kind of BP state, and it’s not really BP. But it’s an aging associated immunologic phenomenon that in its extremist becomes blistering disease.
Do a lot of people sit around with a subset, with this kind of itching, invisible dermatosis. And I think it’s very possible. And I think that the way we have designed these tests is to diagnose BP, true BP, with a sensitivity and a specificity. But that’s not to say that we can’t pick up on these other things. I agree with scabies, my residents will come out and say, it’s not classic first scabies. I say nothing’s classic first scabies.
Cause I’ve been fooled and I’m looking for it. I’ve been fooled number of times, I agree with you. I’ve had people who are about to jump off a bridge and they’re suicidal.
Mark Lebwohl: Right.
Brian Kim: And turns out they had scabies for a long time. I’ve also had such good experience with Permethrin even in people who didn’t have scabies. I wonder if there’s something else we’re doing. There’s a lot of talk about Demadex and things like that. I wondered a bit if there’s something else going on there as well.
Mark Lebwohl: I agree. It’s true. The patient who I couldn’t find classic lesions, couldn’t find a mite or a burrow. We treated with Permethrin and they got completely better. And then, of course we did treat everyone in their family and their surroundings to make sure they didn’t catch it again. I agree many of those patients might not have had scabies.
All I know though, is that it worked and it worked long term.
So I certainly agree with that. I think with the new dipeptidyl peptidase inhibitors, the ones that end in gliptin. Bullous pemphigoid has become much more common. So we probably see 10 cases a year like that, and the patients come in with nothing, no signs other than itch.
Brian Kim: Yeah.
Mark Lebwohl: And we see actually a lot of that and that’s probably why Dr.Stanger ended up recording such a high proportion of patients who had it and your term is probably correct. Don’t call it pemphigoid cause it’s not classic pemphigoid.
But something immunologic is occurring in an older patient.
I actually like the way that you phrase that. So that’s the diagnostic approach and the CMP of course is to rule out liver disease and kidney disease. And usually, that when the patients come in all right.
Brian Kim: Yeah. You do.
Mark Lebwohl: Yeah. We always get it and by the way, we’ve gone over to getting a chest x-ray also and all that’s negative. Most of the time we don’t find anything on that, but every now and then, you do.
Brian Kim: Yeah.
Mark Lebwohl: And it’s a low cost procedure.
Brian Kim: It is.
Mark Lebwohl: We shouldn’t have a major hesitation to use. If somebody has 60 pounds of weight loss, you’re gonna get a whole body CT scan, you’re gonna really look hard for cancer. So patients go through that work up, they end up not having any of the typical things. And a dermatologist more than 100 years ago ended up coining a term which ended up becoming Willan’s pruritus.
And basically to me, that’s a waste basket diagnosis, which means you couldn’t make a diagnosis. So you pinned this guy’s name on it, and you were left with what might become, called pruritus of unknown origin. What’s your therapeutic approach to that diagnosis?
Brian Kim: Yeah. Usually these patients have come in having tried so many things, topical steroids, emollients and antihistamines. But I think the issue with these patients is that, they’ve failed all that. Classical anti-inflammatory agents are generally not terribly effective in these individuals, though it can be, but then your potency has to go way up.
And at that point you’re just mopping up whatever tiny bit of inflammation there is. The things that I like to use, once I’ve arrived at that I like to use Gabapentin, cause you’ll have a lot of patients respond really well to Gabapentin where you won’t eliminate it, but you’ll bring it down to the point where it’s quite tolerable. And then there are a number of patients, if they can do it, it’s a lot of work, light therapy can also take the edge off.
And so it’s not a bad option. Of course, we still want to keep them really nice and moisturized. The idea is that even if they have failed, these other things, these things in concert can add up and they can do quite a bit better. We’ve now moved into these new targeted therapies that do have these broader anti- itch effects than we anticipated. There’s a whole case series out there, have had great experience with drugs like Duplimab.
And it’s because, we believe, it’s a lot of science that we’ve done is that, the drug actually doesn’t [00:15:00] just have an antiinflammatory effect, but it actually does block off at the neural level, some itch, tendencies of the nervous system in a way that’s much broader than just blocking just one cytokine on one receptor. But it actually seems to have, we think, anesthetizing property to these sensory itch, sensory nerves.
Mark Lebwohl: Yeah. And actually we’re gonna get into a discussion of all the therapies that are on the horizon that being one of them. But let me divert a little bit and ask you the question, why is itch becoming so big now?
Brian Kim: Yeah. So I think that itch is becoming very big for a number of reasons. I think one we can start with the science. There’s been some really good science done. And what people have proven, especially in the last 10 years, is that there are itch specific pathways. There are pathways that are very specific. In other words, things that you could hang your hat on and say, that’s an itch mechanism, that is apart from histamine that’s also separate from pain. And there was this historical conception that itch was just another form of pain. And if you could just solve that if you could solve pain better, you solve itch. We knew clinically this wasn’t the case. Most analgesics were not good for it. In fact, the best analgesics like mu-opioids would only serve to exacerbate itch in subpopulations of patients or trigger itch.
So this was already debunked at the clinical level, I think, but the science has already proven this is clearly the case. And then, I think clinically these therapies that are emerging that we thought were just anti-inflammatory actually have a majorly neuromodulatory paradigm that we were being fortuitous, we were to discover in part from our laboratory, but also it was just lucky, that is the case with these pathways.
Evolution has something to do with it. It’s not, I don’t think a complete accident. I think the axes of the immune system that cause a lot of dermatologic, inflammatory diseases are aligned with itch for evolutionary reasons, cause they’re this kind of inflammatory and behavioral response synergizes to fight off warm infections, which is the historical reason for why we have this kind of immune response.
I think what happened when you look at these trials, what happens is that itch resolution was so dramatic. So rapid, unprecedented, and then all of a sudden, all these patients come back and I think my atopic dermatitis patient, they didn’t realize how important itch was until they got better. It wasn’t the suffering that told them how bad it was. It’s actually when they got better, and then they came back and said, why didn’t you have me go on this drug earlier? And I said I was telling you that, but you weren’t hearing it, and then they said, I wish I’d done this earlier. And then once that happened, I think there was a recognition on all parties, all stakeholders that this is really important. This is what patients are really caring about.
Mark Lebwohl: Yeah. I will say with the new treatments for itch, and I’m gonna ask you in a minute to elaborate on them and what’s in the pipeline as well. But that’s one of the reasons you mentioned already that there’s a big case series of patients treat with Dupilumab. Dr. Stanger published, if not the first one, it might have been the first one in Itch of the Elderly, which has been Willan’s pruritus a couple of cases and that’s become actually a routine treatment of ours that, when we reach the end of that diagnostic pipeline and the patient doesn’t wanna come in for light treatments, Gabapentin is not doing enough of a job. Of course we’ve used topical steroids and, moisturization but nothing else is working. We use Dupilumab and it works most of the time.
Brian Kim: Not always, but the majority.
Mark Lebwohl: Not always. Yes.
Brian Kim: Yeah. And it would certainly hold up in a trial.
Mark Lebwohl: Yeah. Yeah. So that’s one biologic, but we now have a new one that’s come along Tralokinumab also very nicely effective. You wanna tell us about the pipeline of what’s currently out and coming?
Brian Kim: Yeah. So it’s literally changing week by week right now. [laughs].
Mark Lebwohl: Yes.
Brian Kim: But we know that, you started with Dupilumab, which blocks both IL4 and IL13 at the receptor level. We’ve got Tralokinumab that just got approval. We have Lebrikizumab that’s both IL13 based. And then we have the JAK inhibitors, we’ve got Abrocitinib and which both got approval. You got Baricitinib. All of these drugs likely have very direct anti pruritic effects in addition to their anti-inflammatory clinically. And we’re seeing a lot of that. And then we have also other agents that are coming from a very different angle. We have these Kappa-opioid agonists which we had Difelikefalin just got approved for uremic pruritus associated with dialysis, which is a big win. That’s truly an itch condition.
Many people think what happens there is that this drug mimics an endogenous opioid, not the mu-opioid, but a kappa-opioid. And then, what happens is it stimulates receptors to suppress it. Essentially what you’re doing is there’s lots of ways to suppress that. One way is to mechanically scratch it. But this, in a sense is a chemical way to scratch and alleviate the itch.
So there’s that as well, but there are also many different strategies emerging that I don’t even know about. It’s every week someone approaches me about a new [00:20:00] approach. You also turned me onto it, over the counter approaches the Dermalid which is actually quite remarkable. There’s a good rationale for why it would work. Cause it has a kind of a heavy metal based kind of property, which may actually clog up some of these channels that are dependent on calcium. So there’s a lot happening. And I think the point here being is that the spotlight has been lit on itch and I’m seeing just, and I think people realize how big of a market it is as well. And now the patients are actually getting heard finally that this is a real thing. And I think we’re gonna see more and more, much more coming.
Mark Lebwohl: Yeah, I agree. And so two things you haven’t mentioned, one of em, I’m glad you didn’t mention, which is systemic steroids and we often will have patients come in on systemic steroids, and for certain conditions they actually work well.
Brian Kim: They do.
Mark Lebwohl: You- but you can’t keep a patient long term on systemic steroids. So we essentially, almost never use them. If a patient’s miserable, to me, it’s sometimes a diagnostic trial that, you know, oh- I did miss some immunologic condition, even, subclinical pemphigoid, which responded to steroid. And I actually never keep the patient on systemic steroid so actually really glad you didn’t mention that. And then, the other one is anti IL31, as biologic which I’ve shown some evidence. You wanna say a bit about that?
Brian Kim: Yeah. Thanks for reminding me. That’s a big omission. And thanks for not letting me miss that. Yeah. IL31 is a big cytokine. It’s the first cytokine shown to directly stimulate a nerve fiber to trigger itch. And so we refer to it as the progenic cytokine levels are high in atopic dermatitis, high in Prurigo nodularis and in fact that’s where the drug blocking at the receptor level, Nemoluzimab has shown success, but there are others in, along the pathway Oncostatin M receptor, which is the co-receptor for it as well. So we have vixarelimab, which blocks the same pathway. And we have a lot coming in and we’ll see where that lands. My personal belief is that atopic dermatitis is not the best place for it. It might be a starting point, but I think that it connects back to a lot of these other itch conditions we’ve been talking about and poking up.
Mark Lebwohl: I’m so glad to hear you say that because I have been approached, as I’m sure you have, with questions from pharma, they have drugs that work for itch, but don’t do anything to examine those lesions and they decide that their target disease is gonna be atopic dermatitis and just getting rid of the itch. And I will say Nemolizumab has a decent response in atopic dermatitis, but not an overwhelming response. I believe I’m blocking the name of the drug. I believe Trevi made it, oh, Serlopitant was studied for HIV dermati-
Brian Kim: Menlo.
Mark Lebwohl: Menlo had it. That’s right. And actually, Trevi has something similar to what Cara has-
Brian Kim: Nalbuphine.
Mark Lebwohl: Yeah. And those, by the way Difelikefalin is approved for uremic Pruritus and works well-
Brian Kim: It does.
Mark Lebwohl: Given intravenously. And you go to clinicaltrials.gov and you’ll see that they’re doing a trial for other pruritic diseases. Like notalgia paraesthetica, send this to your patients. But I will say Nemoluzimab did do well, but, serlopitant failed in atopic dermatitis.
Brian Kim: Yep. And Nemoluzimab did well in prurigo nodularis.
Mark Lebwohl: That’s right.
Brian Kim: There’s a lot going on here. And I think you mentioned most of em, but believe it or not, it doesn’t end there. There’s actually a lot more that people are doing in this area. So yeah, absolutely. And I think that when you start looking at, you go broader and broader into itch, I think we’re going to now see how these Venn diagrams come out in terms of the different therapeutics and where they land and how they can fill different, big niches actually.
So it’s a really exciting area to be in, but I also think that atopic dermatitis, to your point, I think you were getting at this a little bit, there’s been so much enthusiasm for atopic dermatitis that I think everyone’s putting it in that box, but that may not be the best box for all these therapeutics. [laughs] I think, even though that it was the kind of canonical disease, I try to urge a lot of the companies to be a little bit more targeted and tailored to the mechanism of the drug and to the disease and really match it and go quickly forward instead of having to go through the whole ringer of atopic dermatitis first. [laughs].
Mark Lebwohl: Yeah. So it’s interesting, the day will come, I believe, based on this conversation that we will be able to have a patient walk in with an itch and will have literally an algorithm, it’s this kind of itch or this kind of itch, or this kind of itch.
Brian Kim: Yeah.
Mark Lebwohl: Caused by this mechanism, and we’re gonna hit that mechanism and get rid of their itch in the most efficient and effective way, and hopefully, safe way as well, because, you can use systemic steroids in anybody. But we can do a lot better than that today. And I think that in the future, we’ll do much better than that. So I wanna thank you, Brian. This has been a really intriguing, interesting, eye opening conversation. And I am sure it’s not gonna be the last one we have about this. I wanna thank Vial for sponsoring it. And hopefully we’ll have many more conversations about this to come. Thanks everybody.
Brian Kim: Thanks, Mark.
Vial’s mission is to run clinical trials with faster execution and higher quality in order to bring new therapies to market. Vial has over 70 employees and is based in San Francisco, California. Vial partners with Dermatologists to support their research teams and has created a network of over 35 Dermatology clinics. The Vial network has contributed to over 150 trials for many of the leading sponsors in Dermatology having run trials across common Medical Dermatology indications (Atopic Dermatitis, Psoriasis, Vitiligo, Alopecia Areata, Rosacea, Hidradenitis Suppurativa, Prurigo Nodularis among others) as well as Aesthetic Dermatology indications. The clinic network runs trials from Phase I through Phase IV.