Dr. Brian Kim, Sol and Clara Kest Professor, Vice Chair of Research, Site Chair, and Director of Mark Lebwohl Center at the Icahn School of Medicine at Mount Sinai, and Simon Burns, CEO and Co-Founder of Vial, dive deep into the current challenges in SCC trials.
Simon Burns: Thank you for joining us Dr. Kim. I appreciate you jumping on to discuss latest developments in itch and the clinical trials ongoing and how to advise biotech companies on how to run their trials in pruritis. Quickly, we’d like to introduce ourselves Vial is a next-generation CRO helping early stage biotech companies run trials faster and more efficiently using technology and network of clinics. I’m one of the two co-founders and CEO. Dr. Kim, thank you for joining. We’d love to quickly if you could quickly introduce yourself, that would be great.
Dr. Brian Kim: Yeah. Thanks for having me. Brian Kim. I’m professor of dermatology at Icahn School of Medicine at Mount Sinai. Vice Chair of Research there.
Simon Burns: Awesome. Let’s jump in. We’ll do uh, something akin to a lightning fire round around pruritis clinical trials. First off, what are some of the common pitfalls in clinical trial design for pruritis trials?
Dr. Brian Kim: I think there are a number of different pitfalls that you could run into. One of the things that concerns me a lot is the placebo effect and getting a good handle on the placebo effect. We’ve also learned from other clinical trials, itch is very similar to a lot of other patient reported symptoms, such as cough.
And one of the issues that we do see is that you’ll have a good result in a phase two clinical trial. And as you goes to phase three what will happen is you won’t necessarily lose the efficacy that you saw in phase two of the agent, but you’ll see an acquisition of a placebo effect. And what that tells us at least me, is that what’s happening as you go from phase two to phase three, the trial sites, the quality of the trial sites are actually going down. It doesn’t necessarily mean that it’s a bad trial or bad drug. I think a lot of drugs have actually been killed unfortunately because of this. So that’s one of the major pitfalls we see in an itch trials.
Simon Burns: So on some of those challenges in scaling quality and in phase three trials what, if anything, do you think can be done, whether on the CRO on the sponsor side to, to manage quality?
Dr. Brian Kim: Yeah, I think that it’s a challenge ’cause sometimes the field isn’t quite, oh, where it needs to be. So itch is very unique in that chronic itch conditions and criminal trials have exploded just in the last few years. And it’s getting ahead of even the clinical paradigms if the, if I’m making sense. So the success of the therapeutics and targeted therapeutics is go going so fast that it’s leapfrogging ahead of even providers seeing patients with that condition at a high volume, having good experience with it.
So I, I think that it’s just… It’s not like you have a lot of people with a lot of experience in this area and they say, okay, this is what we’re gonna do and this is how we need to design it. And so one of the things I think we have to do as you design a phase two clinical trial is make it really rigorous and make it aim for something where it’s full proof.
So even if say the quality of the trial sites start to go down as you go into phase three, that you’re still gonna enrich and enroll for population that’s very robust. To be concrete there are, for instance, chronic pruritus is defined as itch of six weeks or greater, but in a trial design, I would not necessarily use that as the inclusion criteria. I might actually extend it to three months, six months to increase durability.
So these aren’t people whose itch are just gonna get better. There’s also ways to look at the severity of itch over a long period of time. So is the itch pretty severe for many weeks, leading up to the trial. The other thing that I toyed around with a bit is the idea that you do a run in.
So every… The big joke in chronic itch is that everyone’s been treated with antihistamine and no one responds. So then why not use an antihistamine as a run in two weeks leading up to it to wash out people, particularly you don’t want to be enrolling people who are gonna respond to drugs, you could get at the pharmacy over the counter, for instance.
Simon Burns: That makes sense wash out some of the placebo effect there by makes sense. Tell us more about the recruitment challenges. Here, you mentioned it a little bit, but we’d love to get a better handle on it. How do you advise sponsors and and early stage companies on how to run trials and run them with kind of a faster moment time, window.
Dr. Brian Kim: Yeah, I think it’s tough. I think one of the things that has to be used more for a lot of chronic conditions and I’m speaking from personal experience too is that you need more of a direct to patient communication channel about the trials. So if you completely… For instance, if you have cli-, clinics where they don’t see a lot of patients with, I’m gonna give one example notalgia paraesthetica where you have itching in kind of the middle of the back can keep you up at night, it’s difficult to concentrate.
Those patients aren’t necessarily flooding dermatology clinics but they’re very common. So what do you do in that situation? And you could really try to focus on the clinical trial sites but actually having advertisements out to patients in the [00:05:00] community may actually much more helpful.
And I am speaking for personal experience and that, even though, I had an itch clinic, it actually was very helpful to get the out to the greater community and patients would say, oh, that’s what I have. And they would call in and say is, would I meet criteria for this trial? Something that I’m very interested in participating.
Simon Burns: Great. We’d love to hear from you, what are some of the developments in the field that you did not expect? Any exciting developments in itch that caught you off guard or that made you rethink your model of itch?
Dr. Brian Kim: Yeah, so I think, one of the things that I didn’t really anticipate was I’m gonna be very specific here, but I didn’t really think for instance, that nimolisma, which is an L31 receptor blocker would have such a actually unexpectedly, in my view, really good effects in prurigo nodularis.
For instance, I thought that blocking that pathway, it would have to get really lucky. But I think it actually is a biological phenomenon where that pathway is not so much that you have to necessarily just block that pathway because it’s elevated, but it represents actually an ac-, biological access where those nerves actually get very hyper stimulated and cause a lot of itch and just calming the nerves down is actually a strategy.
It’s not so much that this causes that, but that anything that stimulates this nerve, if you can calm down, it would actually lead to that nerve becoming anesthetized to a lot of other stimuli. And I think this is an emerging therapeutic concept. It in terms of itch therapeutic. So that’s one thing that surprised me. I also think that pathway may actually broaden to other conditions.
And I actually believe that a lot of these, what we’ve traditionally considered pro-inflammatory age pathways may extend to other areas like itch associated with dialysis, which we don’t consider in the same way. So I think we’ll see a lot more developments in that regard.
Simon Burns: There’s a lot going on as you mentioned, I’m curious if you take a wide angle lens and zoom out five years, once the data comes out of these latest trials and in the field digested all where does the top topic or conversation move to? What is the… What is on the podium being discussed about in five years time?
Dr. Brian Kim: It’s moving really fast. If you asked me five years ago where we would be in five years, I would not have anticipated it. I actually predicted we would be here in terms of our conversation about itch in 10 years, if you talk to me five years ago. So it’s already moving really quickly. I think what’s going to happen in five years [laughs] I’m gonna be even more, more optimistic is you’re going to have drugs that are approved for three itch conditions and you may then have actually a drug that’s just approved for just itch in general.
So it’s not gonna be notalgia paresthetica, it’s not gonna be prurigo nodularis, but itch. The way we have for kind of chronic pain. So I think we could conceivably be there in five years.
Simon Burns: On a scale of one to 10, I’m curious to get your lens of what’s going through the clinic today. What are you most optimistic about and what drives that that scale rating?
Dr. Brian Kim: One, 10 being the most excitement?
Simon Burns: Yes, that’s right. What’s your level of optimism of what’s going through the clinic right now?
Dr. Brian Kim: Yeah it’s 10. It’s very exciting. So we’re gonna see… We, we already see it we’ve seen great phase three data for prurigo nodularis that I don’t think I would’ve imagined before that kind of efficacy and low placebo rate. We’ve had a drug approved for uremic pruritis in the context of dialysis now. I talked about nimolisma. I think that’s gonna be very positive as my prediction.
And we now see a lot of different companies redirecting towards itch conditions. So they’re not just saying atopic dermatitis or a rash with an itch, but just itch itself. Can we tackle that? So I think, and this was not even really with trying, so to be clear, this itch field was accidental.
I don’t know if a lot of people are aware of that but a lot of these drugs were actually designed just to be anti-inflammatory drugs to really go off their eczema, atopic dermatitis, but that the discoveries, some of the, that we’ve had a hand in that there’s actually very distinct neuromodulatory properties that these pathways has to embolden these companies to say no, we’re not just gonna try to go after a rash or the it associated with the rash, but we’re gonna go after the edge itself.
Simon Burns: I’m curious if someone were to give you the the a chance on the other side of the table being an investor or running the budget of the NIH, and you had a significant budget to invest in, in, in the future of it, its research where would that budget be going? Say you had 250 million, where would you be deploying it?
Dr. Brian Kim: Yeah, I think the areas that I would go after is if you could break it down is new ways to actually deliver drugs to the peripheral nervous system. Like it’s as a concept. So all the drugs that we take, we haven’t really been thinking of it in terms of compartmental. So how do we get it to that compartment? Are [00:10:00] there ways we can deliver it whether it’s topical through other kind of technological means? I think that’s a big area.
Are there ways we could actually neuromodulate so maybe not even use drugs, are there devices that we could approaches that we can take to restore the nerve health? I think those would be very interesting areas. And then I think a third dimension, and I’ve been talking about this a lot lately is that the science of itch is much, much bigger than itch itself.
And not to… I know this conversation is about itch and itch trials, and I think we have a long waste that this is gonna balloon out to a really big field. If you compared to psoriasis, which is one disease, there’s so many itch diseases, but it gets even bigger than that. That’s just really the tip of the iceberg. What the science is telling us is that the molecular and cellular mechanisms that drive itch are actually are also represented within the body.
So organs like the esophagus, the stomach intestine, the heart, the lung we’re finding that the same pathways exist within the nervous system to those organs. So what we actually think is that itch represents a model paradigm of kind of irritability. And we may have even over called things as being pain. It might even extend to things like fibromyalgia.
What I’m saying is that itches has a bright future, but I think it may also shed a lot of brightness onto a lot of other irritable conditions that we have not really thought about as itch. We went, we thought about them much more as pain, migraine headaches, gastroesophageal reflux, irritable bowel syndrome, intestinal cystitis. If we could revisit them with some of the itch science, I think it could really expand the efficiency with which how we think about say new drug development.
Simon Burns: [inaudible 00:13:29] I’ll give you a series of topics. You tell me first if it’s overrated or underrated and explain why the first is the size of the itch market. Oftentimes viewed as a smaller condition overrated, underrated?
Dr. Brian Kim: The size is always underrated. So we always think it’s smaller than it is. We learned that from atopic dermatitis. So the early days of atopic dermatitis, a lot of people said how big really is moderate to severe? With the advances there it’s shown itself to be a very big market. I think a similar thing is gonna happen with prurigo nodularis. Once those drugs are approved, I think we’re gonna see that it was a lot bigger. I call it the woodwork effect. The patients have given up on conditions that are unmet.
So they, they’re not really on the radar. You can’t get good epidemiology, so then those patients come outta the woodwork and everyone says, oh my gosh, this is so much bigger than we ever thought. That ki-, ’cause what happened with, when we cured Hep C, we were shocked at how many people actually had Hep C, but, they weren’t coming to the providers to get tested ’cause why would they, if there was no treatment?
Simon Burns: So I think that’s what’s gonna happen with that. So I think it’s very underrated. Let’s go back to endpoints. We talked briefly about two phase three endpoints inclusion criteria overrated underrated, the four, four point reduction in itch as the gold standard?
Dr. Brian Kim: Yeah. Itch as an endpoint in general is still a little bit underrated [laughs] as an endpoint but the four point reduction might be a little bit overrated. So that’s somehow become the kind of gold standard, the kind of of what is the clinically meaningful endpoint. We have to keep in mind that these concepts emerge from moderate to severe atopic dermatitis trials really is what I think solidified this dogma. But much a severe atopic dermatitis is a pretty uniquely, in my view, still severe population of people with itch.
So I don’t think that should hold for people say with moderate itch. So I have patients come fly into my clinic from across the country with moderate itch. It’s not the severity of the itch, which is bothering them only. It’s also just the chronicity. Why should someone live with moderate itch day in and day out that still affects their life a lot. So I think from that stand point, the four point reduction we have to revisit, it can’t be for everything. It can’t be for all itch comers. And we need to think about it more.
Simon Burns: And I think there’s a growing growing view that, that itch and its association with dermatology is, is maybe misplaced. What’s your view of overrated, underrated itch and it’s associated with dermatology versus like you mentioned dialysis and other other specialties?
Dr. Brian Kim: Yeah, I think itch wi-, itch having to have a a clear kind of disease always is overrated. The traditional kind of thought was that if you have itch, but you don’t know what the cause is that means that you don’t have a disease to hang your head on. But I think that itch in itself we have patients with chronic pruritis, what we call unknown origin, big problem big problem, lots of patients with it.
But because we couldn’t diagnose them with atopic dermatitis or psoriasis we just brushed it under the rug and said until, we could figure this out. We can’t do anything about it, but I don’t think that’s necessarily true. I also think that itch can be treated independently of its underlying disease. So you can have atopic dermatitis for whatever reason you can’t control it but you can still [00:15:00] treat the itch in atopic dermatitis or the itch in psoriasis.
And I think, again, looking five years ahead, like you said, these are the things we’re gonna start to see. But also, itch in the setting of other medical conditions. Very important. I don’t think that’s actually under-, underrated. I think that’s appropriately rated. When people take cholestatic itch very seriously, they take pru-, pruritus very seriously in the context of dialysis. What I think we have to take more seriously is that itch in and of itself is serious. So it’s not that you have to have a serious disease for itch to be taken seriously.
Simon Burns: And lastly, for the segment that the number of conditions of itch are we appropriately are we at the early stages or the late stages of our deep understanding of the number of conditions of itch? Is our view today appropriately reading the number of it conditions or is there many more to, to find out?
Dr. Brian Kim: So there, there are lots of itch conditions. And I think that we still are underestimate how many it conditions there are. In fact there are new itch conditions emerging. A sizeable percentage of patients who are undergoing treatments, for instance, with checkpoint inhibitors for metastatic cancer will develop itch or a rash even associated with itch. That’s very difficult to treat could even lead to patients coming off treatment.
So they’re even new itches like that, that we have no idea how to treat ’cause you’re not gonna give them an immunosuppressant ’cause the whole point was to boost their immune system. So in that case you have to treat the itch. You don’t want to suppress the immune system or anything like that. And I think it’s much, much bigger, but to get to there, I think we have to believe that these conditions are distinct and we’re starting to get there.
There was a day when everyone thought it was just one itch. So it didn’t matter what kind of disease you had. It was all just one itch. I don’t think anyone believes that anymore. So that’s a big step forward and it’s just now trying to figure out which ones we can go after development treatments for and target
Simon Burns: No more. Thank you Dr. Kim, what did we miss asking you, what should we have asked you about the state of the future of, of each research?
Dr. Brian Kim: Gosh I, I think we’ve covered a lot of ground. I think it’s I think the what, I think what we need to do is catch up to the therapeutic developments. So what we really need to do is for providers to really embrace itch now. There, I think we’ve been shy because of the lack of therapeutics appropriately in some ways because there weren’t good therapeutics.
We weren’t really trying to run towards itch as a condition that we would embrace. So I think as a field whether it’s dermatology or even feels like allergy we have to now embrace it, really open up the doors to get those patients in, better understand a disease, better understand epidemiology, better be able to better execute clinical trials from phase two to phase three. And also if the drug is approved, get the drugs out to the patients.
Simon Burns: Great. Thank you for your time.
Dr. Brian Kim: Thank you.