"Perspectives on Treatment Developments for Psoriatic Disease" Transcript

Max: My name is Max Blitstein and today I'm excited to discuss the latest treatments in development for psoriasis with one of the world's leading experts in dermatology, Dr. Steven Feldman. Dr. Feldman is a Professor of Dermatology, Pathology, and Public Health Sciences at Wake Forest University School of Medicine. He specializes in the care and treatment of people with psoriasis and other skin diseases and is active in clinical research for the development of new dermatologic treatments. Dr. Feldman is a former member of the Medical Board of National Psoriasis Foundation, and in 2019 received the Foundation's Outstanding Educator in Psoriatic Disease Award. Welcome Dr. Feldman. It's a pleasure having you back on Psound Bytes™.

Dr. Feldman: Oh, it's my pleasure, Max. Thanks so much for including me today.

Max:  Yeah. So before we start, I wanted to find out why did you go into dermatology with a focus on psoriasis? Why the interest in this disease?

Dr. Feldman: I think having had poison ivy as a child led me to, I mean, I've been practicing over 30 years. I've never seen anybody with poison ivy as bad as what I had when I was a kid, and that probably contributed. But just the idea of being able to do research and see patients. Dermatology seemed very, very suitable for that and that helped. And then I got hired at Wake Forest University to do test tube research mostly. They didn't really want me seeing many patients. They wanted me to focus on the lab. They only gave me a half a day a week of clinic to do, Friday afternoon of course. And after I'd been there a year, our awesome Psoriasis Specialist, Dr. Michael Zanolli, truly one of the greats, and he left. And I'd been sending all my psoriasis patients to him. And so the next day I became the psoriasis specialist for three states.

Max: Well, that's amazing. We're so glad that you chose to treat patients with psoriasis. What key pathways do you see as being important in the development of new treatments for psoriasis or psoriatic arthritis?

Dr. Feldman: Yeah, you know, I've been blessed to have ridden an incredible wave over these past 30 years of new treatments for psoriasis and our understanding of the immune system has led to new treatments or maybe the development of new treatments has led to a better understanding of the immunology of psoriasis. Could work either way. Theres over 100 genes that are associated with psoriasis, so presumably targeting any one of those genes could represent a psoriasis treatment. Early on, I had relatively nonspecific treatments like methotrexate and cyclosporine. It could make psoriasis better by turning down the immune system causing psoriasis. But those drugs would inhibit the immune system in relatively nonspecific ways. Now we know that psoriasis involves Interleukin-23, as a key signaling molecule in the immune system that activates immune cells to make another signaling molecule, interleukin-17. And that pathway goes through intracellular signals like TYK2 (T Y K2). And so this pathway is fundamental to psoriasis and if you block this pathway, you can make psoriasis better and if you can block this pathway without blocking other stuff, then you can have extremely effective and extremely safe psoriasis treatment. So this essential interleukin-23, TYK2, IL-17 pathways seems to be a real sweet spot for developing new psoriasis treatments.

Max: So I've actually had psoriasis since I was about 10 years old and was diagnosed with psoriatic arthritis in my early 20’s. I'm now 34. Over that time, I've tried and seen a lot of treatments released for psoriasis and psoriatic arthritis. You mentioned Interleukin-17. There's a lot of excitement about Bimekizumab, which was released last October. In February of 24, Bimekizumab received approval for the treatment of active psoriatic arthritis. Why is this latest addition to the biologics for psoriatic disease so important, and how effective is Bimekizumab for both psoriasis and psoriatic arthritis?

Dr. Feldman: We have several drugs that block interleukin-17 already, but there's different forms of interleukin-17 and two of the ones we have Secukinumab and Ixekizumab block interleukin 17A. Bimekizumab blocks interleukin-17A and interleukin-17F, and both appear to be important in psoriasis, and so bimekizumab seems to be even more potent for psoriasis and psoriatic arthritis than the existing treatments. Now normally I'm not terribly excited about new drugs because I don't know what the side effects are gonna be and because this drug blocks more interleukin-17 than the other ones, you wonder what kind of side effects are we gonna see?

Max:  Yeah.

Dr. Feldman: The older interleukin-17A blockers have an increased risk of developing a yeast infection. So maybe it's a, the chance of developing yeast infection is so low that maybe the tenfold increase risk gets you up to a risk of maybe 1 in 100, 1 in 50 with the older drugs. But the Bimekizumab gets you another tenfold on top of that roughly and so maybe one in five, to every one in 10 people will have a yeast infection. But if you have yeast in your mouth, you can take an anti-yeast lozenge, or you could take an anti-yeast pill if you're having a yeast infection in the vaginal area or something like that. So it's not that big a deal. The other limitation of IL-17 drugs is they seem to either cause or unmask inflammatory bowel disease, which psoriasis patients are at risk of in like 1 in every 300 people roughly, maybe it's one in 500. It's not common, but it happens and I was worried that, gosh, you're blocking even more of IL-17 is there gonna be an even bigger risk of that with Bimekizumab. Now you mentioned that it was approved in 2024 and that's true in the United States. But the U.S. FDA was slow to approve this drug, and I think it's been approved in Europe for three or four years already and we haven't seen as far as I can tell any epidemic of inflammatory bowel disease. And so I think you do get added umph without other than the yeast infections you know added much in the way of added risk.

Max: So Dr. Feldman, are there any oral interleukin-17 agents in development for treating psoriasis? Pills could be a lot more easy to take as a medication as opposed to injections.

Dr. Feldman: Yeah, there is an oral interleukin-17 in development and I imagine it's gonna be very effective if it blocks IL-17, and I imagine patients are gonna love it because patients will often choose an oral that is not nearly as effective as an injection just to avoid injections. My only concern is that inflammatory bowel disease issue and I don't know how common it will be with the oral. I just worry that gosh, if you see inflammatory bowel disease with the injectable, are you gonna see even more inflammatory bowel disease when you're delivering the drug through the bowels? It just remains to be seen. I'm in no hurry to use it in people who don't need it. In people who desperately need it, yeah, I'd be glad to prescribe it should it come to market. And then once I've had more experience with it, been around a while, we can make sure there aren't any unknown side effects then I'd be more likely to be thinking about it as more of a first line treatment.

Max: You mentioned IL-23 earlier as an important pathway. I've heard there's also an IL-23 oral agent, J&J 2113, currently in clinical trials. Can you discuss how this treatment works and how effective it is as an oral agent?

Dr. Feldman: You know, it's hard to get me excited about new drugs and a lot of things in development for psoriasis and both the topicals for milder disease and systemics for the more severe patients and nothing really excites me - except for this new oral IL-23 inhibitor. And I say that because I just love interleukin-23 blockade because, the genes for the two subunits of interleukin-23 are genetically linked to psoriasis. The gene for the interleukin-23 receptors, genetically linked to psoriasis. It seems like you're getting at the root cause of the disease. The drugs, the injectable drugs that we have that block, interleukin-23 for psoriasis, psoriatic arthritis, maybe even inflammatory bowel disease at some point. Those drugs seem extraordinarily effective, especially in the long run. Maybe not be as fast as the IL-17 drugs, but in the long run they seem exceptionally effective and they seem to have little to no risk. Some of them are approved for the treatment of inflammatory bowel disease, so I don't have to worry about them causing inflammatory bowel disease and they don't seem to cause yeast infections. They seem, hard to believe basically to me, completely safe. I mean, yes, there were adverse events in the studies, but you saw the same adverse events in the placebo group.

Max: That's pretty amazing.

Dr. Feldman: Yeah so that's for the injectables. Now for them to come out with an oral, to have an oral that does this. This is not perfect. What would be perfect would be a no risk, one time cure for the disease, OK. So we're not there yet, but to have an oral that has all the other characteristics of the efficacy and safety of IL-23 blockade is something I'm really enthusiastic about.

Max: Well, that's great to hear. So with the success we've seen of Deucravacitinib, more focus has been placed on developing other oral TYK2 inhibitors. Do you have any updates on potential upcoming TYK2 or JAK inhibitors?

Dr. Feldman: There are a couple of other TYK2 inhibitors in development. And gosh again the genes for TYK2 is genetically linked to psoriasis, psoriatic arthritis, and inflammatory bowel disease. So blocking TYK2 makes a lot of sense. But blocking TYK2 doesn't just block the IL-23, IL-17 pathway. TYK2 is also involved in mediating the signal from interferon. And interferons are important for controlling viruses and so when you block TYK2 with Sotyktu (Deucravacitinib) you get a small increased risk of having latent viral infections pop up. So viruses on the herpes family there seems to be some increased risk of this. Maybe like one in 100, which gosh one in 100 might actually sound scary. 99 times out of 100, we don't see it, which sounds better. And for shingles, there's a vaccination. And for herpes simplex, I mean it doesn't cause you to get herpes simplex, but if you had herpes simplex, you could have a flare of it. There's a good pill valacyclovir, great treatment for it. So pretty minor issue unless some years from now we discover that after tons of people were treated, other worse latent viruses pop up. But so far it looks very safe and Deucravacitinib seems to be about twice as effective as apremilast or Otezla. But I guess my concern is with the newer TYK2 agents in development they may block more TYK2 than Deucravacitinib does and if so hey, the good news is they could be even more effective. Deucravacitinib seems to be about as effective, more effective than etanercept (Enbrel), less effective then adalimumab (Humira) in the short run, but maybe in the long run it would be comparable because you wouldn't get antidrug antibodies to it. And so if you could make a TYK2 inhibitor that blocks more TYK2, maybe you could get those higher levels of efficacy like you see for secukinumab (Cosentyx), or maybe the IL-23 blockers. But my concern is if you block more of that TYK2, you will be blocking more of the interferon and maybe you will see more of a recurrent virus signal. So far, the drugs look pretty safe. These new TYK2 inhibitors that are in development but large numbers of patients haven't been treated for long periods of time. So I really don't know what the safety of those will turn out to be.

Max: That is really good news to hear that more oral treatments are being developed to treat psoriasis. Biologics and newer oral treatments have really revolutionized treatment for many people with psoriasis including myself. Are there any other promising injectable interleukin-17 or interleukin-23 inhibitors in development?  

Dr. Feldman: Yes, there's other interleukin-23 molecules in development. I don't know that they’re any better than what we have, but you know, people can eventually become immune to their treatment probably because of anti-drug antibodies and when that happens it's nice to be able to switch. Currently we have at least four drugs that block Interleukin-23. We've got Tremfya, Skyrizi, Ilumya, and the older drug, Stelara - it blocks IL-23 along with other things.  So there's options to switch among them, and if new ones are developed, we'll have more options for people who lose efficacy to a therapy. The other thing that's in development are biosimilars. We have adalimumab a biosimilar for Humira now, and a biosimilar for Stelara, ustekinumab is available. And on the one end I'm not terribly excited about them because they're not gonna be able to help people I can't help already because I can prescribe the branded Humira and Stelara for people, but on the other hand patients who are on one of these drugs or the other, they ought to know about these biosimilars that are coming because the packaging's gonna look different, the cost to the insurer is gonna drop, and eventually that hopefully will be translated into lower health care premiums. And the biosimilar should be just as good. They're similar to the originator products, otherwise they wouldn't make it onto the market.

Max: So biosimilars have been in development for a while with a number being released lately for Humira, as you’ve said. Are there any other biosimilars in development? You mentioned Cosentyx earlier. With the patent expiring in ‘27 and ‘28 and more biosimilars for Stelara. So curious about that.

Dr. Feldman: Yeah. So the biosimilars for Stelara are hitting the market already, I think. And the ones for Humira are already far enough along that insurers are telling me what they pay for. If a patient wanted to pay for the Humira out of their pocket, the 10s of thousands of dollars a year, I guess they could. But you know, if the insurer says we cover this other one, then pretty much we're going to go with that other one.

Max: Yeah. So I appreciate that answer. I'm curious about what are resident memory T cells and how important is the development of therapies targeting resident memory T cells in the pathogenesis of psoriasis?

Dr. Feldman: You know the immune system is so complicated that it is completely inscrutable, and it's really hard to predict from our understanding of the immune system what’s actually gonna happen in patients. The best example of that may be when IL-17 drugs were being tested, they worked for psoriasis. They worked for psoriatic arthritis, so we assumed that they would work for inflammatory bowel disease and two of them were tested in patients with inflammatory bowel disease and the patients did worse, then the patients who got placebo. It was just totally unexpected. But then after it happened, the gastroenterologists, the GI doctors, they came up with some theory based on the immune system “oh yeah, we should have known because it's important for the bowel barrier function or something”. Look, the resident memory T cells are important we think because they will once they're trained to cause psoriasis, they're gonna keep causing psoriasis and in theory, if you get rid of them, then maybe you could cure the psoriasis. And I think it's very reasonable to think that maybe if we give patients enough of these really super great psoriasis treatments that we have now up front, in big enough doses to make those resident memory T cells disappear or at least forget about psoriasis that we could induce a cure or at least a long term remission. And that's good.

Max: That would be amazing.

Dr. Feldman: Yeah, that would be amazing. It would be great and it's a great theory and we should test it, but is that gonna happen? Yeah, I don't know.

Max: And Dr. Feldman, are there any new developments for topicals?

Dr. Feldman: We've got a number of topicals that have hit the market and there could be more topicals in development. The roflumilast foam is very safe. There's a cream version. There's tapinarof, is another nonsteroid agent that's very effective for psoriasis. Possibly has some remittive properties, although I don't know that we've compared it head to head to see whether the remissions are more than with other things yet. But I am not bullish on new topicals because of three things. Number one, patients aren't great about putting topicals on. Number 2 patients aren't great about putting topicals on, and number 3 patients aren't great at putting topicals on. Now I've done studies where we gave patients topicals to put on and we put computer chips in the caps that would record the day and time they open and close the containers and their use of the medicine drops really quickly and the long term adherence was so bad, so abysmal that when we published the one year adherence data on use of a topical high potency cortisone medicine in the British Journal of Dermatology, the British Journal of Dermatology let us put the word abysmal in the title of the paper. So clobetasol is extremely effective at clearing up psoriasis and it doesn't work if you don't put it on and if it's not working cause you didn't put it on, is the next topical going to work?  I don't know. I don't, I don't think so. So you know, I would be more excited if a company came out with a pill, that was safe and effective and low cost and approved for patients with mild psoriasis. I think there's much more unmet need for patients who have limited areas of psoriasis then for the people who are covered, cause for the people who are covered, we talked about all these different products. You know it would be nice to have pills that you could use for people with mild disease. Otezla, Apremilast is approved for all psoriasis now, but it's not the most effective drug. It's got some annoying side effects. It's not particularly low cost, so it's may not be the idea. I think it works about as well for mild psoriasis as it does for more severe psoriasis. If the patient's happy with it, great, but I think most people with really extensive psoriasis want their psoriasis to get a lot better. I think most people who come in with just a few spots on their elbows and knees and legs, they want them gone. I think women who have spots on their legs, you get those spots 90% better, they're like I still got spots. I still can't wear a short dress. So it would be nice to have really, highly effective, easy to do treatments for psoriasis and the new topicals, yeah, if you'll use the foam, great. If you didn't use your clobetasol because you were afraid of the steroid side effects, yeah, these non-steroidals are good treatments and use them well to get the maximum benefit out of them.

Max: It sounds like it. Any news regarding the A3 adenosine receptor piclidenoson?

Dr. Feldman: Yeah, that's another pill option for psoriasis and it's not one that I'm terribly excited about because it may inhibit the immune system in a more general way. It may have effects on the heart.

I think you have to get an EKG when you're go on this drug. I mean, I am so spoiled by drugs that block interleukin-23, even IL-17. Those drugs are so effective and so safe, and they don't do other stuff. Back in the 1990’s when all I had was methotrexate and cyclosporine, if you had told me, hey, I got a JAK inhibitor for you like the ones approved for psoriatic arthritis, the Rinvoq (upadacitinib), tofacitinib (that’s Xeljanz) approved for psoriatic arthritis. If you told me you had those drugs back in the 1990s that affect the immune system and don't destroy your liver like methotrexate does, and don't destroy your kidney like cyclosporine does, I would be ecstatic. I'd be like, oh, this is awesome. But now I'm anchored on drugs that are so safe like IL-23 inhibitors that are inhibiting the psoriasis pathway and they don't do much of anything else that having relatively nonspecific effects on the immune system are no longer exciting for me.

Max: So we touched on this a little bit earlier, but we know people with psoriasis are at a higher risk of developing related conditions. Do you think it's possible to develop treatments that can address both? Say for example, diabetes and psoriasis.

Dr. Feldman: Yes, I think there's some evidence that weight loss can make psoriasis better. It's not the strongest evidence. But I think there's drugs now that will help you lose weight and make your diabetes better, and I think those drugs may make psoriasis better too. Sometimes I wonder though, if the studies where they put people on a really super low calorie diet and regiment their lives and show that there's weight loss and psoriasis gets better. If the regimenting of the person's life results in they’re being more compliant with their topical psoriasis regimen, and maybe that's why their psoriasis gets better. It's hard sometimes to tease out the behavioral effects from the effects of the drug.

Max: So thank you, Dr. Feldman. There are so many treatments continuing to be developed as we gain a better understanding of what causes psoriasis. Are there any other treatment developments that we haven't covered?

Dr. Feldman: Yeah, one that I shouldn't miss - ultraviolet light treatment. Before we had even methotrexate and cyclosporine we were treating people with ultraviolet light and it's a good treatment for many people with psoriasis. You can come to the office three times a week and get light treatments, and that's probably the least convenient and most expensive way of accessing light therapy. If you live in a place where you can get sun, that's another good option. The latest research, work done by Joel Gelfand out of the University of Pennsylvania. Joel's an amazing researcher. He's done so much in the area of psoriasis. But he led a study of home light versus office light for psoriasis and the home light worked just as well as office light treatment. And I think subjectively it worked even better. Patients were happier with home light therapy than with office light treatment, and I think, man, if I was an insurer, I would strongly be trying to give psoriasis patients home light units just because a home light unit would cost far less than some of these awesome biologic treatments we've been discussing.

Max: So out of all the treatments in development we've discussed, which is the one that excites you the most?

Dr. Feldman: Oh, I think that was obvious. The oral IL-23 inhibitor seems like number one and an oral IL-17 would be a close second, especially if it proves not to cause too much in the way of inflammatory bowel disease.

Max: Do you think it's possible for a cure for psoriasis to be found and could treating psoriasis early in the disease process lead to a cure?

Dr. Feldman: You know I became the Psoriasis Specialist at Wake Forest in 1992 and when etanercept came out, I think around the year 2000 or early 2000’s I thought I am never gonna see another quantum leap forward like that again in my lifetime. And then there was Humira, which was more effective than etanercept, Enbrel, without much more in the way of side effects. And then I thought, OK, I'm done and then Stelara came out. It seemed completely safe and more effective than Humira.  And then you got Secukinumab (Cosentyx) and Taltz and then another quantum leap forward, IL-23 inhibitors and now the potential for an oral IL-23. I mean, I I guess I think it's possible we will see a cure. I think treating it early or treating it aggressively enough with these drugs.  Andy Blauvelt's been doing some work giving people high doses of interleukin-23 and marry that with a little IL-17, and possibly something else. I think we might be able to. There's certainly hope, yeah

Max: This sounds so promising for a patient suffering from disease, looking forward to the future of treatment for them. But I wanted to thank you Dr. Feldman for such an exciting discussion today. It's really good to be aware of what treatments are in development. This hits really close to home for me as I've taken quite a few of the medications we've discussed today. Do you have any final comments that you would like to share with our listeners today?

Dr. Feldman: Yeah, I got one final comment for y'all and that is a great way to stay on top of developments in this field is to be a member and use the resources of the National Psoriasis Foundation. Just go to psoriasis.org. Now I know everybody listening to this already knows about the Foundation, but the people who aren't listening need to know about it. So you might share this podcast, share information about the Foundation, especially if you found it helpful with people on social media.

Max: Thank you again Doctor Feldman for providing such an amazing update on treatments in development and for being here today. And for our listeners as Dr. Feldman mentioned, if you know someone who could benefit from listening to today's episode about upcoming treatments for psoriasis, please share the episode link with them. You can continue to learn more about biosimilars by contacting our Patient Navigation Center at education@psoriasis.org to receive a free Biosimilars Quick Guide. And finally, thank you to our sponsor Bristol Myers Squibb for their support of this Psound Bytes™ episode.