The University of Nevada, Reno School of Medicine

MD, MPH

Identify the role of IL-17A and IL-17F inhibitors across multiple disease pathways and how therapies target this pathway 

Discuss the benefit-risk profiles of IL-17 inhibitors for the management of psoriasis 

Describe strategies on how to work as a multidisciplinary team to individualize patient care with IL-17 inhibitors 

Psoriasis

On-Demand CME Videos

Taking a Deep Dive Into the Role of IL-17 Inhibitors for Psoriasis: What do PAs and NPs Need to Know? Seminar-in-Depth Online CME Activity

Taking it around. And hopefully we'll be able to incite some knowledge about the aisle seventeen s and psoriasis. There we go. Okay, so the clicker is right here. Excuse me. Thank you. And April and I will. I'm actually very honored to be on the same stage with April, who is an expert in this condition. These are objectives here. We want to talk about the aisle seventeen s and about the mechanism action of il 17 a and 17 f inhibitors. Talk about the risk benefit profiles, and talk about how to work in a multidisciplinary way to individualize patient care. So April is going to start off by talking about the role of il 17 in inflammatory diseases, and then we'll go from there. Great. We ask a lot of you, take the quiz, and then also absorb the information at the same time, but really appreciate your energy and attention. So we're going to dive a little bit into the science for the first section, and then Dr. Paris is going to talk about some of the clinical data, and then we're going to bring together with regards to the clinical relevance. So why do we care about il 17? So, IL 17 has been implicated by in a number of different inflammatory conditions, not only in the skin, but also, importantly, in the joints. And the three conditions that are relevant to what we practice is psoriasis, psoriatic arthritis and hydranitis separativa. And I'm going to show you a little bit with regards to where il 17 acts and how that matters. So, when we look at the psoriasis pathogenesis, for example, we have il 23, which is important for the differentiation of the adaptive th 17 cells. So the blue cells on the top. And then we also, however, have contributions from the red cells, which are those innate lymphocytes. So they both produce il 17. They produce il 17 a as well as il 17 f, which then lead to the skin inflammation that we see clinically. So, not only is this seen in the skin of patients with psoriasis, the same process is also seen in the joints, as well, with bone remodeling, as well as cinovitis, typical findings that we can find in psoriatic arthritis. So what we've noted over time is that IL 17 A as well as IL 17 f, they share some overlapping biology. They're cousins of one another. In fact, they share about 50% similar homology. And both adaptive as well as immune system as well as the innate system, can be responsible for their production. So you can get AA homodimers, FF homodimers, or AF heterodimers, and they can signal through a number of different receptors. So here, the AAF and FF, they signal through one set of receptor. Now, the IL 17 family also has other members as well. We have IL 17 e and its role is still being elucidated. And then we have IL 17 c, and then IL 17 c is very important for the amplification of the cascade. Now, this is important. So what we're looking at on the left hand side are psoriasis, lesions, and the expression of IL 17 A and IL 17 f compared to non lesional psoriasis. And what we see is that we know a is very important. We already have segukinumab and execismab against a, and then the a level is actually relatively, compared to f is less abundant. So we actually have more abundant levels of IL 17 f in psoriasis. Skin on the right hand side, what we see is a level of IL 17 f in HS lesions. And this is something I think we've really come to appreciate, something novel, that IL 17 f is present at high levels in HS lesions as well. And here is a summary of the biologics that target IL 17 axis with regards to what has been approved and as well as what is emerging. So, as you can see here, sekukinumab and ixicismab have the same mechanism action focusing on inhibiting IL 17 A. Bimikizumab, which is an emerging agent. It targets both a and F. Brodalamab, which is also approved for psoriasis, it's a receptor inhibitor. It inhibits IL 17 receptor alpha, and by doing so, it inhibits the actions of signaling pathways of AFC. So with that bit of science as a background, I'm going to turn the podium to Dr. Parasar. Okay, so, real good review of the biology of the drugs that are out there now. I want to talk to you about the clinical safety and efficacy data, and I'm going to do it in a little different way than you're used to seeing. These are the four agents that I'm going to speak about. I want to emphasize that vimakismab is not FDA approved at this point. It's under review. Brodalumab, ixicismab and psychicinimab are all approved. You know, we don't like to compare clinical trials, one clinical trial against another clinical trial, when they weren't a head to head comparison within the same trial, but yet we all kind of do that. And I'm going to take the liberty to sort of do that in this presentation, because all of these il 17, inhibitors for psoriasis had very, very similar clinical trials. They all enrolled adults, some also enrolled children, but all adults, the patients had passes a BSA of 10% or more and a passy of twelve or more. And they all had an IGA of moderate or severe. In that respect, they were pretty similar. So let's talk about these in alphabetical order. Bimikizumab first, because it's the first. In alphabetical order, it is. Again, I'll just emphasize for the last time, this is not an FDA approved. The BLA has been submitted, it's undergoing review. We don't really even know what the approved dose is going to be, but we do have some ideas about that. So there were several studies, and I'm going to throw together the results of different studies, but I'm going to try to make a point. The BIMIC hasemabs start off with this comparative study, double blind study, between the active drug and the placebo, and eustachinumab as another active control with a 16 week primary endpoint, and then continuation for week 52. And so this one we can say, yes, there's a valid, statistically significant difference between the efficacy, the passing 90 and the IGA one clear, or almost clear, in the patients who use bimachizumab versus eustachinumab. And this was because it's the same study, randomized control, good statistical significance. If you look at the passy 75, there's also the same spread. First was passy 75 was on the left side. On the right side is passy 100. And look at that, 58% passy 100. We haven't seen that before, really, in anything, in any of the psoriasis drugs. Secondary endpoint of bimikismab 90, Pazi 90, and the IGA one over a year, basically a very slight decrease in the efficacy. But I want to make a point with this one. If you look at week four already, the Bimachismam group is having a 43% improvement reach, passing 90, 49% IJ of zero one works very, very quickly and it stays effective over a 52 week study. In a long term side effects on biblicismab that we want to look at, I could show you this same slide and tell you it was from any of the biologics, because it really would be any of the Il 17s, rather. And these are all nonspecific ones. If we look at the common ones that are important, we're going to see down near the bottom, candida and candida. The presence of candid infections, mostly mild, some moderate, no real severe candidate infections in any of the biologics. But that's the IL 17 adverse event of interest. Now, they also did in head to head studies not only the eustachinumab that I showed you, but also adelimumab and secukinimab, and showed in a blinded study, increased efficacy in terms of looking at the passing 90 at week 16, which, remember, wheat 16 was not the primary endpoint for the other biologically other IL 17s that we're talking about. Okay, Bimacam is again looking at adelinemab, secukinimabs, igA, one at wheat 16, and for long term three years, it seems to not lose very much effectiveness. The people who achieved apacia 100, still 60, some percent all the way out to week 152 adverse events. Again, this is one of the other studies. And there's Candida again, as the one was the one of significance. All right, let's talk about the others. Bridalumab, the other one, that's another one that's currently on the market. There were two primary studies, placebo controlled registration studies, and again, compared to eustachinumab. Everybody wants to beat up on that, on that one. And you can see that the bridalumab people achieved passive 75 at a rate of 85% with the higher dose at week twelve compared to eustachinumab. And the lower dose, bridalumab, which didn't do quite as well. Long term extensions out to week 52 and beyond seemed to maintain most of its efficacy in both the higher and the lower dosage. Just so very briefly, there were in the phase two study some exacerbating based on existing Crohn's disease. And we know that that's one of the issues with il 17s, inflammatory bowel disease. Candida again, but no neutropenia, some neutropenia, no mace. Bedalliumab has a boxed warning for suicidal ideation and behavior. We can argue whether that is justified or not, but it's there. And there is a REMS program for bridalumab that you have to sign up for exechismab, another currently market drug. Complicated study, but I'm really focused on the induction period. That first twelve weeks were the primary endpoint of two doses of ixicismab versus placebo. And both of those doses showed obviously significant improvement over the placebo in results of passing 75 9100. And the SPGA just focusing on the passing hundred for a minute. A third of the patients, a little more than the third got the passing hundred. That's what we want to see. Nowadays, passing hundred is a realistic goal for most patients and slight decrease of efficacy over time, but not much. Again, the people who were clear through week 60 longer term studies, it stayed about the same as it was at the primary endpoint. So it did not lose a whole lot of efficacy over time. Here's the adverse events from one of the exechismab studies. And where is it? Again, it's Candida. There is the one that shows up as something of significant importance. All right, long term exechismab out to week 60 and in a different study. Again, just to make the point that the pasi 75 rate maintained itself all the way through till the end of the study in week 60, as did the passy 90, and as is the PGA, zero or one. So good improvement. The primary endpoint, long lasting improvement with ixacizumab. Finally secidumab, the other last one, very complicated slide. Don't even look at this except I want to make the point that this was studied in double blind fashion against itself and against the tannercept and in two different doses of secukinimab. Looking at the iga of zero one, passing 90 and passy hundred responses, you can see that again at passy hundred, which is what I always focus on now, is passing 145% with secukinimab. Passing 90, 76% Iga clear. Almost clear. 78. Week 52 pretty much maintained efficacy over that amount of time. Passing 90 results in the passing hundred and iga one. Again pretty much response over time and again, long term result. This was a DLQi which I didn't report on the other ones, but that remained as well about the same as it was at the primary endpoint. Adverse events. I could show you the same table again and look at the bottom last one, candida. That is the major adverse event of the aisle 17s in general. And looking at the rest of them, looking at the other serious the mace events and the inflammatory bowel disease, some one case actually of inflammatory bowel disease, mace events were not much. So this is a slide on the approved dosing. Now for the vimicismab. We don't have an FDA approved dose. What I've listed here for you is the dose which is approved in the EU where it has been approved for a while and this data is available on the handout that you get, but not for bimbikism because that's not approved in the US later. Until later, maybe later this year. We hope so. I will turn it over to April to bring it home about the real world use. So I'm going to talk a little bit about real world applications. This is a slide that I kind of put together, really think about some of the common shared characteristics among IL 17 inhibitors. So they are overall great in terms of the skin psoriasis efficacy, as David has shown, they also have very good efficacy in psoriatic arthritis. So this is one of their key strengths, not only peripheral psoriatic arthritis affecting the hands and the feet, but also axial spine psoriatic arthritis. They have pediatric dosing for secucunumab and ixicismab for six years and older for psoriasis. Where you want to avoid IL 17 inhibitors are those with a personal family history, a personal history of inflammatory bowel disease, and also there's low rates of oral candidiasis, as David has pointed out. In general, I will say that oral candidiasis is not prohibitive. Most of them can continue their il 17 with oral candidates treated with a few days of oral fluconazole. And also one thing that's interesting, based on the literature, is that you can actually switch from one IL 17 inhibitor to another IL 17 inhibitor. So this is a study by Dr. Lebwell's group that looked at people who have failed ixicizumab and failed psychicinumab. And if you put them on brodalamab, as you can see, that patients, about 76% of the patients would still achieve posey 75. Could it be because brodalamab is a receptor inhibitor and therefore is inhibiting other pathways? Possibly, but something to consider, and I'm just going to show some of the strength of IL 17 inhibitors is really inhibiting radiographic progression. And just for 1 minute, I'm going to pretend, have you pretend you're radiologists. So if you look at the left hand side is a normal hand, and on the right hand side is a patient with psoriatic arthritis. So you'll see the joint space is narrowed and joint space narrowing is a bad thing. And they can be quite progressive in our PSA patients. The other finding in PSA is hand. So this is the same picture of someone with PSA. And so what you see, radiology calls these mouse ear signs, where you get erosions, or maybe in Orlando we'll call them Mickey Mouse signs. So you get these erosions that can progress over time. And that's what we try to avoid as well. And what IL 17 inhibitors do, and all of them both approved as well as emerging, what they do is that they are best in terms of halting these radiographic progression, in terms of what I showed you, also, we have data showing that this is with secuchinumab. This is the only trial currently that's showing IL 17 inhibitors being very effective in terms of treating axial psoriatic arthritis. And those are the patients who wake up with a stiff back as their primary manifestation of their PSA in the morning, and it takes them a while to move. All right, what's exciting in the horizon is our IL 17 inhibitors for hydranita separativa. I know tomorrow you're going to hear a talk on HS, but what we see is that this is secukinumab with regards to treatment of patients with HS, as you can see, effective in terms of achieving high score of 50, so at least 50% improvement. So something we are looking to see coming down the pipelines. So secicinumab actually has already been approved in Europe for the treatment of HS not yet approved in America. I feel like usually we get approved in the US, always first. And then recently we've seen this kind of reversal of it being approved elsewhere than in the US, but very exciting. Also, I showed you earlier about IL 17 F and its role in terms of HS. And here we're looking at bimakismab, not yet approved in the US for any indication currently. But this is bimikizumab data in HS as well, showing really great efficacy in this area, too. So very exciting. So now we're going to have, in addition to adelemumab, hopefully very soon, both sekikinumab and bimikizumab for our patients with moderate to severe HS. And just to echo what Dr. Paraser have said, taking a multidisciplinary approach to care. Talk to your rheumatologist when you see a patient with psoriasis and psoriatic arthritis, which I'm sure you are doing already, the trouble is figuring out when you have a mutually agreeable time to talk. But I think having a multidisciplinary approach would be very helpful. And here's conclusion of what we talked about. Il 17 family of cytokines, important in inflammatory skin and joint disease, IL 17 F. We are gaining appreciation for its role in psoriasis, psoriatic arthritis, as well as HS. And we talked about the multiplinary approach. We want to thank you so much for your attention. Thank you. April and Dave bed.

Taking a Deep Dive Into the Role of IL-17 Inhibitors for Psoriasis: What do PAs and NPs Need to Know? Seminar-in-Depth Online CME Activity

About

Availability

Learning Objectives

Intended Audience

Faculty

April Armstrong, MD, MPH

David Pariser, MD

Accreditation Statement

Credit Designation Statement

Disclosures & Disclaimers