Safety and Efficacy of IL-17 Blockers for Psoriatic Arthritis

As more targeted treatments for psoriasis and psoriatic arthritis (PsA) become approved, several emerging therapies still on the horizon were highlighted at the American College of Rheumatology (ACR) annual meeting.

MedPage Today brought together three expert leaders in the field: moderator Andrew Blauvelt, MD, of the Oregon Medical Research Center in Portland, is joined by Melinda Gooderham, MD, MSc, of the SKiN Centre for Dermatology in Peterborough, Ontario, and Neil Korman, MD, PhD, of Case Western Reserve University in Cleveland, for a virtual roundtable discussion on two studies from the meeting that focused on treatments targeting interleukin (IL)-17.

This is the first of three exclusive episodes.

Following is a transcript of their remarks:

Blauvelt: Hello everyone. My name is Dr. Andy Blauvelt. I’m a dermatologist and president of Oregon Medical Research Center in Portland, Oregon. This is a large clinical trial center. I also have a lot of experience taking care of psoriasis patients with and without psoriatic arthritis. Joining me today are Melinda Gooderham from Peterborough, Canada, who also runs a large clinical practice and clinical trial center, and Dr. Neil Korman from Case Western Reserve University in Cleveland. So, welcome to the two of you.

Today I just wanted to talk about what happened just at the ACR. So the ACR meeting just concluded, there’s several interesting abstracts that were relevant to psoriatic arthritis, and today I just wanted to get your views on these abstracts and discuss the data that we just saw at ACR. So, welcome.

So the first one, first kind of category we’re going to touch on, are IL-17 blockers for psoriatic arthritis. And the first one was an abstract that was presented by Eli Lilly and colleagues on the safety of ixekizumab [ixe; Taltz], a selective IL-17A blocker for psoriatic arthritis. It’s also approved for psoriasis. And in this abstract the authors looked at long-term safety data for ixekizumab, and it included a very large number of patients that were pooled together that had either psoriasis, psoriatic arthritis, or ankylosing spondylitis.

And so they took pretty much all of the trial data that have been accumulated over years with all of these different diseases, accumulated all the safety events, and looked at it with patients, some of them on 5 years of ixe with psoriasis and at least 3 years of ixe for psoriatic arthritis and [ankylosing spondylitis].

And what we saw are things that I thought were typical for ixekizumab and IL-17 blockers, a candidiasis rate, although it was pretty low, and the incidence ratio was about 1.3 to 1.8 events per 100 patient-years. And then we saw some cases, of course, of inflammatory bowel disease. But the incidence ratio again was less than 0.8, was pretty low for this particular side effect.

And, in general, everything else seemed consistent with what we knew from ixe over time. But I’m curious to get your guys’ thoughts on the safety of ixekizumab and maybe IL-17 blockers, whether you think it might be less safe or more safe, a psoriasis patient versus an arthritis patient. Melinda, can you give us your thoughts on this abstract?

Gooderham: I found it very reassuring. I mean it’s very consistent with what I see in my office. Very few rates of candidiasis in my ixekizumab patients. IBD, I have seen, but there’s this controversy whether blocking IL-17 causes it or just is not treating it. I think it’s probably just not treating and unmasking some underlying disease. But seeing this poster with the PsA patients and the axial patients, I felt was more reassuring about the safety of this class.

Blauvelt: Yeah, one of the things I didn’t mention, cancer rates and serious infections rates and those things that we don’t tend to see with these drugs or at least at a very low level. So that’s reassuring, as you said, that over time we’re not seeing bad things pop up, so to speak. Neil, do you have any other thoughts about the safety of ixekizumab in your experience?

Korman: Well, I mean the abstract was boring in the sense of there was no surprise, right? And that’s pretty much the same story, thank goodness, for every single drug that we’ve looked at long term in psoriasis to date — in the whole psoriatic disease spectrum. So that’s wonderful. Your side effect profile is what it is when you look at your week 16, or maybe week 52 data, and it doesn’t get worse as the years go on. And this fits with my observations as well in managing patients and talking to them about what I might give them and what the risk might be and what the benefit might be.

Although I must confess that we’ll get to it, we’ll talk about [IL]-23s as well. But I’m definitely starting to lean more towards 23s. I don’t have to talk about inflammatory bowel disease. It’s a rare event, but rare events can be a big deal.

Blauvelt: Yeah. So just one last thing on this one. So how do you guys actually, do you introduce the topic of possible inflammatory bowel disease if you start a patient on an IL-17 blocker, how do you describe that to them?

Korman: It’s kind of evolved over time. Back when I was first doing it, I actually just asked, did they have a history of it. And if they said no, then I said, okay, good. And then what I would do is after I got them on the drug, then I would say, “oh, by the way, I forgot to tell you that this drug can actually cause inflammatory bowel.” Because what I learned was that when I did tell them about it causing it, that nobody wanted to go on it! Patients can’t make sense of “you might get this” and “it’s a rare event,” and you’re most likely not going to get it. As soon as you tell them, they say, “oh, I get every side effect, I’ll get that too.” So I’ve evolved to — I had done it that way — I’ve now evolved back to “this is a rare side effect and I’m not worried about it and I think it’s a great drug for you, but I gotta tell you about it.”

Blauvelt: Yeah. How about you, Melinda? How would you describe it?

Gooderham: It’s interesting, I have also changed the way, because at the beginning I would ask about the history. Do you have inflammatory bowel disease or Crohn’s disease or ulcerative colitis? — and using these terms. And then when I had some cases develop, they would admit that, oh yeah, before I always had chronic diarrhea. It just was never diagnosed. So I realized the wording might be a bit different. So now I will ask, do you have any problems with your bowels? Do you have any issues with stooling? Or whatever the discussion leads to. But I don’t specifically ask about the diagnosis. I ask more about symptoms.

Blauvelt: All right, thank you for that. So I’m gonna switch to the second abstract, which is also an IL-17 blocker. But this drug is a little bit different. It’s called bimekizumab, it actually blocks IL-17A and IL-17F — two isoforms of IL-17. It’s thought that that second blockade of that second type of IL-17 can confer some better efficacy with this drug than blocking only IL-17A alone. And this drug, we should have seen it on the market by now. It’s been delayed, its FDA approval. It’s actually approved in Europe. I believe it’s approved in Canada as well, right, Melinda?

Gooderham: Yeah.

Blauvelt: So what we saw at the ACR was the phase III data for bimekizumab and psoriatic arthritis at week 52. So, earlier in the year we had the report of the initial primary endpoint data, the week 16 data. And so now we see bimekizumab over the course of 1 year. And this was in DMARD [disease-modifying antirheumatic drugs]-naive patients were the ones coming into this trial.

A few other things, the dosing was a little bit different than the psoriasis dosing. It’s 160 mg every 4 weeks over the course of 1 year. And they reported out several measures. They reported out ACR50, PASI100, Sharp progression, and a variety of other endpoints. And they also had what we call a reference arm. So a reference arm was adalimumab [Humira].

And the numbers here, I’m just going give them to you guys — at week 52, we had ACR50 of 54.5% for bime [bimekizumab] and 50% for adalimumab. And for the patients switching from placebo to bime, it was 53% — that’s ACR50. So slight increase of bime over adalimumab.

And then the PASI100 data was in the 60s for bime and it was 48.5% for adalimumab. So more clear difference for PASI100. And then the Sharp progression — no sharp progression via x-rays and 94.1% of patients on adalimumab. And the patients in the bime group, the numbers were 87 to 89%, no Sharp progression by x-ray.

So, bottom line here, kind of sustained and increased improvement from week 16 to week 52, and maybe a bit better than adalimumab and joint scores, but clearly better for skin scores.

So, again, let’s start with Neil this time. What do you think of bimekizumab maybe for psoriatic arthritis, Neil, what do you think of these data?

Korman: I’m a little disappointed. The hype has been bimekizumab is a home run for skin and joints, and this does not seem to support that. I’m very unimpressed with skin scores in a psoriatic arthritis trial because they never have a high enough PASI to make those numbers statistically important, significant. So numerically 62% PASI100 versus 48%. Yeah it sounds like more, but what was the average PASI in these patients? It was probably 6 or 7, or 10 would be super high. It’s probably 6 or 7 or 8.. And then I just care less about that data. I care more about the psoriatic arthritis data in this trial.

Blauvelt: I’m agreeing with you too because of the phase II data. So the phase II data, we saw ACR50s, I think, near the 70% range and now we’re seeing it near the low 50s and not a big difference over adalimumab. So, Melinda, what do you think about this?

Gooderham: Yeah, I agree it was a bit hyped up. I agree with that. I think the study overall to me supports the fact that interleukin-17 compared to TNF is superior in that whole patient treatment, as far as clearing skin and being equivalent in joints. So I think it was SPIRIT-H2H that also did sort of a similar analysis looking at ACR improvement plus PASI100.

So it supports that IL-17 mechanism of action. But yeah, blocking 17F seems to be that added benefit to the skin that we’re just not seeing as much in the joints.

Blauvelt: And just to throw this back to you because you mentioned it, and this abstract addresses it, IL-17 inhibitors versus TNF inhibitors for psoriatic arthritis. Do you have a favorite class of choice, or as Neil said, is it IL-23 blockers in the mix now? So how do you compare these? If you have a patient with fairly bad joint disease, what is going to be your first class of drugs you go to?

Gooderham: For me, for a PsA patient that may have skin, I’ll probably do IL-17 over a TNF just because of that added skin efficacy. But if they have any issues like chronic diarrhea, then I’m going to be choosing a TNF inhibitor for that patient. Or an IL-23. But if I have to choose between a TNF and an IL-17, and they have some bowel symptoms, I may go with a TNF but also consider IL-23, which is also one of my favorite classes.

Blauvelt: And Neil?

Korman: Well it’s good to have three different classes, and usually the answer is it doesn’t matter what we think anyway. The insurance company makes the final call.

So, I mean, I practice at a large academic medical center where we see tons and tons of Medicare and Medicaid patients, and the answer there is, yeah, oh, it’s a Medicaid patient. Oh well, you gotta start with the TNF. It doesn’t matter what you think, what our opinions are.

Blauvelt: Right. Well, thank you very much both of you for discussing these two new interesting IL-17 blocker abstracts in psoriatic arthritis from the ACR.