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IL-17, IL-23 Blockers for Treatment of Plaque Psoriasis
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Mark Lebwohl, MD: Let’s talk next about the interleukin [IL] 17 blockers, which I think represented a breakthrough, both in psoriasis and in psoriatic arthritis. They are so effective for the skin and rapidly effective. We see in days an improvement in the skin lesions of psoriasis, and … in psoriatic arthritis, too. I’m just going to say they’re profoundly effective. We’re now no longer talking about Psoriasis Area and Severity Index [PASI] 75, we’re talking about PASI 90 or 90% improvement in psoriasis severity scores, so what’s their impact on psoriatic arthritis [PsA]?
Philip J. Mease, MD: They do have very quick and profound effects on the skin. When they were introduced, there was sort of a bias that … maybe the tumor necrosis factor [TNF] inhibitors might work better in the musculoskeletal domains. But what we’ve seen is that these drugs work very well in all aspects of musculoskeletal disease: arthritis, enthesitis, spine disease, and now we have 2 recent head-to-head trials between the 2 approved IL-17 inhibitors and adalimumab, the SPIRIT head-to-head trial [NCT03151551] with the ixekizumab agent and the XC trial [NCT02721966] with secukinumab, and what has been shown is that both the speed of onset of action in the musculoskeletal elements as well as the magnitude of effect is just as good. They’re very similar and clearly, the IL-17s are superior in the skin and slightly better in terms of safety, and so I think that that has helped cement the place for ixekizumab and secukinumab. We anticipate additional IL-17s coming along to have a substantial place in the management of psoriatic arthritis, along with the TNF inhibitors.
Mark Lebwohl, MD: Now, along come the IL-23 blockers, and now we’re not talking about PASI 75 at all anymore, it’s just PASI 90, and even PASI 100 for some of them. The other advantage of them is, they’re given infrequently, every 2 or 3 months, so certainly for the skin, they are profoundly effective and are so targeted, like the IL-17s, where they appear to be extremely safe.
The IL-17s have a small drawback in that they can cause Crohn disease, it appears. The IL-23s, probably, at the end of the day, will treat Crohn disease. It’s great for the skin and great for the gut. What’s the impact on the joints?
Philip J. Mease, MD: From the data that we’ve seen, primarily from phase 2 trials with risankizumab and tocilizumab and phase 3 trials with guselkumab, we see that the musculoskeletal effects are comparable to what we’ve seen with the IL-17 inhibitors and the TNF inhibitors. There’s a question mark around their full benefit for the spine, but interestingly, 1 of the substudies in the guselkumab program was looking at patients with radiographically defined sacroiliitis in finding that their symptoms improved as well in the spine, so we’re hoping that this new drug class for us will have the same benefit across all musculoskeletal domains as the other biologics, and clearly have very significant impact on the skin disease and are very safe.
Mark Lebwohl, MD: In terms of radiographic progression in joint disease, guselkumab has looked at that, and if you move the dosing to every 4 weeks, the American College of Rheumatology [ACR] scores aren’t that different than every 8 weeks, but in terms of the x-rays, it looks like every 4 weeks achieves the prevention of radiographic progression of joint disease. I will say also, these are not head-to-head studies, but the difference between active and placebo in the IL-23 blockers appears to not be as great as in the TNF blockers or the IL-17 blockers. Am I putting too much weight on that?
Philip J. Mease, MD: It’s a little early for us to tell, and we need a little bit more time. I must say that I’d like to see the phase 3 programs for risankizumab and togekizumab coming along, but I think that what we're going to find is that these have a good, strong place in the armament. Just to comment on that radiographic observation, the once-every-8-week dosing came close to being statistically significant, so I’m not overly worried about it. I do think that it has the capability of inhibiting radiographic progression even though it doesn’t have a formal indication for that.
Mark Lebwohl, MD: Let’s just talk a little bit about the future. We already mentioned tocravicitinib coming out for psoriasis. I believe it is being studied for psoriatic arthritis, is that right?
Philip J. Mease, MD: That’s right. In fact, next week, I will be presenting as a late breaker in the ACR meeting, the PsA data from a phase 2, which is very promising in all the ways that we’ve been discussing. It will clearly move into a phase 3 program, and hopefully, at some point, we will see an improvement in psoriatic arthritis.
Mark Lebwohl, MD: I would have hoped that that would be the outcome. Tofacitinib, as you know, is approved for psoriatic arthritis, and we have an occasional patient who is just not doing well with any of the biologics. We switch them to tofacitinib, and their psoriasis and their psoriatic arthritis improved. Now, you know it wasn’t approved for psoriasis, because the FDA had concerns. It was an increase in cases of herpes zoster. They were worried it was too immunosuppressive, but in fact, in practice it’s proving to be fairly safe.
We do some blood monitoring, but unlike methotrexate, you don’t lose sleep over the blood monitoring as you do for tofacitinib. Same with cyclosporine. You do lose sleep, so I think it is a pretty benign treatment that is quite effective. Of course, tocravicitinib, from what we've seen in phase 2, looks like it’s even safer, so I would hope that would be useful in the future. I always wondered, why does the package insert for tofacitinib allow its use with methotrexate but not with biologics, which we know are safer than methotrexate?
Philip J. Mease, MD: Unlike the discussion we had earlier with apremilast, I would be a bit more cautious with a combination of Janus kinase [JAK] inhibitor with biologics only because they both have the capability of causing severe infections, and so there could be some additive effect there. I’m just generally more cautious about that particular combination recommendation, until we see a formal trial that assesses safety with a combination between a JAK inhibitor and a biologic.
Mark Lebwohl, MD: My reaction to that is methotrexate is even more immunosuppressive, and we use that with biologics all the time. I think the answer is that it just wasn’t studied, and it was studied with methotrexate, which unfortunately ended up in an increase in herpes zoster. Biologics and tofacitinib were not studied together.
Philip J. Mease, MD: That’s right.
Mark Lebwohl, MD: I’m hoping that eventually we end up with the ability to prescribe these together. I think they will be safer than the combination with methotrexate, and that is my gut feeling, although that, of course, is very off-label.
Philip J. Mease, MD: For us to break through our current situation, where we do have patients failing treatments, we’re going to be pushed to doing more and more experimentation with combinations.
Mark Lebwohl, MD: Yeah, I would agree, and I think an exciting new development for both us is bimekizumab, which has just great psoriasis skin scores and psoriasis joint scores.I believe that 1 is probably due next summer, so hopefully, we’ll be seeing that eventually.
Philip J. Mease, MD: It will be a little bit beyond that before it’s realized. We’re very excited about some of the data we’re seeing in phase 2 for psoriatic arthritis, and they’re in phase 3 trials now.
Transcript Edited for Clarity
