Psoriatic Arthritis Podcast

PsA Pipeline Evaluation: Progress and Unmet Needs

Stanley Cohen, MD; Philip Mease, MD


May 24, 2023

This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.

Stanley Cohen, MD: Hello. I'm Dr Stan Cohen, and welcome to Medscape's InDiscussion series on psoriatic arthritis (PSA). Today, we'll be discussing the highlights of the American College of Rheumatology (ACR) Convergence meeting in 2022 and also delving a little bit into clinical trials and also unmet needs in PSA.

I'm very pleased to have an old friend here, Dr Philip Mease. Dr Mease is clinical professor at the University of Washington School of Medicine and director of rheumatology research at the Swedish Medical Center in Seattle, Washington. Phil is a well-known expert in PSA and an exemplary clinical trialist, and he has led many of the programs resulting in approval for the therapies that we have now to use in the clinic. Welcome, Phil. Glad to have you here today.

Philip Mease, MD: Stan — so glad to be here with you.

Cohen: Before we talk about the abstracts and what was exciting at the ACR meeting 2022, I've never asked you this question, and we've been weaned together way back doing clinical trials. Why PSA for you? What was the drive, the stimulus that got you into that field and made you such a leader that you are today?

Mease: Way back just before the year 2000, in the late '90s, I was a practicing private practice doc in downtown Seattle, working at a multidisciplinary clinic that included a whole dermatology group. They ran a large psoriasis treatment center where people came down and had their phototherapy. I ended up being the person who saw all of the PSA in that group of patients. As we know, about 30% of people with psoriasis will have PSA.

I'd collected quite a collection of patients at that point, and around that time, a company called Immunex based in Seattle was starting to develop a drug called etanercept. They turned to me and asked me to contribute a few patients with rheumatoid arthritis to do some pharmacokinetic studies. When I saw what that did in rheumatoid arthritis, I turned around and I wrote out a two-page investigator-initiated study proposal, took it down to Immunex, and asked them for drugs. They said, fine, we'll supply you with etanercept, but you've got to do everything else. You've got to go to the US Food and Drug Administration (FDA) and do this study and approval and all that sort of thing. I figured out how to do that and then ran a trial that enrolled about 60 patients in 4 months. Imagine if we could do that now. It showed that the drug worked very well.

We published in The Lancet , and ever since then, my career has taken a sharp turn. I ended up very fortunately being able to design and conduct many of the studies that we now know of for the approval of multiple drugs in PSA, as well as helping to initiate a research education group known as GRAPPA. And it's within that framework that I've been able to do quite a bit of research and teaching and mentoring younger folks in the field. It's been rewarding.

Cohen: GRAPPA is a wonderful organization, and we always look forward to the newest treatment recommendations. It is amazing how things in life are serendipity. You just happened to be down the street from Immunex, a few guys hanging around with this soluble tumor necrosis factor (TNF) receptor.

Tell us about what you found most intriguing at this year's ACR 2022 meeting. There are obviously several abstracts on present treatment strategies, but also talk initially about what's coming down the pipeline; what should we expect in the next few years for management of PSA?

Mease: We saw quite a bit of data coming out from the UCB program with bimekizumab, which is a combined interleukin (IL)-17A and IL-17F inhibitor, and we've come to learn that IL-17F is an important proinflammatory cytokine as well as IL-17A, which is targeted by the currently available drugs.

We saw, as a late breaker, the 52-week data from the BE OPTIMAL trial, which was their biologic-naive population. It showed terrific responses: an ACR 50 response of 54%, minimal disease activity (MDA) achievement of 55% at week 52, and Psoriasis Area and Severity Index (PASI) of 100 in more than 60% of patients. These are really high thresholds of response. It was reassuring when we saw that sustained effect. The main side effect is that a small percentage of patients get Candida infection, and that remained relatively small — in the single digits — with the 160-mg dose. Otherwise, nothing different from what we tend to expect for safety from an IL-17 inhibitor.

We saw more data coming out of the BE COMPLETE trial, which had a TNF inadequate responder population. I was involved with an abstract, in which we presented on an achievement of composite endpoints and again very high rates of, for example, MDA achievement, which is a target of treatment in 45% of patients. Low disease activity by Disease Activity in Psoriatic Arthritis (DAPSA)/Psoriatic Arthritis Disease Activity Score (PASDAS) was seen in more than 30% of patients. Even in these presumably more refractory patients in whom a TNF inhibitor or two has failed, we're seeing good responses.

By the way, we're expecting approval for bimekizumab sometime later this year in psoriasis and soon thereafter in PSA.

Cohen: Obviously, excellent clinical data, and we have very good IL-17 inhibitors on the market presently. I'm not going to put you on the spot, because I know there are no head-to-head trials. We do know that bimekizumab was superior to adalimumab in psoriasis, and we've seen that with ixekizumab as well — we're not surprised. What is the role going to be for bimekizumab? Is it going to be the be-all, end-all IL-17 inhibitor? How do we pick one over the other? Do you have any strategies for that? I don't, and I don't see that in the GRAPPA outline. It's really IL-17, IL-23, for a specific drug. Again, I don't think the data exists, but curious what your gestalt is.

Mease: As you know, in your place as well as mine, some of this [using medications] is going to be driven by the formulary managers and what side of the bed they got up on that particular morning. We'll certainly be trying it in patients that have had been around the block several times with different biologics. I think there will be situations where we have a patient in front of us who has very bad skin disease and very bad musculoskeletal manifestations. It seems to hit multiple targets, including not only the arthritis and enthesitis, but also spine disease that's been demonstrated in this axial spondyloarthropathies. Once we start to use it, we're going to reach for it and then it comes back to, well, what side of the bed did the formulary manager get up on that morning?

Cohen: Can you tell us about deucravacitinib?

Mease: Deucravacitinib has a relatively unique mechanism. It's a very specific tyrosine kinase 2 (TYK2) inhibitor. It's a member, but sort of a distant member, of the Janus kinase (JAK) family.

One of the remarkable things with deucravacitinib this year is that it has been approved by the FDA for the treatment of psoriasis, and it doesn't have some of the really negative safety labeling that the other JAK inhibitors have. You don't have to wait until a patient has been on a TNF inhibitor. There's no specific laboratory monitoring required, unless you've got a patient in whom you're really worried about a liver problem. We were pleasantly surprised that it had such a good safety label in psoriasis. It remains to be seen whether that will be the case when it ultimately gets approved for PSA. It doesn't look like it's going to have the same label as the other JAK inhibitors. The data at this meeting were the 52-week data, which showed sustained effect in the various domains like arthritis, enthesitis, psoriasis, and so forth.

It looks like it's going to be a solid player both in psoriasis and PSA, but also they had a positive lupus trial with deucravacitinib. That's partly because it not only inhibits IL-23, which allows it to be so effective in psoriasis and PSA, but also interferon. It's on the path to getting approved, ultimately, in lupus, we hope. I think that was very exciting.

The other medication you mentioned from the meeting is one that I continue to struggle to know how to pronounce. And what is unique about it is that it's an IL-17 inhibitor, but it's also a nanobody. It's 16 kDa, and it's targeting the business end of the IL-17A molecule, but it also binds to albumin. The idea behind the small size and the albumin binding is to try to get better tissue penetrance. There is some science with these nanobodies, that they can achieve that. We had a meeting to discuss the design of a specific trial to look at its penetrance and in enthesitis, which is a vascular tissue compartment where tendons or ligaments insert into bone. It showed a dose response and its ability to treat enthesitis, with about 50% of complete clearance at week 16 of enthesitis at the lower dose and the higher dose 88% achieving complete clearance. It's tantalizing evidence that maybe there is something to this. I think we're going to see more of these nanobodies coming along not only in this field, but also in other fields of medicine.

Cohen: Years ago, we looked at an IL-6 nanobody molecule and it never really got off the ground, but we discussed the moving ahead with it. With deucravacitinib and PSA, you think it's an oral IL-12/23 inhibitor? We don't know the true mechanism of action; we know the TYK2 23 signals through that, 12 signals through that. Is it like an oral ustekinumab?

Mease: It does include those mechanisms, so it is in that pathway. TYK2 inhibits IL-12 and IL-23. You would expect that. The true test, of course, would be to have a head-to-head with a drug like ustekinumab to really tell.

Cohen: Can you walk us through some of the other presentations looking at treatment in management?

Mease: There were three abstracts that caught my eye on whether or not, after a first TNF inhibitor has failed in a person with PSA, you should switch to a different mechanism after that or you can cycle to another TNF inhibitor. This is a really practical question that we face daily in the clinic.

An abstract from France with a very large group of patients and a registry study suggested that there was a slight benefit to switching to a different mechanism, either an IL-17A inhibitor or an IL-12/23 inhibitor. There was one study from Portugal, with fewer patients and shorter period of observation, in which it made absolutely no difference. And the patients who went on to a TNF inhibitor after the first TNF inhibitor did just as well as those that switched to either an IL-17 or ustekinumab. There was a study from the CorEvitas Registry that I was involved with asking the same question, and we found that, although not statistically separated, there was a numeric differentiation that favored switching to a different mechanism.

A lot of this kind of question is going to be contextualized to the patient in front of you. If the patient has had a terrific and long-running effect from their first TNF inhibitor, I might consider switching to a second TNF and they might as well. On the other hand, if a person has a short-ish response to a TNF inhibitor or has a side effect, then I'll very readily move to a different mechanism. Fortunately, we're seeing more new mechanisms being approved.

Cohen: We've made a lot of progress in PSA — just a tremendous number of new therapies. Your group and GRAPPA and others have educated us about stratifying patients for skin, musculoskeletal manifestations, and so forth. What remains? What's the unmet need in PSA that can continue to need to be addressed?

Mease: I have three right off the bat that I think are diagnostic unmet needs, and then several treatment needs.

From the diagnosis point of view, we need biomarkers. We have none at the moment. There is nothing that teaches us whether this patient in front of us who was seronegative for rheumatoid factor or anti–cyclic citrullinated protein (CCP) has PSA, unless they have the classic features with dactylitis and so forth along with psoriasis. We see plenty of patients where we're not quite sure if they are more of a seronegative rheumatoid arthritis (RA)–type presentation or a PSA patient. Even worse, if the patient happens to present predominantly with spinal manifestations initially, sorting that out from degenerative arthritis of the spine or fibromyalgia is difficult. We need biomarkers that help us make a diagnosis. That's something that dermatologists can use because they are seeing these patients in their dermatology clinics up to 10 years before the patient develops PSA. Being able to predict who is going to develop PSA and then jumping on it when it does emerge is something that I think is sorely needed.

The other is, of course, education. We need education of nonrheumatologists about how to recognize the disease, and continued education of dermatologists to recognize the disease so they can get the patients to us at an earlier stage and we can potentially get more effective treatment response by treating earlier. As I mentioned, I struggle sometimes, in the axial component, understanding whether the patient has PSA driving their axial symptoms or degenerative arthritis. Help with either imaging or serum biomarkers is going to be important.

From a treatment point of view, I think we need to continue to have new mechanisms and new medications approved, partly because, as in other disease states like rheumatoid arthritis, we have the problem of patients losing their response to these very effective therapies over time. We have to switch or cycle to a new medicine or mechanism. Many of my patients worry about running out of options. So far, we've done pretty good with having some options in front of us and new medicines being approved, but increasingly we're having to turn to using combinations of biologics or a combination of a biologic and a targeted synthetic disease-modifying antirheumatic drug, which is tough to get through insurance. To do this, sometimes we need a couple of different practitioners: a dermatologist or gastroenterologist working with us to get patients on to some of these combination therapies.

I think the whole issue of precision medicine — where we can use biomarkers, either serum or imaging, to better pinpoint which patients are going to respond better to a particular medication rather than just throwing a dart at the dart board or acquiescing to whatever the formulary manager says — will help. Instead, we can target patients based on their particular immunobiologic phenotype for more accurate and reliable treatment.

Cohen: That's certainly very important. We're so frustrated by the lack of treatment biomarkers and the lack of precision medicine. Our good friend Len Calabrese has asked me to come to Cleveland Clinic in May and give a lecture at his series on precision medicine for rheumatoid arthritis. I'm just now trying to figure out, do we have any precision medicine in RA? I know in working with a few companies that it's a long way off and a lot of money is spent on it.

This has been terrific. It's been a great summary of what was presented at the ACR meeting, and you helped us to understand treatment strategies and the unmet needs. Thanks for taking time with us today, Phil, much appreciated

Mease: You're welcome, Stan, Thanks so much.

Cohen: Thanks, everyone, for joining us for this discussion today. This is Dr Stan Cohen for InDiscussion.

Listen to additional seasons of this podcast.


Etanercept in the Treatment of Psoriatic Arthritis and Psoriasis: A Randomised Trial

Group for Research and Assessment of Psoriasis and Psoriatic Arthritis

American College of Rheumatology (ACR) Convergence

Bimekizumab Treatment in Biologic DMARD-Naïve Patients With Active Psoriatic Arthritis: 52-Week Efficacy and Safety Results From a Phase 3, Randomized, Placebo-Controlled, Active Reference Study

Bimekizumab Treatment in Patients With Active Psoriatic Arthritis and Inadequate Response to Tumor Necrosis Factor Inhibitors: 16-Week Efficacy and Safety From a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study

Bimekizumab Improvements in Efficacy on Disease Activity Assessed via Composite Endpoints in Biologic DMARD-Naïve and TNFi-IR Patients With Active PsA: Pooled 16-Week Results From Phase 3 Randomized, Placebo-Controlled Studies

Bimekizumab Versus Adalimumab in Plaque Psoriasis

A Head-to-Head Comparison of the Efficacy and Safety of Ixekizumab and Adalimumab in Biological-Naïve Patients With Active Psoriatic Arthritis: 24-Week Results of a Randomised, Open-Label, Blinded-Assessor Trial

GRAPPA Treatment Recommendations: 2021 Update

Deucravacitinib Prescribing Information

Safety and Efficacy of Deucravacitinib, an Oral, Selective Tyrosine Kinase 2 Inhibitor, in Patients With Psoriatic Arthritis: 52-Week Results From a Randomized Phase 2 Trial

Deucravacitinib Reduces Interferons, B Cell Pathways, and Serological Biomarkers of Systemic Lupus Disease Activity: Pharmacodynamic Analysis From the Phase 2 PAISLEY Study

Nanobody: A Promising Toolkit for Molecular Imaging and Disease Therapy

Izokibep Demonstrates Clinically Relevant Efficacy Benefits on Enthesitis, Dactylitis and Nail Outcomes in Active PsA Patients: A 16-Week Randomized, Placebo-Controlled Trial

Long-Term Persistence of Second-line Biologics in Psoriatic Arthritis Patients With Prior TNF Inhibitor Exposure: A Nationwide Cohort Study From the French Health Insurance Database

Cycling Versus Swapping Strategies in Psoriatic Arthritis: Results From the Rheumatic Diseases Portuguese Register

The Impact of Cycling Among Tumor Necrosis Factor Inhibitors on Disease Control in Patients With Axial Spondyloarthritis: A Study From the CorEvitas PsA/SpA Registry

Dawn of Precision Medicine in Psoriatic Arthritis

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