Activity Transcript

Philip Mease, MD, MACR: Hello, I'm Dr Philip Mease, director of rheumatology research at Swedish Medical Center, Providence-St. Joseph Health, and clinical professor at the University of Washington School of Medicine in Seattle. Welcome to this program titled "Optimizing Care for Psoriatic Arthritis: Current Data on New and Emerging Therapeutics." Joining me today is Dr Alexis Ogdie, associate professor of medicine and epidemiology at Penn Medicine. Welcome, Alexis.

Alexis R. Ogdie, MD, MSCE: Thanks so much for having me.

Dr Mease: Over the past decade, the treatment of psoriatic arthritis has improved considerably as a result of several clinical advances including development of targets for treatment and an expanded range of treatment options. Our understanding of the pathophysiology and involvement of cytokines in psoriatic arthritis has paved the way for development of new drug targets. We now have a number of treatments available for patients with varying mechanisms of action with additional therapies in development. In today's discussion, we will review the inflammatory pathways involved in the pathophysiology of psoriatic arthritis and some of the latest data on the efficacy and safety of new and emerging therapies. Alexis, could you walk us through the basics about pathogenesis of psoriatic arthritis and its treatment?

Dr Ogdie: Sure, thanks so much. First of all, what we know about pathophysiology is changing pretty rapidly. Actually, there's been a lot of developments particularly in the last few years, so the framework I'm going to give you is a framework, but is being worked on as we speak. The concept is that there is a T cell that is either resident in the skin or in the enthesis, for example, or in the synovium, and that T cell can be stimulated by interleukin (IL)-23. When it is stimulated by IL-23, it kicks out IL-22 and IL-17, and downstream of IL-17 are TNF and kind of those JAK/STAT pathway inflammatory proteins. And talking through those few steps, I've talked about a number of cytokines you're going to see in the therapies that are targets for our therapies for psoriatic disease. As I said, this is a very rough framework and there's a lot to be worked out individually in those different pathways, but with that, at least you hear some of the key cytokines that are involved.

Dr Mease: Thanks, Alexis. We will now review some of the most recent data from the last year or so. We're going to start with discussion about JAK inhibitors, in particular, upadacitinib and the SELECT 2 trial. In the 24-week SELECT PsA-2 trial, upadacitinib 15 mg and 30 mg daily compared to placebo, there was clear-cut evidence of benefit and no new significant safety signals identified. This was looked at over 56 weeks in patients with PsA who had had an inadequate response or intolerance to biologics. The original improvement in ACR and skin responses that's measured by PASI, including PASI 100, as well as minimal disease activity were maintained through 56 weeks. There were no new safety signals through that period of time. I should mention that there is an updated safety label for upadacitinib as there is with other members of the JAK1, 2, or 3 inhibiting class such as tofacitinib, in that there is a warning about the potential for increased frequency of major adverse cardiovascular events, malignancy, or death, as well as thrombotic events in JAK inhibitors as compared to TNF inhibitors. This was derived from a study known as ORAL Surveillance with tofacitinib in which patients with rheumatoid arthritis over the age of 50 and with very specific cardiovascular risk were enrolled.

There were abstracts at the recent ACR Convergence Meeting on upadacitinib, and one that caught my eye was abstract number 2137 in which Lihi Eder and others looked at the impact of gender in terms of response to upadacitinib and adalimumab from the SELECT PsA-1 trial. What they found was that there was a slightly reduced response when it comes to things like ACR responses and various subjective patient-reported outcome measures in the female population as compared to the male population, and that there was a little bit more impact in relation to adalimumab in this regard than upadacitinib. This is an important contextual factor when taking into account response in our PsA patients.

Also reported upon recently has been a novel approach inhibiting TYK2. Now, TYK2 is a member of the JAK family, but it is slightly different from JAK1, 2, or 3. Inhibition of TYK2, in particular, has an impact on reducing IL-23 and alpha-interferon. There is a very selective TYK2 inhibitor known as deucravacitinib that has been studied in a Phase 2 trial in psoriatic arthritis in which patients were assigned to either 6 mg or 12 mg daily of deucravacitinib vs placebo. What was shown was that there was a significantly increased ACR20 response as well as other ACR responses, as well as other key domains of psoriatic arthritis, including enthesitis and dactylitis and significant improvements in skin disease. There were occasional adverse events, but overall the safety profile of the drug has proven to be fairly benign. This drug has, based on the Phase 3 trials done in psoriasis, has now been approved for the treatment of psoriasis and does not have an adverse safety label, unlike the other JAK inhibitors. For example, there is not a black box warning and the only laboratory monitoring that's required is in patients who have a risk for hepatic disease. There was an abstract at the recent ACR Convergence Meeting in which 52-week data from this trial was demonstrated and shown a continuance of beneficial effects as well as continuous efficacy measures such as the PASDAS or the DAPSI scores and also demonstrated no new safety issues.

Alexis, can I turn things over to you to discuss, for example, the IL-17 pathway?

Dr Ogdie: Sounds great. We've become very comfortable with the IL-17 pathway with both secukinumab and ixekizumab in psoriatic disease and axial spondylarthritis, but now, there are a couple of new ones coming. Bimekizumab is the first one. This is actually already approved for psoriasis in Great Britain and in Europe, but we're still waiting for that approval here in the United States. Bimekizumab is an IL-17A and F inhibitor. This differs from secukinumab and ixekizumab, which are IL-17A-specific inhibitors.

At EULAR, they presented the phase 3 study, BE OPTIMAL, which is the biologic naïve population, as well as the phase 3 BE COMPLETE study, which is in that subset of TNF inadequate responders. The trials were very similarly designed in that they tested bimekizumab 160 mg every 4 weeks compared to placebo. In the biologic naïve trials, the BE OPTIMAL trial, they also included an adalimumab reference arm, which is our standard dose. One thing to note about the dose is that the dose for psoriasis is 320 mg, so it's twice the dose of that tested in the psoriatic arthritis population.

The primary outcome was ACR50 response at 16 weeks, and what they saw is what we would expect, that the drug works significantly better than placebo. However, there are some interesting things. One was that the drug performs very similarly to adalimumab when it comes to joints compared to placebo and specifically the ACR50. Then we see the skin responses, and as we would expect for an IL-17 inhibitor, the IL-17 inhibitor did a better job with the skin than adalimumab.

Then, the very interesting thing is that in the TNF inadequate responders, actually you saw very similar ACR50 responses with the bimekizumab compared to placebo as you did in the biologic naïve trial. Usually, we see some differences there, so that difference wasn't tempered as much as it usually is in the other studies, so it's just interesting to point out. The AEs were as was expected for secukinumab or ixekizumab, so it actually looked much more like those drugs. One thing is the typical thing we see in these studies is infections and nasopharyngitis, oral candidiasis as we would expect, and upper respiratory tract infections. The oral candidiasis was much higher with the psoriasis dosing in the psoriasis trials. In these bimekizumab trials using 160 mg, it actually looked quite similar to ixekizumab and secukinumab, so probably similar levels of oral candidiasis. Maybe more, but in these trials looked similar. There was another study presented at ACR this year with the 52-week data and, again, no new safety signals. Looks very similar to what we would expect after you kind of take out that placebo arm and transition people onto the active drug.

Besides bimekizumab, there have been some other IL-17 inhibitors that are being developed, in particular sonelokimab for psoriasis, and izokibep is the one that was presented for psoriatic arthritis at this last EULAR Meeting. This has since been published as well. This is an IL-17 inhibitor, but it is a small molecule, and the idea is that with this small molecular structure, it may be able to better penetrate tissues such as the enthesis, for example. This was trial was designed as most Phase 2 studies are, patients with inadequate responses to NSAIDs, csDMARDs, or some proportion who are inadequate responders to TNF inhibitors. It was a dose-finding trial, so they tested 2 doses, 80 mg or 40 mg compared to placebo using ACR50 at week 16. As you would expect, the drug did better than placebo and probably what we'd expect from another IL-17 inhibitor again. One finding that this particular group raised was that they felt that there was really good penetration in enthesis, and there was really good enthesitis resolution. I think we'll see more about this in the Phase 3 studies as they move forward.

Next, let's move to the IL-23 inhibitor pathway, or IL-12/23 and IL-23. We already have for IL-12/23, ustekinumab. I think people are pretty comfortable with that, but then we have the new class of IL-23 inhibitors. These are p19 subunit inhibitors and there are 3 of them. There's guselkumab, risankizumab, and tildrakizumab, all approved for psoriasis. Over the past 2 years, guselkumab was approved in 2020, and then risankizumab more recently for psoriatic arthritis.

At EULAR 2022, the phase 3 results for the KEEPsAKE 1 and KEEPsAKE 2 trials were presented. KEEPsAKE 1 was csDMARD inadequate responders, and they were randomized to risankizumab 150 mg vs placebo at week 0, 4, and 16. The primary endpoint for this trial was at 24 weeks and it was an ACR20 response. As we would expect, patients who got treatment did much better than placebo. Common AEs were the usual ones we see in trials, nasopharyngitis, upper respiratory tract infection, AST/ALT elevation, and headache. The interesting thing is that there were actually numerically more events in the placebo group than in the treatment group, which is always fascinating about these in IL-23 inhibitors, so nothing substantial stands out except for the usual stuff we see in trials. One of the interesting findings from the KEEPsAKE 1 trial is that there was not a statistically significant difference from placebo in terms of x-ray progression. We know that this is not a really great tool for monitoring disease damage over time because damage happens so slowly on average in psoriatic arthritis, and actually both groups progressed the same, so there just really wasn't a difference there. Not sure that it's a drug thing so much as a disease population at this point in time using that particular outcome measure, but still something to be aware of.

In the second trial, KEEPsAKE 2, was patients who had an inadequate response to or intolerance to 2 or less biologic therapies, so 1 or 2 biologic therapies. They were given the same exact trial design, so risankizumab 150 mg vs placebo at week 0, 4, or 16. ACR20 at 24 weeks was the primary outcome. AEs looked exactly the same as in the previous trial and results were slightly attenuated given this biologic inadequate responder group, but otherwise still significant compared to placebo. Other studies, again, at ACR this year, there was 52-week data and actually 100-week data from the KEEPsAKE 1 and KEEPsAKE 2 trials, so again, they continue to work if you continue to take them. Dr Mease, you want to tell us a little bit about some of the updates with regard to IL-23 inhibitor guselkumab?

Dr Mease: Thanks Alexis. Guselkumab is an IL-23 inhibitor like risankizumab. Its efficacy has been established through the DISCOVER-1 and 2 trials. The DISCOVER-2 trial was one in which patients were bio-naïve. In the DISCOVER-1, there were 30% who were previous TNF inhibitor inadequate responders. What was shown in these trials was efficacy across the various clinical domains of psoriatic arthritis and the now-approved dose for psoriatic arthritis is 100 mg given once every 2 months subcutaneously.

Also, there was an interesting substudy from these trials. Investigators identified patients they had thought had axial psoriatic arthritis, that is inflammatory immunologic spine involvement. Not only did they have back pain, but they had to have objective evidence of sacroiliac joint abnormalities on imaging, either x-ray or MRI. In this subpopulation, about 30% of the patients in both trials, it was shown that there were improvements in subjective measures of spinal pain and including various BASDAI measures and the ASDAS outcome measures. It raises the possibility that not only in general clinical domains like peripheral arthritis and enthesitis as well as skin disease, but also in the spine, there might be improvement. This is being further investigated with a large trial dedicated just to axial PsA patients being treated with guselkumab vs placebo.

At the ACR Meeting, there were a host of abstracts documenting the ongoing improvement of patients who were treated with guselkumab. There was a fascinating study in which they looked at not only the patients that I just mentioned in this axial PsA substudy, but also a group of patients that were considered to have axial disease based on a machine learning approach that looked at data in an unsupervised fashion in DISCOVER-1 and 2. It was shown that the outcomes were very similar between these two populations, thus supporting the idea that there might be improvement in the spine by using this medication. Alexis, there's also a fascinating trial that's just begun known as the AFFINITY trial. Do you want to explain what this is about?

Dr Ogdie: Yeah, one of the things we often wonder about is, could we get better results for individual patients, particularly those with more aggressive disease, if we use 2 biologics at once? We already know that we use combination therapy with oral therapy, but can we use these combination biologic therapies? Well, there was an interesting trial in ulcerative colitis examining guselkumab vs golimumab vs the combination of the 2 together and found that the 2 together actually did work a little bit better with no significant increase in adverse events. The same type of trial is underway, the AFFINITY trial as you mentioned, to test a similar combination in psoriatic arthritis to see if we can get patients to lower disease activity and then you could potentially continue maintenance therapy looking at a different treatment pattern. I think we're all very excited to see how this turns out.

Dr Mease: Thanks so much, Alexis. We've just been reviewing a rich array of abstracts and articles that have summarized a very plentiful number of options that we have for treating psoriatic arthritis. We've gone truly from bench to bedside with a greater understanding of the pathophysiology of the disease, the key cytokines and cells that are involved in the destructive changes that we see in joints, inflammatory changes in the skin and entheses, as well as the spine. Targeting those with a number of different mechanisms, including our historic TNF inhibitor pathway, but also newer pathways including inhibition of IL-17 and IL-23. We're finding that we can achieve states of remission, states of low disease activity. We can improve overall quality of life with these new medications. It's a wonderful time to be treating patients with PsA.

Thank you very much for participating in this activity, and thanks, Alexis, for helping present this rich array of data, and thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This transcript has not been copyedited.