Philip Mease, MD, on the POETYK Trials of Deucravacitinib in PsA: Part 2
Dr Mease continues his review of the findings of the POETYK clinical trials of the TYK 2 inhibitor deucravacitinib, including patient-reported outcomes among patients treated with the therapy.
Philip Mease, MD, is director of Rheumatology Research at the Swedish Medical Center/Providence St. Joseph Health and Clinical Professor at the University of Washington School of Medicine in Seattle, Washington.
Clinical Practice Summary
Deucravacitinib (TYK2 inhibitor) for Psoriatic Arthritis and Psoriasis: Phase 3 Outcomes and Clinical Integration
- Condition: psoriatic arthritis (PsA) with psoriasis; Drug: deucravacitinib (TYK2 inhibitor); Trials: phase 3 (e.g., POETYK 2 comparator arm)—Clinical efficacy showed improvements in joint and skin endpoints (ACR20/50/70 and PASI responses), alongside consistent patient-reported outcome gains in pain, fatigue, and physical function, with rapid onset and maintained response, supporting quality-of-life benefits in both musculoskeletal and dermatologic domains.
- Mechanism and safety context—TYK2 inhibition targets interleukin-23, interleukin-12, and interferon pathways, aligning with observed dual skin and joint responses. In phase 3 comparator data (apremilast safety reference arm), expected gastrointestinal adverse events (nausea, diarrhea) were observed with apremilast, while deucravacitinib demonstrated fewer such tolerability issues, supporting a favorable safety profile in this setting.
- Regulatory status and clinical use (United States)—Deucravacitinib is recently approved for PsA (in addition to prior psoriasis approval), enabling use by rheumatologists and dermatologists across care settings. Anticipated positioning includes early use after or around methotrexate and in later-line patients after TNF inhibitors. Limitations include non-significant enthesitis endpoints (high placebo response; assessment variability), with ongoing research in biomarkers, imaging, and additional indications (phase 2 success in lupus; phase 3 ongoing).
TRANSCRIPT:
Welcome to part 2 of this podcast with Dr Philip Mease on the POETYK trials of deucravacitinib in treating psoriatic arthritis. In this part Dr Mease will discuss patient-reported outcomes and the integration of deucravacitinib into the clinical armamentarium for PsA.
RALN:
Patient-reported outcomes improved alongside clinical measures. Was there any particular finding among the PROs that stood out most to you? What did your participants tell you was the biggest change, I suppose, in their quality of life?
Dr Mease:
Yeah. So it was the big three—pain, fatigue, physical function—all improved as measured by the various outcome measures that we look at for patient reported outcomes. And this is what's important to patients. It's harder for them to relate to say an ACR20 response rate or a PASI skin response rate. But when they look at graphs, and sometimes I pull my laptop into the exam room and show them data from a clinical trial when they're in the process of thinking through what medication do we start with now or move on to. And so they really appreciate seeing graphs that show that pain rapidly improves and has maintained response as well as fatigue and physical function, all of which are important factors in a patient's quality of life.
RALN:
These studies showed strong results in the ACR category, ACR20, even 50 and 70. And then I suppose it was in the studies for arthritis that you saw the PASI endpoints really improve as well. So this seems to position this drug as a particularly good agent for someone who has both psoriasis, active skin psoriasis, and psoriatic arthritis. How do you expect that this will translate into the real world, into clinical practice?
Dr Mease:
We really like to take as holistic an attitude toward our assessment and treatment of psoriatic arthritis patients as possible. So we're looking not only at improvement in arthritis, but also improvement in skin scores, because the skin really is a problem for many patients. Really difficult scalp psoriasis, very itchy, cosmetically troublesome changes of the skin and nails, especially for people that are working in the public. And so to have an agent that crosses over to effectively treat not only the musculoskeletal manifestations, but the skin is really important. So we can turn to patients and say, "This works."
Think about, too, the TYK2 mechanism. So what are the key cytokines that are being inhibited by TYK2 inhibition? And that includes interleukin-23, which is really important in the skin as well as the joints, interleukin-12, and interferon. And so we're seeing this mechanism of inhibition of these 3 key cytokines translated into the musculoskeletal and skin responses that were demonstrated in the studies.
RALN:
This wasn't powered to compare deucravacitinib and apremilast, but there were some observed differences that were noted in these studies. I guess it was POETYK 2 that had certain patients on apremilast. How should you interpret those results? What can clinicians do with that information when it comes to choosing an agent for their patients?
Dr Mease:
One of the things that regulatory agencies like to see is some comparison data. And so it's very common to have in phase 3, what we call a comparator reference arm. It's not a head-to-head trial. In this case, apremilast was the comparator agent, but it was more to see, is there a result that we expect to see from this already approved comparator medication? And in this case, apremilast was chosen as a comparator for safety, not efficacy. And so then the regulatory agency can look at the apremilast arm and say, "Is this about what we would expect from a safety profile of an agent like apremilast?” and the answer is yes. So we saw overall good safety from apremilast, but there were some tolerability issues that were seen—nausea, diarrhea would be examples of gastrointestinal adverse effects. And it was seen in about the frequency that we have seen in the apremilast trials.
So that can tell the agency, okay, this was a patient population that was sort of what we would expect. There was nothing really odd about the patient population. So the results with the apremilast were as expected and reassuringly in the case of deucravacitinib, there was less of these particular issues of nausea or diarrhea. We didn't really see that as a problem. And so that was probably the key take home from the safety and tolerability comparison with apremilast.
RALN:
So what comes next for integrating deucravacitinib into the PsA treatment landscape? Where does it stand in terms of approval for PsA?
Dr Mease:
It has been approved very recently. And so now rheumatologists can start to use this medication for treatment of psoriatic arthritis as well as dermatologists are likely to do so. Dermatologists have already had access to deucravacitinib for the treatment of psoriasis, which has been a previous approval for the drug. And now we're getting the full spectrum by including psoriatic arthritis as well.
I expect, as I mentioned before, that we're going to see the use of this medication in both early patients, perhaps as early as one of the first advanced immunomodulatories out of the barn, like perhaps right after methotrexate or even before methotrexate. But I also anticipate that it would be tried in patients who are further down the road who've been on TNF inhibitors or other types of medications and now is needing to have a new therapy because they're losing response to their previous medication. And since deucravacitinib is newly on the market, it will be used in that setting as well.
RALN:
Some endpoints such as the resolution of enthesitis were not statistically significant for deucravacitinib in these trials. So there’re still some unmet needs for PsA treatment. Where does this take you in terms of further research? What's next on the research agenda for you?
Dr Mease:
Regarding enthesitis, one of the things that is a problem, if you will, about enthesitis assessment. So enthesitis for the listener is inflammation and pain at sites where tendons or ligaments insert into bone. This is a fairly unique clinical characteristic of psoriatic arthritis. Classic is Achilles tendon insertion pain or plantar fascia insertion pain or pain around the elbow or knees where ligaments or tendons are attaching.
The assessment of it is, from a clinical point of view, is not easy. All you're doing is you're pressing on this site and basically asking the patient, "Is this painful or not? " In certain centers where ultrasound is available, you can have a more objective way of looking for inflammation in the enthesial insertion site, but that's not something that's typically done and not in a large clinical trial. So I can imagine that we might have some more ...
And you're absolutely right. There was not a statistical separation between deucravacitinib and placebo, but that was mainly because the placebo response was very high. It wasn't that deucravacitinib wasn't also very ... Deucravacitinib's enthesitis performance was analogous to what we've seen with some other medications, but it's just simply that the placebo response was also very high here. And part of my going through how it's assessed clinically demonstrates that it's a little bit of a fuzzy outcome. It's not as objective as some of our other measures like feeling for swollen joints.
So I think that we might see a more look-see coming down the road and if we did some advanced imaging like ultrasound or MRI, that would give us better, more clear evidence about enthesitis. Otherwise, we've got a variety of studies coming along. Multiple biomarkers were obtained in the deucravacitinib phase 3 program. And so I'm anticipating that we're going to see more biomarker data coming out to buttress the clinical data from these trials.
I'm also anticipating that we're going to have some subset analyses, for example, the pain response and whether the pain improvement is mainly due to suppression and resolution of inflammation in say peripheral joints or entheses, or might there actually be some central nervous system impact of the drug on what we call nociplastic pain, which can be part of the pain response. Sorry, I'm getting into the weeds in some of these measures and outcomes, but these are things that get us researchers very excited.
And so another would be a more careful look-see at differences between males and females. There didn't seem to be much difference in terms of whether the patient was overweight or not, but I suspect we're going to see more analysis in that regard, partly because of the high interest these days in concomitant use of our advanced immunomodulatories along with GLP-1 receptor agonists that can help patients with weight loss, which we're now realizing can improve psoriatic arthritis outcomes.
So there's a lot to come, and we look forward to that.
The other key thing to mention is that this drug is also being studied in lupus. It had a successful phase 2 trial in lupus. Part of this has to do with the fact that it's inhibiting interferon, and so we're going to be seeing results from a phase 3 trial in lupus fairly soon. And if this drug is approved for that indication, then I think that expands its potential use as well.
RALN:
Across all of rheumatology, perhaps?
Dr Mease:
Well, at least a couple of- A lot of it. Yes.
RALN:
Yes. Well, that's very interesting. So we've got a lot to keep our eye on for the future, and I hope that we will have you back to talk about what happens next.
Dr Mease:
Well, thank you for having me with, and I'm very excited that we're getting new medications, new mechanisms of action, available to us to try to achieve our goals of putting this awful disease into a low disease activity or remission state. So thanks for having me on to educate more about this.
RALN:
It's our pleasure and we're always delighted to have you as a guest for a podcast or a video or anything else that you would like to contribute. Thank you so much, Dr. Mease. We appreciate your time today.
