Philip Mease, MD, on the POETYK Trials of Deucravacitinib in PsA

In part 1 of a two-part podcast, Dr Mease reviews the findings of two clinical trials of the TYK 2 inhibitor deucravacitinib: POETYK 1 of patients without previous biologic treatment, POETYK 2, which included some patients with exposure to biologics.

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.

Deucravacitinib in Psoriatic Arthritis: Phase 3 POETYK-1/POETYK-2 Trials Show Efficacy Across Biologic-Naive and -Experienced Patients

• Phase 3 POETYK-1 (biologic-naive) and POETYK-2 (mixed prior biologic exposure); 16-week primary endpoint: Both registration trials met the primary endpoint (ACR20 at week 16) with statistically significant separation vs placebo, alongside significant improvements in PASI (skin), physical function, fatigue, and pain, with similar efficacy across populations.
• Patient populations and structural outcomes: POETYK-1, which had a larger, biologic-naive cohort, demonstrated inhibition of structural damage progression on radiographs in hands, wrists, and feet. POETYK-2 included biologic-experienced patients, showing efficacy even in more refractory disease, with only slightly lower responses vs biologic-naive patients.
• Onset, durability, and safety context: Clinical responses occurred within 16 weeks, with placebo-to-active switch patients “catching up,” and sustained or numerically improved responses through week 52, supporting durability. No signal for cardiovascular events or malignancy has emerged and there is no requirement for prior TNF inhibitor use.

Welcome to this podcast from the Rheumatology and Arthritis Learning Network. My name is Rebecca Mashaw. I'm the managing editor for the network, and I am delighted to be here this morning with Dr. Philip Mease. And Dr. Mease, would you introduce yourself please?

Dr Mease:

Yes, Rebecca. My name is Dr. Philip Mease. I'm a rheumatologist based in Seattle. I direct the research division for rheumatology at Providence Swedish Medical Center, which is a large healthcare institution in Seattle. And also I'm clinical professor at the University of Washington.

RALN: Thank you for joining us and talking about these two different trials of deucravacitinib for the treatment of psoriatic arthritis, POETYK-1, and you presented some results of that at the ACR Convergence last year, and POETYK-2, which you presented at EULAR. Let's start with you explaining how these trials differed in terms of patient characteristics, key outcomes, and any other important factors.

Dr Mease:

When a medication is in the development process, the FDA requires that in phase three, there be at least two very substantial trials in order to confirm efficacy and safety. So these were the 2, as I call them, registration trials that followed the original successful phase two study with deucravacitinib and PSA. POETYK 1 was with a patient group of psoriatic arthritis patients who were naive to any biologic treatment. They could have been on methotrexate or leflunomide or sulfasalazine previously, but just not treated with any biologic. It was a slightly larger trial, and one of the key outcome measures besides clinical efficacy and safety was looking at x-rays of hands and wrist and feet in order to determine whether or not deucravacitinib could inhibit structural damage progression, which it turned out it could. And so this is an important outcome when we're developing medications for treating a potentially destructive arthritis condition.

So that was POETYK 1. POETYK 2 was a trial in which there were some patients involved who had had previous biologic therapy and some who had not. And so it was a slightly different patient population, some of the patients more refractory. And there too, we were learning about how well the drug would work in patients who had been previously treated with other agents like TNF inhibitors, for example. Otherwise, the trials were really identical with a 16-week primary endpoint, key measures such as ACR20, response, skin measures, and so on, quality of life, physical function, fatigue, all the kinds of things that we like to see being done in a large phase 3 program.

RALN:

So tell us about the trial results. Did deucravacitinib meet its key and secondary endpoints, and how did it do in these two different patient populations?

Dr Mease:

So the results for the primary endpoint, which was ACR20 response at 16 weeks, was achieved, meaning there was a highly statistical separation between the treatment group and the placebo group, and the results were very similar. So high levels of ACR20 response, and then also key secondary endpoints showed high level of response, such as the skin score, which we call PASI or Psoriasis Area and Severity Index, which was highly significant in the deucravacitinib group compared to the placebo group. Both patient populations had similar degrees of efficacy. Also, besides some of these quantitative measures of joints and skin, we saw highly significant improvements in physical function, fatigue, pain. These are the things that are important to patients, and they too showed significant separation from placebo.

RALN:

Did you see any differences between patients who were entirely naive to biologic DMARDs and those who had been exposed to anti-TNFs or other biologic therapies?

Dr Mease:

As is typically the case, we saw very slightly better results in the bio-naive population than in the bio-experienced population, but not enough to say, "Oh, this isn't going to work very well in a patient who's already experienced a bunch of biologics previously." I think it's going to be fair game for this agent to be used both early on as one of the first treatments that a patient might appreciate. And the fact that it's an oral medication is something that many people might well appreciate. Sometimes when I'm presenting to a patient for the first time going on a biologic therapy that is either injected as the subcutaneous medication or given as an infusion, their eyes grow wide and they, "Wow, that's a pretty big deal, putting me on a parenteral therapy." And so some patients prefer an oral because it seems like an easier introduction, and then some patients really hate needles.

So for those reasons, I think having a highly effective oral medication is a plus. So the other point to be made is that even in patients who've been on various biologics previously, there's still efficacy that can be achieved with this new mechanism of action. And so I think at both ends of the spectrum, this can be effective.

RALN:

Did you find that there were any subgroups of patients, whether it was baseline disease severity, CRP levels, age, sex, whatever kind of other factors might have been involved, who responded particularly well or didn't respond very well to this treatment?

Dr Mease:

It seemed like when you looked at various subsets like the ones that you've just described, there really didn't seem to be anything that stood out. I'm going to point out one in particular, but this is, I have to acknowledge this is based ... A lot of this analysis was based on the phase 2 data. So one of the things that we have seen is a difference between males and females in response to biologic therapy. In a large meta-analysis conducted by Lihi Eder from the University of Toronto, she found that patients who were on various biologic medications for psoriatic arthritis, that men had a better response than women.

And we're in the midst of a large study called the SAGE study that is being sponsored by the GRAPPA organization and I'm helping Lihi in this particular study in which we're collecting ... We're looking at men versus women who are starting a biologic medication and studying the heck out of them, looking at neuro-hormones, looking at various immune characteristics and so forth to try to understand what are the factors behind this apparent difference.  Is it related to immunologic pathways in their body or their central nervous system? Does it have to do with neurohormones? So this observation has been made. But interestingly, when we look at the JAK inhibitor family of medications, there didn't seem to be a big difference. And this included deucravacitinib from their phase 2 study. And so we're going to be looking at that more carefully here in this phase 3 program, but for whatever reason, we're seeing similar responses between men and women.

RALN:

That's very interesting. And we'll be looking for those results as they become available. One thing I have heard from other experts in this field is that women often report more pain in psoriatic arthritis than men do. And did you look at pain as one of these markers?

Dr Mease:

Yes. So you're correct that besides some of the immunologic differences that we have found between men and women, there are differences in the way pain is experienced and with women being slightly more sensitive and having slightly greater pain response. So we're in the midst of looking at that for these phase three studies.

RALN:

You mentioned the JAK-STAT family. This is a TYK2 inhibitor, as I understand. That's part of the JAK-STAT family, the pathway. Does this TYK2 inhibitor differ significantly from the JAK inhibitors? Is it safer? Is it more efficacious? Have you even looked at a direct comparison of those compounds to see how they might differ?

Dr Mease:

It's an important point because one of the issues that's arisen with the JAK1, 2, and 3 inhibitor agents, which, for example, tofacitinib or upadacitinib or baricitinib, they now have a safety label from the FDA that raises an issue that came out of the ORAL surveillance study with tofacitinib where there was slightly more, underline the word slightly, more risk for either cardiovascular events or malignancy with the JAK1 and 3 inhibitor, which is tofacitinib. And so the FDA said, "Well, given this finding, we're going to put that safety label on all of the members of that JAK 1, 2, and 3 family, and we're going to ask that they be given after a TNF inhibitor is given because in that particular study, the results were slightly worse for the JAK family compared to the TNF inhibitor family."

This has not surfaced with TYK2 inhibitors. We haven't seen a signal for cardiovascular adverse effects or malignancy, for example, and so we don't have that as part of the safety label for the TYK2 inhibitors. So that's really a key difference from the rest of the JAK inhibitor family. In terms of efficacy, that's harder for me to say whether there's one or the other is more efficacious because we don't have head-to-head comparisons to look at, which I would need to see in order to make a comment about any efficacy difference.

RALN:

But you do have the advantage with deucravacitinib that you don't have to have the TNF experience before the patient is eligible to take this particular drug?

Dr Mease:

That's correct.

RALN:

Patients who switched from placebo at week 16 to the active arm and received the TYK2 inhibitor appeared to catch up to those who had started off with deucravacitinib in terms of improvements in both skin and joint pain and the other factors that you measured. What does this tell you about the drugs onset of action? Is it a fast initial response? What do you derive from that result?

Dr Mease:

That the drug works. So it's reassuring when we see placebo catching up the way you've just described it in a similar way as the patients that were initially from the start treated with deucravacitinib. So that A, it buttresses the overall efficacy data, that it works well. The safety profile was similar in that originally placebo patient population and the working within a 16-week time period is pretty quick. It's similar to what we have seen with other agents, TNF inhibitor class, IL-17 class, and so that's all reassuring. And we can turn to our patients and say, "We can expect over this period of time these kinds of results."

RALN:

You also observed continued improvement through week 52. Do you have any idea what's driving that sustained response? What does that tell you about the durability of this for long-term disease management?

Dr Mease:

So when we see a sustained efficacy results out through week 52, that's reassuring about the durability of effect. In this particular study, we saw that there was numeric improvement over the course of the 52 weeks, so a higher response, and most of the endpoints at week 52 is compared to week 16. We don't have a placebo group to compare to during the week 16- to 52-time period, and so it's a little hard to say whether that's truly a climbing result or just basically a maintained result.

The key point though is that it looks as though the effect is durable and so I take heart in that and appreciating that we can have sustained effect because that's one of the big issues we face in practice is that the effectiveness of all of these agents tend to wear off in time and we need to move on to another agent. So the longer we can have data on durability of effectiveness, the better.