Deucravacitinib demonstrates sustained efficacy and safety in biologic-naïve patients with PsA: Insights from POETYK PsA-1

Hello, my name is Dr Philip Mease. I’m Director of Rheumatology Research at Providence Swedish Medical Center in Seattle, Washington and also Clinical Professor at the University of Washington.

Q. What is the mechanism of action of deucravacitinib and what was the rationale for investigating this therapy in PsA?

Deucravacitinib, is a unique inhibitor of TYK2. TYK2 is a member of the Janus kinase family, and we’ve seen previous studies and approvals of various Janus kinase inhibitors, such as tofacitinib and upadacitinib. Deucravacitinib is very specific for TYK2 – it binds to the regulatory domain, as opposed to the ATP binding site, of TYK2 and by doing so, it is very specific for inhibiting TYK2 alone and not JAK-1, -2, or -3. The types of cytokines that are inhibited when TYK2 is inhibited include interleukin-23, interleukin-12, and also interferon. The result of this is going to be potentially beneficial in psoriasis, which is heavily IL-23 driven, as well as in PsA, but also lupus because of the inhibition of type 1 interferons.

Q. What do we already know about the clinical profile of deucravacitinib from previous studies in plaque psoriasis?

We have seen approval of deucravacitinib for the treatment of psoriasis based on pivotal studies comparing deucravacitinib with apremilast and placebo, in which deucravacitinib was superior in efficacy. We have data out now through 5 years, showing sustained efficacy and also a good safety profile. There is no black box warning, and we really are not seeing any meaningful safety signals in terms of infection, malignancy, cardiovascular issues, and so forth. So, this is a simple, daily, oral medication that’s been approved for the treatment of psoriasis based on its ability to inhibit interleukin-23 and interleukin-12. We’ve also seen phase 2 studies in psoriatic arthritis be successful, and in lupus where the inhibition of type 1 interferons is a key element of the drug success, and it’s in phase 3 now for lupus.

Q. Could you describe the aims, design and inclusion criteria of the phase 3 POETYK PsA-1 study?

The POETYK PsA-1 study was conducted in patients with psoriatic arthritis who were naïve to biologic treatments. A key element, besides showing clinical benefit, was to assess whether the drug had the capability of inhibiting structural damage progression as measured by X-ray changes of hands and feet.

The key inclusion criteria included, of course, patients who had psoriatic arthritis, active disease, and these patients were treated either with deucravacitinib 6 mg per day or placebo out through week 16. Then the patients who were on placebo were switched over to deucravacitinib, and the patients who were already on deucravacitinib continued with their treatment. The primary endpoint, as mentioned, was at week 16, and that is the ACR20 response. Then there were a number of other secondary measures, which I’ll comment on. We’re reporting data now out to week 52 as a late breaker abstract at ACR.

Q. What were the key clinical endpoints of the study and how well were they met at week 52?

The primary endpoint of the study was achievement of ACR20 response. During the placebo-controlled period out through week 16, 54% of patients on deucravacitinib achieved this response, and then as we track those patients out to week 52, that number was 63% achieving an ACR20 response. We also saw proportionally similar improvements in ACR50 and ACR70 response over time. Other improvements included the skin score, for example, PASI75 out through week 16 was achieved by 52% of patients, and at week 52, 66%, and all of these were statistically separated from placebo. One of the fortunate things is that as the placebo patients switched over to deucravacitinib, they saw similar degrees of improvement out through week 52.

One criteria that we measure for a targeted treatment is called minimal disease activity. This was achieved by 19% of deucravacitinib treated patients out through week 16 and then at week 52, a full 34%, a third of the patients, were able to be in a state of minimal disease activity. There were, of course, other improvements that occurred, including enthesitis as measured by the SPARCC score and dactylitis. A key outcome measure for this study was assessing the drug’s ability to inhibit structural damage progression.

If we look at the post-hoc analysis, in all patients who had appropriate X-rays at baseline and in follow-up, using Rank ANCOVA statistical analysis, there was statistical separation between the deucravacitinib treated group and the placebo group, showing ability to inhibit structural damage progression. Another key point is that more patients receiving deucravacitinib showed no radiographic progression at both week 16 as well as week 52. This is important for patients and the understanding that a therapy that they are using can inhibit structural damage progression.

Q. From this study, what can we conclude about the safety profile of deucravacitinib?

The safety profile was very similar to what we have seen in previous studies, including the large psoriasis program. There was no safety signal regarding malignancy or cardiovascular side effects. The rate of infection was very low, especially the rate of serious infection. There was one element that has been seen in other studies, in which a slightly greater proportion of people on deucravacitinib experienced mild-to-moderate acne, which is fairly easily treatable, and a handful of rashes were noted.

Q. What is the clinical significance of these findings?

As mentioned previously, in the approval for psoriasis there is no black box warning for this daily oral medication, and we are hopeful that as this goes forward for approval in psoriatic arthritis, that the regulatory agencies will treat it similarly from a safety perspective. It’s really important for us to be able to have a an effective medication, especially one that is oral for patients who prefer oral versus parenterally administered treatments.

It is also important to have a new mechanism of action to be approved as many of our patients may have tried and maybe had success with various other mechanisms of action, but eventually lost effectiveness. Having the ability to have a new mechanism of action is very important for us both at an early stage of treatment, for a patient who’s looking for relatively safe and effective oral medication, but also later in the treatment ladder, as we seek to have our patients with psoriatic arthritis get into a state of low disease activity or remission.