Optimal Management of Rheumatic Disease During COVID-19 - Episode 8
Philip J. Mease, MD: These were very interesting data. Deucravacitinib is an oral medication. It is a selective tyrosine kinase 2 inhibitor, a TYK2 inhibitor. So in the Janus kinase family there is JAK1, JAK2, JAK3, and TYK2, so all these are considered part of the Janus kinase family. They have a role in facilitating signaling from a receptor on, say, an immune cell surface for a potentially pro-inflammatory cytokine, which then signals into the cell and gets the cell to turn on and produce more inflammatory cytokines. Giving an inhibitor to 1 of these JAK molecules inhibits this signaling. There are many pro-inflammatory cytokines that signal through this mechanism. And whether it’s a JAK1 and JAK3 or a JAK1 and TYK2 at the receptor site makes a difference in which cytokines are doing the signaling. For example, if they are, TYK2 we know has a role in inhibiting signaling by interleukin-23. From the data that we just discussed with guselkumab, we know this a very important cytokine in the pathogenesis of psoriasis and psoriatic arthritis. There are other cytokines that are affected as well.
This particular molecule, deucravacitinib, is also unique in that it is an allosteric inhibitor that attaches to the regulatory domain instead of the ATP-binding active side of the catalytic domain. It is extremely specific for TYK2 in that way, and this ultimately may have some impact on efficacy or safety.
This was a phase 2 trial, and the results were good. We saw at ACR20 [American College of Rheumatology 20% improvement] that the response at week 16 with the 6-mg dose was 53%; with the 12-mg dose, it was 63%. We also saw over time that there was a quick onset of action upon reaching these particular end points. We saw a statistical separation between the treated groups and placebo with ACR50 response or ACR70 response, and we also saw significant improvement in function, SF-36 [Short Form 36 health survey] physical component, the Leeds Enthesitis Index, the SPARCC [Spondyloarthritis Research Consortium of Canada] Enthesitis Index, and the achievement of minimal disease activity goal in about 23%, 24% of the patients, depending upon the dose arm.
Of course, we anticipated that we would see a good skin response because of this particular mechanism of TYK2 inhibition. We’ve seen a separate psoriasis phase 2 study, in which 69% of patients had achieved a PASI 75 [Psoriasis Area and Severity Index decrease of 75%], response. This is a little higher than what we’ve seen with the other JAK inhibitors, and it’s consistent with this mechanism. We saw good rates of skin improvement in this trial, and this is exciting. Oral is a new mechanism; the safety profile was very good in both this trial and the psoriasis trial. We really haven’t seen much in the way of signal of major problems, so we’re very much looking forward to this moving forward into a phase 3 study.
Transcript Edited for Clarity