Emerging Plaque Psoriasis Agents: Deucravacitinib


An overview of the novel selective tyrosine kinase 2 (TYK2) inhibitor deucravacitinib for the management of plaque psoriasis.

Jerry Bagel, MD, MS: Deucravacitinib is a new brilliantly designed molecule that binds the allosteric pseudokinase portion, pseudodomain of the JAK [Janus kinase] molecule. It doesn’t really bind the JAK where it phosphorylates STAT [signal transducer and activator of transcription], it binds it at another part of the molecule; it twists it, so it doesn’t allow it to phosphorylate all the JAKs, and that’s the point. It’s not inhibiting all the JAKs; it’s only inhibiting some of the JAKs. Therefore, it’s not resulting in all the adverse events that you would see if you were inhibiting JAK1, JAK2, JAK3, etc. It’s only inhibiting tyrosine kinase. It’s a different mechanism of action completely. So, by binding and inhibiting that, STATs don’t get phosphorylated, they don’t go down to the nucleus and induce transcription of these inflammatory molecules, specifically IL [interleukin]-12, IL-23, and interferon. That’s what it’s inhibiting. By not inhibiting all the JAKs, you don’t see thrombosis, malignancy, or high triglycerides in its adverse event profile, so it’s slightly different.

As far as how it works, it’s 6 mg PO [by mouth] QD [every day]. And at week 16, head to head with placebo and also against apremilast, it had a PASI 75 [75% reduction in the Psoriasis Area and Severity Index] of about 65%. It also has some good PsA [psoriatic arthritis] efficacy. When you go head to head with apremilast, which has a PASI 75 of about 30%, it’s about twice as good, which to me is a game-changer. This is a game-changer. I didn’t prescribe apremilast much because at 30% efficacy I didn’t feel that I was offering my patients a high enough benefit to really take a chance on the nausea, bellyaches, diarrhea, headaches, and possible depression. I never used it a lot, but it’s a $13 billion drug, so someone is using it.

But this now has efficacy that’s twice as good. I will definitely offer this oral medication. It will be interesting to see how when you pitch it to your patients directly, like, “Hey, I’ve got a pill that works, you’re going to get 75% better two-thirds of the time, or I’ve got a shot that I can give you every 12 weeks, and you’re going to get 75% better 95% of the time.” It will be interesting to see what people choose.

I think a lot of people do want pills, just by the fact that apremilast is a $13 billion drug. When [a patient] enters into a psoriasis center, you really want to give everybody the best options, and that’s why I didn’t always offer apremilast. It’s usually those people who would ask for it.

I think ultimately people prefer pills to shots. In the end, as long as there’s efficacy and the adverse event profile is good, I think many people will prefer a pill to start with to see how it works, and we give it 16 weeks and see if they’re happy with their overall response. That’s the major one that’s different. The question will be though, as I said, if it’s a JAK, then it’s going to have to be monitored. Apremilast didn’t have to be monitored, so we’ll have to see where it turns out.

Hopefully, it will get a favorable PI [prescribing information approval] from the FDA, and it’s not necessarily in the JAK family, but we’ll see.

Basically, it’s head to head with placebo, 6 mg PO QD for 16 weeks. The average person had an affected body surface area of about 20%. They were about 45 years old. They were mostly biologically naїve, and there were about 1000 people overall in the study, which is quite a few. At week 16, that was a primary end point of PASI 75, but they also showed that there was a significant improvement in itch, DLQI [Dermatology Life Quality Index] was significantly improved down to almost nothing. The adverse event profile looked really clean. And at week 16 they all converted over, including those on placebo, to continue deucravacitinib through week 52, and the efficacy improved somewhat to I think about 65%, 70% of PASI 75 by week 52.

Assuming that there’s not much monitoring, then I think it will go over really well. But let’s look historically. Even apremilast took a few years before the insurance companies were really letting us write [a prescription for] it. They were actually having patients fail Humira [adalimumab] or Enbrel [etanercept] before going on apremilast. That could transpire here as well. It’s going to depend a lot on how BMS [Bristol Myers Squibb] and the insurance companies work their magic to allow for access. That’s going to have to be an easy one because people aren’t going to fight too hard because they don’t have the time.

The TYK2 [Tyrosine-protein kinase 2], even though it may have a JAK PI [phosphatidylinositol], is not a JAK inhibitor, and the adverse event profile does not show any of the JAK troubles like thrombosis, MACE [major adverse cardiac event], malignancy, and triglycerides. I think they need to be more aware of the safety of this drug compared to other JAKs that are going to be out there.

Transcript edited for clarity.

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