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Efficacy of Deucravacitinib in Plaque Psoriasis


Lakshi Aldredge, MSN, ANP-BC, reviews the mechanism of action of deucravacitinib, commenting on its efficacy in the treatment of plaque psoriasis.

Alexa Hetzel, MS, PA-C: Lakshi, can you explain what the distinctive selectivity of deucravacitinib is, the mechanism of action, and how it differs from the different JAK [Janus kinase] inhibitors we have for atopic dermatitis?

Lakshi Aldredge, MSN, ANP-BC: Yes, and just carrying on with your conversation, it’s amazing to see the expansion of treatment options that we have, going from topicals, where we really thought that the action was purely in the keratinocytes, to the advancement of understanding that this is an immunological disease. Then moving from not only topicals but to oral treatments and then biologics has really transformed. It’s an interesting paradigm shift now that we’re seeing new agents that are oral therapies, so pills again, as well as new topical treatments. We’re coming full circle in our understanding of how effective treatments can be.

It’s been interesting to me to see the efficacy of an oral agent that mimics the efficacy that we’ve seen with our biologic therapies. Deucravacitinib has a novel mechanism of action. It’s a TYK2 [tyrosine kinase 2] selected inhibitor that is an oral agent taken once daily that targets IL [interleukin]-12 and IL-23. It has the same mechanism of action and focused target of action that we see with the biologic agents.

One of the differences between biologics and pills is that we’re used to thinking of biologics being highly targeted and very safe, whereas the traditional pills that we’re used to, such as apremilast, methotrexate, and cyclosporine, we think about them having a wide effect within the immune system and perhaps not being as safe, and perhaps contributing to end-organ damage. With deucravacitinib, this is not the case. We see in this oral agent, highly specific action focusing on TYK2 inhibition, which we know seems to play an active part in controlling IL-12 and IL-23, both of which have been identified as key cytokine players in the pathogenesis of psoriasis.

With deucravacitinib, an oral agent taken once daily, because of its focus on TYK2, we do not see the adverse effects that we see with JAK inhibitors 1, 2, and 3 that, especially in the rheumatoid space, we were concerned about the adverse effect profile. We started to see a lot of major adverse cardiovascular events, especially thrombolytic events. We’re just not seeing that with selected TYK2 inhibition. With deucravacitinib, we see focused inhibition that seems to have high efficacy with a very favorable safety profile that we’re used to seeing with biologic therapies. Again, giving us a lovely alternative to biologic agents because we know there are some patients who don’t want to take injections, or perhaps cannot. Having a once-daily oral formulation is a lovely alternative.

Alexa Hetzel, MS, PA-C: Very nicely said.

Jennifer Conner, MPAS, PA-C: It’s the allosteric inhibition that’s the difference that allows the TYK2, that pathway to be so specific for those inflammatory cytokines for psoriasis. The JAK inhibitors are inhibiting a much broader immune response, and that’s where we see more of those systemic adverse effects and those cardiovascular events that we worry about.

Alexa Hetzel, MS, PA-C: Go for it, Laura.

Laura Bush, DMSc, PA-C: I think the mechanism of action is very cool. It’s neat how the deucravacitinib attaches at the regulatory domain so therefore it’s allosterically changing the actual shape, which is not allowing the active domain to bebound to. Therefore it’s stopping it at that point, which is affecting the IL-23, which is effectually making less IL-17. It’s just a cool mechanism of action, and because it’s so highly specific, it’s not crossing over like the other JAKs. It’s in the JAK family, but it’s so highly specific that it doesn’t leak out like the others do; therefore you don’t have the adverse effects and the events. So that’s really a win-win.

Alexa Hetzel, MS, PA-C: And it’s intracellular. That’s one thing that we didn’t say. The biologics are extracellular, so they’re binding to the T helper 2 cells, whereas deucravacitinib is getting inside the cell and stopping that transcription of the message to the nucleus. So we’re not getting extra IL-17, which is so cool.

Jennifer Conner, MPAS, PA-C: It’s so cool.

Laura Bush, DMSc, PA-C: It is cool.

Alexa Hetzel, MS, PA-C: It’s so different. I love it.

Transcript edited for clarity

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