Review of Current and Novel Treatment Pathways to Manage Plaque Psoriasis - Episode 10

Introduction of a New Class of Agents: TYK2 Inhibitors

January 24, 2022

Dr Lebwohl provides insight on a new class of agents, the TYK2 inhibitors.

Linda F. Stein Gold, MD: Mark, there’s a lot of activity going on with the oral treatments and there we have a new drug, which is now a JAK inhibitor for psoriasis, but this one’s different. This is a TYK2 inhibitor. Can you talk to us about what this is and how does it differentiate from the other JAK inhibitors?

Mark Lebwohl, MD:Tyrosine kinase 2 is interesting because if you block only that, then it doesn’t have any effect on the bone marrow. It doesn’t have any effect on lipids. It doesn’t have any effect on the kidneys. It doesn’t have the effects of the other JAK kinases that we worry about. Unfortunately, because they’re significantly immunosuppressive, they’ve gotten these worrisome black-box warnings. I don’t know if the TYK2 inhibitor deucravacitinib will get that, but it doesn’t deserve it. I’ll explain why in a minute. But when they look at the impact on lipids, on hemoglobin, on white blood cell count, on kidneys, and all the other things that we get into trouble with the other JAK inhibitors, there is 0 effect.

It’s a very safe medicine. Why is that? It blocks a different domain, the regulatory domain of TYK2. All the Janus kinases have an ATP-binding site. The way they work is they release phosphate from ATP, and phosphate is the signal that they then pass on to STAT. That’s why we call it the JAK-STAT signaling pathway. The other JAK kinases block that ATP-binding site and impact the JAKs. This 1 blocks only the regulatory domain, which doesn’t exist for the other JAKs. When you look at the impact on other Janus kinase activity, it’s almost 0.

What does TYK2 interact with? What does blocking TYK2 cause? It causes a blockade of IL-12 and IL-23, just like ustekinumab. It also causes a blockade of interferon-alpha and gamma, which may have some adverse effects that we’ll have to be on the lookout for. But so far, we’re seeing 0 adverse effects from this drug. It’s very promising, and it will be a very widely used oral agent for psoriasis.

Linda F. Stein Gold, MD: That’s a nice description of what makes this different. In fact, sometimes, when we increase the dose of the other JAK inhibitors, we start to see a bleeding over affecting other JAKs. We don’t see that with this TYK2 though. It still stays in specific TYK2 inhibitory process. We have some data here. Jerry, you’re very familiar with the efficacy data. Can you walk us through what we can expect?

Jerry Bagel, MD, MS:I want to go back to what Mark said. This is very different from a JAK inhibitor. It’s not binding the ATP-binding site as other JAKs do. It’s called an allosteric inhibition. It’s binding a different part of the molecule that twists it. It doesn’t allow the ATPs to work in some situations. It’s not as ubiquitous as the other JAK inhibitors. That’s why, ultimately, we’ll see that safety is looking better.

Linda F. Stein Gold, MD: Thank you, Mark, Jerry, and Leon, for this rich and informative discussion. Thank you for watching this HCPLive® Peer Exchange. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your in-box.

This transcript has been edited for clarity.