Understanding the Differences Between Inhibiting TYK2 Versus Traditional JAK Inhibition

Video

Thought leaders talk about the approval and integration of a first-in-class agent into the treatment armamentarium. They also review the mechanisms of TYK2 inhibition.

Linda Stein Gold, MD: We’ve had some new innovation fortunately in terms of our oral agents, and we know that deucravacitinib was recently FDA approved. This oral agent belongs to a class of drugs called the JAK inhibitors, yet it’s kind of a cousin to the other JAKs. Can you help us to understand what is that JAK family, and how do we differentiate a TYK2 inhibitor potentially from a JAK1, 2, and 3 inhibitor? By blocking these different proteins, how does that affect things downstream?

Bruce Strober, MD, PhD: To review, there are 4 JAK kinase inhibitors, JAK 1, 2, 3, and TYK2. Now, they all have very strong similarity, homology as it’s said, in their catalytic domain, the domain that phosphorylates a target. It binds ATP, and it adds a phosphate group to its target. And because they have homology in those domains, if you design an inhibitor to the catalytic domain, it often is not specific. It can inhibit all 4 of those proteins, all 4 of those kinases. But if you design an inhibitor that binds to a nonconserved area of those proteins, and we know what’s called the regulatory domain of those 4 proteins, those 4 enzymes, isn’t conserved across the 4 of them, then you can be very specific. So a TYK2 inhibitor would bind the regulatory domain of TYK2 and not see at all the JAK1, 2, and 3 regulatory domain. In so doing, it creates a confirmational 3-dimensional change in TYK2, and that change, called allosteric, deactivates the kinase domain. It’s sort of an indirect approach to changing the kinase domain from active to deactive, and only doing so through the binding of a regulatory nonconserved domain.

Linda Stein Gold, MD: I’m going to try to summarize what you just said. What you’re telling us then is that each of these molecules has 2 different regions. One is the same across the family, one is unique across the family. So what is different about deucravacitinib is it is binding to that unique area, therefore we don’t expect it to have an unwanted effect by hitting the others.

Bruce, can you explain to us what are the implications of blocking TYK2 compared to blocking JAK1, JAK2, JAK3 in terms of the downstream processes?

Bruce Strober, MD, PhD: To be clear, the traditional JAK kinase inhibitors that block the catalytic domain do have efficacy in a manner that’s similar to a TYK2 inhibitor. But when you block JAK1, 2, or 3, or a subset of those, you bring into play tolerability and safety issues, particularly the need to monitor the CBC [complete blood count], elevations in lipids. Then perhaps adverse event profiles that are unsettling to some extent, for example, increased risk of MACE [major adverse cardiac event], increased risk of thromboembolism, perhaps increased risk of serious infection, and maybe malignancy. When you block just TYK2, you’re essentially being very specific for IL-12 [interleukin-12] and 23, and interferon. TYK2 mediates signal transduction just through receptors for IL-12/23 and interferon. Therefore, you’re very specifically blocking the pathophysiology that we know is most relevant to psoriasis and psoriatic arthritis. For that reason, we get the benefits when we get TYK2 inhibition with regard to efficacy. But because we leave aside the pathways mediated by JAK1, 2, and 3, we lose the adverse events and perhaps the laboratory issues that are more part and parcel of using a traditional JAK kinase inhibitor.

Linda Stein Gold, MD: That makes sense. We’re blocking JAK1, 2, and 3; we have downstream metabolic, hematopoietic effects. That’s why when we use drugs that block those particular enzymes, we worry about the laboratory.

Bruce Strober, MD, PhD: Correct.

Linda Stein Gold, MD: But then on the other side, you’re explaining that TYK2 has more specificity to the inflammatory mediators that we associate with psoriasis, and it doesn’t have that downstream metabolic problem potentially.

Bruce Strober, MD, PhD: Correct.

Linda Stein Gold, MD: So we wouldn’t expect necessarily to need to monitor blood work if we’re very targeted to TYK2.

Bruce Strober, MD, PhD: That’s right. In fact, the laboratory monitoring for the TYK2 inhibitor deucravacitinib is little to none. There are some instances where there’ll be a slight excursion upward of triglycerides. CPK [creatine phosphokinase] might be slightly elevated in some rare individuals. Then in a person with significant liver disease, we might have to monitor the liver. But for your average run of the mill patient with psoriasis, it’s probably not necessary to follow laboratory evaluations like we would have to with a traditional JAK kinase inhibitor.

Transcript edited for clarity

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