‘Next-Generation TYK2 Inhibitor’: Insights into Zasocitinib

In a recent interview with Dermatology Times, Christopher Bunick, MD, PhD, discussed what he calls a “next-generation TYK2 inhibitor,” zasocitinib. Bunick highlighted its high selectivity and potency, sharing data from clinical trials shared at the 2024 European Society for Dermatological Research (ESDR) meeting.

Transcript

Christopher Bunick: Hi, I'm Dr. Christopher Bunick, associate professor of dermatology and translational biomedicine at the Yale University School of Medicine.

Dermatology Times: What new information did Takeda present at the 2024 ESDR meeting?

Bunick: I'm here today to discuss some data from Takeda on their new drug zasocitinib that was recently presented at the ESDR meeting in Lisbon, Portugal. What I'm really excited about is this data is getting to the heart of really how tyrosine kinase 2 (TYK2) inhibitors work and how they're different fromjanus kinase (JAK) inhibitors. So really what we're talking about is what makes zasocitinib that next generation TYK2 inhibitor? How is it different than deucravacitinib (Sotyktu; Bristol-Myers Squibb)? How is it different than JAK inhibitors, and what is it going to do for patients in terms of potency and selectivity? That is really at the root of the data that was presented at the ESDR meeting.

DT: What are some of the highlights of this new zasocitinib data?

Bunick: I'd love to dive into a little bit about what the specifics were in this particular data that we presented at ESDR. Ultimately, what we're wanting to show is that the zasocitinib has really, really high TYK2 inhibition. That inhibition can occur in terms of high binding affinity, high inhibition of TYK2 but we also want to have very little JAK1, JAK2, JAK3 inhibition. That's what creates that selectivity. How we think about in terms of clinical care of patients is that potency may equate with the efficacy of the therapy and that selectivity may equate with the safety of the therapy. What we presented at ESDR, we can divide this up into kind of 3 big studies. The first study was simply asking the question: “How well does zasocitinib, compared to deucravacitinib, inhibit the TYK2 allosteric domain, also known as the JH2 domain, compared to the JAK1 allosteric domain or JH2 domain?” This was done in vitro, and what we found was that the zasocitinib can select or inhibit the TYK2 allosteric domain, 1.7 million-fold more selective than the JAK1 JH2 domain. Now, why is this important? Well, the currently approved TYK2 inhibitor on the market, deucravacitinib, the selectivity for the TYK2 allosteric domain over the JAK1 allosteric domain is only 87-fold. Here, you're looking at over a million-fold difference between the selectivity of the TYK2 allosteric domain over the JAK1 allosteric domain between these TYK2 inhibitors. When we say that zasocitinib is that next generation TYK2 inhibitor, this difference in selectivity is 1 of the major reasons why, and we believe it is going to translate into higher clinical safety. Indeed, in the clinical trials so far published on zasocitinib, that's what we're seeing. We're seeing incredible clinical efficacy but coupling that with very high clinical safety. The second big study that we presented in this data set was now taking whole blood from patients and asking, how well does zasocitinib verses deucravacitinib verses 3 JAK inhibitors (baricitinib, upadacitinib, and tofacitinib) inhibit either a TYK2 dependent signaling pathway or a JAK1/3 signaling pathway. For the TYK2 signaling pathway, we're looking at interleukin 12/18, stimulated interferon gamma, and in the JAK1/3 dependent signaling pathway, we are looking at the IL-2 driven phosphorylated stat 5. In these 2 assays, the take home point is that on the TYK2 driven pathway, zasocitinib outperformed deucravacitinib and all the JAK inhibitors, which we wouldn't expect to necessarily hit the TYK2, but it outperformed deucravacitinib and was the best at inhibiting the TYK2 driven inflammatory signals. But on the flip side, on the JAK1/3 driven pathway, it was the least effective at inhibiting JAK1/3, which is what we want. That is that selectivity for TYK2 inhibition. That was the second major assay. And then the third, final component to our analysis was to, using pharmacokinetic modeling, take the concentration, the mean plasma, or the plasma concentration of all of the drugs that we were analyzing, look at the concentration in the plasma over time and see if the concentration of the drug in the blood of the patient is going to be above the what's known as the IC50 level. We wanted to see what's above that concentration, that 50% that concentration, needed to inhibit 50% of the target. What we found was very interesting. In this modeling, zasocitinib is able to maintain its plasma concentration above the TYK2 IC50 for all 24 hours of the day. I think this is 1 of the biggest surprises in the data that I had, was that the current TYK2 inhibitor deucravacitinib only maintained its plasma concentration for 3 hours. If you're a patient and you're receiving this next generation TYK2 inhibitor zasocitinib, it's in the blood, its concentration is above the threshold needed to inhibit that TYK2 enzyme for all 24 hours, compared to deucravacitinib where it's only 3 hours. By 4 hours, it's below that IC50 level. When you do the modeling, the zasocitinib is not hitting the JAK1/3 and the JAK inhibitors (baricitinib, upadacitinib, and tofacitinib) are not inhibiting the TYK2 any substantial amount. To put all that together, what does this mean for the patient? What it means is when you do the mathematical modeling that in the end this TYK2 inhibition, it’s estimated that zasocitinib is inhibiting on a daily basis 91% of the TYK2 signaling, compared to deucravacitinib, where it's only around 24%.When you think about inhibiting TYK2 signaling and the inflammation and inflammatory pathways that are driven by TYK2, whether this is psoriasis, atopic dermatitis, or other TYK2 dependent inflammatory disorders, what we're seeing is that the next generation zasocitinib has that higher potency, that higher selectivity, and this is going to translate into clinical efficacy and safety, as we're seeing in the clinical trials.

DT: What are the next steps in research for zasocitinib?

Bunick: The next steps in zasocitinib are completing the phase 3 clinical trials in both psoriasis and psoriatic arthritis. I think that this is where it's going to really shine. When these clinical trial data come out and we see not just the efficacy, but the safety, and that's what we're looking for in the phase 3 trials. As I said, there's other TYK2 mediated inflammatory diseases in which the zasocitinib will certainly become a player in those spaces as well. I think that 1 of the important things to take home is that we've experienced over the last couple of years in dermatology this onboarding of different types of JAK inhibitors. This includes, you know, the traditional JAK1/2/3, but also the TYK2 inhibitors. These are first generation molecules in terms of the dermatology space. What zasocitinib represents is the benefit that we can get as a specialty from that next generation ofTYK2 or JAK inhibitor design. In the case of zasocitinib, artificial intelligence (AI) guided structure-based drug design was used to optimize and develop zasocitinib. Here we have a molecule that's, in part, AI driven in its design, and it's outperforming by all measures, the existing TYK2 inhibitor on the market. I think dermatology should be incredibly excited about what zasocitinib can bring for initially psoriasis patients, and then hopefully beyond psoriatic arthritis, atopic dermatitis, and other diseases.

DT: What about this zasocitinib data makes it stand out from other TYK2 inhibitors?

Bunick: One of the questions that dermatologists might have iswhy do we need another TYK2 inhibitor? I think that the goal of this poster and this presentation at ESDR was to really show the dermatology community that there is so much more that can be done to inhibit the TYK2 pathway. Deucravacitinib was a very good first start. But what zasocitinib representsis, again, I call it this next generation, very potent, very selective TYK2 inhibitor. What we're showing in this data is that it is possible to achieve more efficacy and more safety through an oral TYK2 inhibitor. Patients in psoriasis and psoriatic arthritis do want oral therapy, therapeutic options, and we know, from head-to-head trials, from deucravacitinib with apremilast, that inhibiting the TYK2 pathway, is the superior way to go in treating psoriasis. What our data shows is that zasocitinib has all the potential to be a best-in-class oral therapy for psoriasis and psoriatic disease.

[This transcript has been edited for clarity.]