乌鸦传媒

At the American College of Rheumatology (ACR) virtual meeting, promising results were announced from two studies evaluating the efficacy of , an oral tyrosine kinase 2 (TYK2)/Janus kinase 1 (JAK1) inhibitor, and , an oral TYK2 inhibitor, compared with placebo in patients with active psoriatic arthritis.

In this second of four exclusive episodes, 乌鸦传媒 brought together three expert leaders in the field, all from the Cleveland Clinic -- moderator M. Elaine Husni, MD, MPH, is joined by Leonard Calabrese, DO, and Anthony Fernandez, MD, PhD -- for a virtual roundtable discussion about the results of these studies.

Following is a transcript of their remarks:

Husni: Welcome. Thanks for joining us on this virtual roundtable for ACR Convergence 2021. Today, I'm really honored to have my good friends and colleagues here, Lenny and Tony. I have asked them to provide their opinions regarding some exciting abstracts at this year's Convergence meeting around psoriatic arthritis.

I also want to highlight another abstract, 488 on brepocitinib; kind of exciting, this is a new mechanism. We've heard a bit about TYK2 inhibitors in RA [rheumatoid arthritis]. Now, we're seeing some early data on a TYK2/JAK1 inhibitor compared to placebo in patients with psoriatic arthritis. It's only week 16 data, but they're shown to have some good disease domains that are getting better.

So, obviously this is brand new, Len. I'd love your take on how we should think about these TYK2/JAK1 [inhibitors]. Whether selectivity really matters, this combination, now that we only have early-phase data, what are your thoughts on this new mechanism?

Calabrese: Well, I think TYK2 is a very attractive target in psoriasis, it's very involved in interferon pathways. There are a number of drugs which are honing in on TYK2. Brepocitinib is a more traditional JAK inhibitor, it inhibits the kinase domain and has some selectivity for TYK2 and JAK1, and actually JAK2. The data are promising. But I am unconvinced at this early juncture that the selectivity here will be dramatically different than other JAK inhibitors which target that domain.

Deucravacitinib, which we're not really talking about, is also early in development. And this is a more unique MOA [mechanism of action] because it targets the pseudokinase domain of TYK2 and really has some selectivity there. And, at least in the early derm phase of trials, has not had even a zoster signal and we have to wait and see if that holds up in larger trials and moving into other rheumatic diseases. But this will be exciting in lupus, psoriasis, and possibly other diseases.

Husni: Yes, I agree. So clearly this class is sort of making a splash and we're seeing in multiple rheumatic diseases that there are some good outcomes. But I would love to hear, Tony, what is the JAK class for you guys in psoriasis? What are your thoughts on how the JAK inhibitors are working?

Fernandez: Well, I think, as Len mentioned, at least in dermatology there's a lot of excitement surrounding deucravacitinib. There have been two phase III trials completed looking at deucravacitinib in patients with psoriasis and there's been good efficacy. The primary outcome was PASI [psoriasis area and severity index] 75. So not quite what we're looking at for some of the newer biologic classes, but still there were significant percentages of patients who met that primary outcome and achieved at least a PASI 75. The active comparator arm in these studies was apremilast [Otezla], and deucravacitinib was shown to be superior to apremilast.

And I think, importantly also, as you and Len pointed out, the safety seems to be, at least in these clinical trials, better than what we've seen for the other JAK inhibitors, probably because of the pairing with JAK2. So there were not hematologic abnormalities, there were not lipid abnormalities, and there's not that zoster signal. So, we're quite excited.

Husni: Great, really good to see all these options. But, Len, you know there's been a lot of buzz with obviously the JAK inhibitors and some of the safety signals in terms of the thromboembolic events, whether this will be specific to certain classes or a class effect. Any thoughts on moving forward with this and psoriatic diseases?

Calabrese: I think that everyone is asking that same question, and there's two parts of that. What is the regulatory agency going to say, and what are the data over here. A regulatory agency has been very tough on this class so far based largely on data from tofacitinib [Xeljanz]. Deucravacitinib in particular really has a novel MOA and the data will be the data, but this may be something quite different than traditional JAK inhibitors that we've had. But, whenever you are talking about safety, phase I, phase II, phase III, let's talk about long-term extension and really get the number of patient years up before we get too excited.

Husni: Yeah. The other interesting thing I think is that in psoriasis, Tony, I think the patients are a bit younger than perhaps what we see in RA. And I don't know if the population, the nuances of the safety, may play a role in the future, as Len says, as we get long-term extension data.

Fernandez: Absolutely. These are just two clinical trials and may not tell the whole story. So, we always welcome more data and longer-term real-world data to really know what these medications are going to do clinically in terms of efficacy and their safety signals.

Husni: Agreed. Excellent, thank you very much.

Watch the first episode of the roundtable: Exploring the Potential of Guselkumab in Psoriatic Arthritis

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