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Kim Papp, MD, PhD, FRCPC: Exploring the Potential of ESK-001 in Plaque Psoriasis

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Papp shared insights from the recent STRIDE phase 2 trial, which met all its primary and secondary endpoints. Data was presented at the American Academy of Dermatology Annual Meeting.

The phase 2 clinical trial of ESK-001, a TYK2 inhibitor, for treating moderate-to-severe plaque psoriasis, met its primary endpoint of PASI 75 at week 12 compared to placebo, along with key secondary efficacy endpoints across all relevant doses, according to data presented at the American Academy of Dermatology Annual Meeting in San Diego, California.

In the STRIDE trial, dose-dependent responses were observed, with maximal efficacy achieved at the highest dose of 40 mg twice daily. The treatment demonstrated sustained efficacy and safety, paving the way for phase 3 trials planned for the second half of 2024, according to Alumis.

Dermatology Times recently spoke with Kim Papp, MD, PhD, FRCPC, a dermatologist involved in general practice and clinical research, primarily in inflammatory disorders. Papp, who is the founder and president of Probity Medical Research, shared insights from the early data and discussed the role ESK-001 may play in the future of plaque psoriasis.

"I can be confident that it would be a very respectable player if it moves into phase 3 and is successful in completing the phase 3 programs," Papp said.

Transcript

Kim Papp, MD, PhD, FRCPC: I'm Kim Papp. I'm a dermatologist. I have a general practice in dermatology as well as a fairly large portion of my time devoted to clinical research. Most of the clinical research is involved in inflammatory disorders, and that's because that's where drug development has largely occurred, but I've dabbled in many other areas, including non-inflammatory conditions--so quite a breadth of experience.

Dermatology Times: Could you provide an overview of the phase 2 clinical trial of ESK-001 for plaque psoriasis?

Papp: When looking at new new drugs, in even older indications, ESK-001, for example, in the treatment of psoriasis, phase 2 studies are done to explore the dose ranges to see where can we push the dose to find optimal response. You go to the highest dose that gives you optimal response. So if you see several doses that give you the same response, you just take the lowest dose and achieve that level. That's the general rule of thumb.

So what we've seen with ESK-001 is that there was a very good dose response that extended right to the upper ranges of dosing, and that at the upper levels, we still possibly had a little bit more room to go. I think that's the easiest way of summarizing it. I did not show all of the data, because there is a very clear dose response relationship with the lower doses not achieving the same level of efficacy, so measured by PASI 75, 90, or 100.

We also saw very interesting and I think, known but not always appreciated, phenomena. That is, when we take a primary endpoint, which is usually pretty early in the course of therapy, so say 12 weeks and sometimes 16 weeks, we know that there's additional benefit, more often than not, by extending the treatment interval. That's exactly what we saw with ESK-001, where peak response actually didn't occur till about a week 24 or so, which is in keeping with virtually all of the other therapies that we have in plaque psoriasis. So it's a known pathway, but potentially, a molecule that is more effective in blocking TYK2, and therefore eking out higher response levels.

Dermatology Times: The lower dose was achieving not the same level of efficacy as the higher dose. Could you explain why that is the case?

Papp: When we think of what what we're doing, we're using these molecules to typically block a pathway. When you have lower dose, it means you're not blocking as much. Let's say you're trying to drain a swimming pool. If you use a small pipe, a small hose, it's going to take a long time to drain it. If you use a large pipe, something that's more effective, then it'll drain much more quickly. It's almost the same with drugs. When you have something that's either a higher dose or more potent, it's like having a bigger drain pipe, so you're just getting rid of this signal a lot faster, and a lot more thoroughly, than if you have a lower dose or lower potency drug, in which case, you're just not able to suppress the pathway as much.

Dermatology Times: What were some of the safety findings from the trial, related to adverse events and the overall tolerability of the drug?

Papp: Tolerability was excellent, as might be expected with that particular pathway, though every compound is a little bit different. Safety: There are no unexpected or unusual safety signals. I didn't give the complete data set; that we'll have to wait until we have the publication, and for analysis, this is an interim analysis, so we don't have all the data, but I would be surprised if we saw anything that was really atypical or uncharacteristic for the pathway. We know that the TYK2 pathway is largely affecting IL-23, and a little bit of the type one interferons, alpha and beta. Maybe there might be a slight increase in things like zoster, maybe herpes, but that I think we'll have to wait until we see larger samples. This is still a relatively small study. We're only looking at the order of 100 or 200 patients, and at that sample size, you're eking out the big ticket items, and there were no big ticket items.

Dermatology Times: What are implications regarding the initiation of phase 3 trials?

Papp: I can't speak to the anticipated timelines, because it's so variable and depends on so many factors. But I think what the data very clearly support is moving on to phase 3. We see that there are no real tolerability issues. There are no unexpected safety signals, sort of remains very quiet as we would expect and hope, and the fact that we're seeing levels of efficacy that are very, I would say appreciable there, it's wonderful to see, where a molecule is hitting those levels of efficacy. [It] suggests that yes, there should be momentum to go to phase 3. Exactly when that will happen? I don't know. Because like I said, there's so many variables involved, especially these days.

Dermatology Times: How does ESK-001 compare to existing treatments for plaque psoriasis? What does it offer in terms of efficacy and safety versus other treatments?

Papp: Well, it's a little bit premature to comment in detail on any of those topics. Because this is a very limited trial, limited number of patients, we have limited exposure, so it's only a matter of a total of about 6 months. We still need, I would say, more corroborated evidence, both for safety and for efficacy. I would say given where we see it playing in the phase 2 results, at the higher levels of dose, this is going to put it in the the mid to upper mid range of efficacy. When we look at the overall portfolio of therapeutic options, it might be a little bit higher, but it also could be in the low high end. It's hard to say now, because when when we're talking about efficacy, the numbers are getting a little bit compressed. I say that because some some outcomes, when looking at PASI 100s or PASI 90s, and it's getting a little bit crowded, and people think that 3, 5% makes a big difference. That's sometimes within the noise of these assessments. Without having a larger dataset, without having a controlled way of doing a comparison, whether it's head to head or network meta analysis, which is a distant second best, I would say I would want to be very cautious about making drawing too many inferences or comparisons. But it will be respectable. I can be confident that it would be a very respectable player if it moves into phase 3 and is successful in completing the phase 3 programs.

When we're looking at these early phase results, for someone like myself who's very invested in drug development, this just means, "Okay, now we have something more to look forward to." Each molecule has its nuances. There are these subtle little things that give us information.

I think for someone who is really vested in the day to day practice, these results are just tantalizing. They're kind of interesting; I think it's a way of keeping one current, keeping one interested and engaged. But we haven't we haven't got a drug yet. It's hope; not necessarily a promise. It's hope, and I think from my clinical side, as a practitioner, where I'm seeing patients every day, I'm very aware that we have an increasing number of patients who have burned through all the treatment options that we have available. It's always nice to have another one.

If there is one good point it would I would make to the general practitioner or others in my arena, but they may not have the same exposure to clinical research that I've had, is it's not about the pathway. We know the pathways very well for psoriasis: You block IL-23, you block IL-17. You are going to see the nuances. Each drug behaves a little differently; they may block the same pathway, they may block the same pathway to different degrees. But how that molecule engages or interacts with the biology, this biology, your biology, and all the patients sitting across the room from me, how their biology interacts with a molecule, will differ. We're all roughly the same, but we also have differences, and those differences are often manifested in how well we absorb a drug, how rapidly we metabolize it. As clinicians, we see either great effect or not so great effect. As patients, they appreciate, or feel a great effect or not so great effect. In our heads, we're trying to go through, "Why is that happening?" Quite often, not the pathway. Almost never is it the pathway. It's the drug. Having the opportunity to see a new drug come forward just means that we have more opportunities to treat our patients better.

[Transcript has been edited for clarity.]

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