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The investigational oral PDE4 inhibitor orismilast provided significant improvements in psoriasis skin clearance compared with placebo at 16 weeks, according to findings from a phase IIb trial presented at the American Academy of Dermatology (AAD) annual meeting.

MedPage Today brought together three expert leaders in the field: moderator , a dermatologist and clinical researcher from Peterborough, Ontario, is joined by , a dermatologist and director of clinical research at Southern California Dermatology in Orange County, and , founder of FACET Dermatology in Toronto, for a virtual roundtable discussion. This third of four exclusive episodes focuses on the results of the .

Following is a transcript of their remarks:

Gooderham: Hello, I'm Melinda Gooderham. I'm a dermatologist and clinical researcher from Peterborough, Ontario, at the SKiN Centre for Dermatology and an assistant professor at Queen's University. I wanted to welcome you to this roundtable discussion on top news from AAD 2023, and I'm delighted to have with me today, Dr. Geeta Yadav, who is the founder and medical director at FACET Dermatology in Toronto and a lecturer at the University of Toronto, and Dr. Jennifer Soung, who is the director of clinical research at Southern California Dermatology and is on the clinical faculty at Harbor-UCLA.

Okay, moving on. Dr. Yadav, can you tell us about the efficacy and safety of orismilast in patients with moderate-to-severe psoriasis, looking at the results from the phase IIb IASOS trial?

Yadav: Yeah, this is a really interesting one because apremilast [Otezla] was approved quite awhile ago it feels now, and so the exploration of another agent in the same kind of class is interesting to me. My understanding of why it's a phase IIb is because the previous molecule ... was a bit more quick release and this one's a bit more of an extended release. And this study looked at that anti-inflammatory effect and what kind of dosing it would take.

So, it's a randomized, double-blind, placebo-controlled, four-armed, dose-finding trial, where the dosing that was given to patients was 20 mg, 30 mg, and 40 mg, and these are all BID [twice a day] or placebo BID. And looking at the primary endpoint, which was the percentage change in PASI [Psoriasis Area and Severity Index] score from baseline at week 16, and then the secondary endpoints being PASI 75 response at week 16.

And so kind of going through that study, you sort of see that the dosing, the efficacy kind of plateaus a bit around 30, 40 mg. You don't see much percentage change in the PASI at week 16 between the 30 mg and the 40 mg. The 20 is also a little bit consistent, slightly less effective, but it does kind of start to plateau out. And then looking at the PASI 75 and 90 improvement at week 16 across doses, you sort of start to see also a little bit of comparability between the different dosing at that higher end, like 30 and 40 and the 20.

I think what was sort of striking is when you look at the adverse events, you do see significant adverse events and that led to quite a high rate of dropout from the study, from the trials. So something like 50% of patients on the 40-mg dose ended up dropping out of the study because of intolerability, and that includes diarrhea, GI side effects, nausea, and some of what we've come to expect from that class, in PDE4. And so that made the drug quite intolerable at those higher doses. And so I think this study sort of looks at this effect with different dosing. I don't know if this is a drug that people would want to take. I don't know what you ladies think about that.

Gooderham: Yeah, I think with apremilast we're used to that, that GI effects and counseling our patients about it. I think actually Dr. Soung and I were both investigators in the apremilast studies back in the day. So we're used to that in the trials as well. But I think when, as you pointed out, the higher dose has higher AEs, so you'll have to kind of step it back, okay, well maybe we'll look at the 20-mg dose, the AEs are a bit lower, maybe a bit more acceptable to patients. But then you kind of lose that edge over apremilast in the efficacy arm. Jennifer, what did you think?

Soung: Right. I think apremilast has now been on the market since 2014, and very well established. Going forward with so many different agents that we have in our toolbox for psoriasis, tolerability is going to be key if we're going to look for more efficacy, right?

As we've seen in the last 6 months, we also have a new addition, topical roflumilast. And we see a tiny, tiny signal with even diarrhea and GI upset there, which is not unexpected for a topical. But luckily most cases were mild and patients were able to continue the cream. However, it is fascinating to see how PDE4 has so many different potencies and whether we can find that perfect balance of efficacy while minimizing the GI side effects.

Gooderham: Yeah, I agree. So it's overall a very safe mechanism. I think many doctors feel very comfortable prescribing it. It's that tolerability piece that might be an issue. And I think the next poster that we're going to discuss even goes a bit deeper into roflumilast. So thank you very much, guys, with that one.

Watch episode one here: Trial of Novel TYK2 Inhibitor Hits Its Endpoint in Plaque Psoriasis

Watch episode two here: Switch to IL-23 Blocker Yields Deep Responses in Recalcitrant Plaque Psoriasis

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