PDE4 Inhibitors in Treatment of Plaque Psoriasis - Episode 9

Plaque Psoriasis Treatment: Roflumilast

Neal Bhatia, MD, FAAD, discusses the current treatment landscape for patients with chronic plaque psoriasis, focusing specifically on PDE4 inhibitors.

Neal Bhatia, MD, FAAD: Topical and systemic phosphodiesterase-4 [PDE4] inhibitors have been established as being effective in psoriasis for many years now. We’ve had good use with oral apremilast in the market for many years. We also now have the advent of the topical roflumilast cream, which is 0.3%—it’s been studied once daily for 8 weeks and in a couple of different trials for psoriasis—most recently approved to the market. This is all based on phase 3 data that’s been conducted at 40 different centers in a first trial called DERMIS-1 [and at] 39 centers in [a second trial called] DERMIS-2, so it’s pretty exciting where these fit. Mechanistically, if you look at what phosphodiesterase-4 does, it basically inhibits the enzyme that converts phosphorylation of AMP [antimicrobial peptides and proteins] so that that phosphorus can be donated to serve other enzymatic functions or other cytokine activations. The point of it, both in psoriasis and in other applications such as atopic dermatitis, is to slow down the progression of cytokine activation as well as cytokine propagation with the inhibition of that donation of phosphorus from what phosphodiesterase-4 does as an enzyme. For example, in the application of a cream, just like with the systemic agent, the delivery is not based on impacting cells or direct inhibition of cytokines. It’s more the understanding that the conversion of cytokines can be inhibited, which, in that broad brush, will slow down the inflammatory cascade that will make inflammation potentially worse in psoriasis. Working on the Th17 and Th1 sides will have a lot of impact from the inhibition of some of those cytokines and is the result of the enzymatic change, not direct targeted blockade.

We’ve had dermatology and apremilast systemically, we’ve had crisaborole for atopic dermatitis, and we’ve had other applications of phosphodiesterase-4 inhibition in many other disease states outside of dermatology. What’s unique about roflumilast is not only the efficacy and the binding of the molecule to the enzyme, but also its impact and specificity of inhibition of certain cytokine-based profiles that result from that phosphodiesterase-4 inhibition. The concept that roflumilast can be a potent inhibitor comes back to many different aspects of roflumilast as a molecule. What’s interesting about some of the studies is that roflumilast was looked at for many indications, such as atopic dermatitis and seborrheic dermatitis because of its impact on the inflammatory cascades. In the DERMIS studies, the idea is that we’re looking at the concept of the inhibition of the propagation of psoriasis, based on the binding as well as the impact on inhibiting phosphorylation of the cytokines on the Th17 side. When we look at once-a-day application, we know we’re looking at a sustained impact rather than twice a day, which might have a more sprint effect; that might also have some potential for slowing down or being less specific. I think what we’re also seeing with roflumilast, especially in terms of the efficacy measures from the trials, is it has a lot of potential for long-term benefit because it’s not going to thin the skin like a steroid, nor is it going to cause some of the other potential adverse outcomes like we’ve seen with other topical agents over the long term.

Transcript edited for clarity