Patrick Burnett, MD, PhD, FAAD, chief medical officer of Arcutis Biotherapeutics, discusses the mechanism of action for roflumilast cream, the only phosphodiesterase-4 inhibitor approved by the FDA for the treatment of plaque psoriasis in patients aged 12 and older.
Roflumilast cream (ZoryveO) is a phosphodiesterase-4 inhibitor that is steroid free and targets a different signaling pathway than other approved topical agents for the treatment of psoriasis, said Patrick Burnett, MD, PhD, FAAD, chief medical officer of Arcutis Biotherapeutics.
Can you discuss the mechanisms of action for roflumilast cream and how it compares with other topical therapies approved for the treatment of psoriasis?
So, the mechanism of action for roflumilast cream is a phosphodiesterase-4 inhibitor. What that means is, phosphodiesterase metabolizes, or breaks down, cyclic AMP [adenosine monophosphate]. The cyclic AMP is a very common intracellular signaling molecule. So, different cell types, whether they're keratinocytes, or inflammatory cells, or liver cells, or intestinal epithelial cells, they all use cyclic AMP to signal different types of activities within the cell. How that signal is interpreted depends on the cell type.
What this drug does is it hits specifically phosphodiesterase-4, which is just one of many different phosphodiesterases, and it changes the way cyclic AMP is actually being metabolized. And therefore it changes how specifically inflammatory cells and skin cells understand how the levels of cyclic AMP should be telling them whether or not to ramp up the amount of inflammation or to reduce the amount of inflammation. cAMP signaling, when it's altered with a phosphodiesterase-4 inhibitor like roflumilast, what that does [is] it has an overall effect of reducing the amount of inflammatory signaling, that inflammatory cells that are located within the skin of patients with psoriasis or atopic dermatitis, it reduces that inflammatory signal. And over time what you see are changes in the signs and symptoms of the disease.
Now, that effect is having a similar kind of impact on the skin to some of the other mechanisms of action, but most of the drugs that are approved right now for psoriasis have some kind of a steroid in them. And a steroid works by a completely different mechanism of action. It has a specific steroid compound, which it binds to within the cell, and then that also acts by changing cell transcription to reduce inflammation in the skin.
One of the big differences is that steroids also, when they're absorbed, can hit steroid receptors in other organs and other parts of the body as well. And so that is one of the challenges with both local administration of steroids as well as systemic administration of steroids, because steroids are made normally by our body, that when you give a very high potent molecule either topically or systemically, then you kind of cross over and hit some of these same pathways. So, it really is a very distinct mechanism of action that results in a similar kind of effect in the skin, which is it reduces inflammation by a different kind of pathway.