Difamilast: PDE4 Inhibitor Ointment

Abstract

Phosphodiesterases (PDEs), which were discovered by Sutherland and Rall in 1958, are enzymes that hydrolyze phosphate diester bonds in molecules such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Among the 11 PDE subfamilies, PDE4 is the most diverse and is expressed in numerous cell types. Signaling pathways involving cAMP and cGMP play crucial roles in regulating various physiological functions, including those related to inflammatory diseases and cardiovascular, immune, and central nervous systems. Although PDE inhibitors were recognized for their potential therapeutic benefits, their widespread application was delayed due to the associated systemic side effects. Rolipram is the first PDE4 inhibitor and was developed in 1977. However, its use was discontinued due to side effects such as nausea and vomiting. The PDE4 has four subtypes, PDE4A, PDE4B, PDE4C, and PDE4D, which share similar sequences and structures; therefore, the development of subtype-specific inhibitors is challenging. Difamilast ointment is a PDE4 inhibitor which was introduced for topical treatment of atopic dermatitis in 2022, addressing previous challenges by enhancing PDE4 subtype selectivity and topical formulation. Phase III trials for difamilast ointment in both adults and children with atopic dermatitis demonstrated significant efficacy and safety, with proven effectiveness over a 52-week period. Japan's approach to topical treatment for atopic dermatitis has evolved, positioning difamilast ointment as the fourth treatment following topical steroids, tacrolimus ointment, and delgocitinib ointment. This article reviews the evolution of systemic PDE4 inhibitors and compares crisaborole ointment, a topical PDE4 inhibitor, with difamilast ointment.