High marks for modified-release oral PDE4 inhibitor in moderate-to-severe psoriasis

The modified-release formulation of novel oral phosphodiesterase-4 (PDE4) inhibitor orismilast shows therapeutic potential in adults with moderate-to-severe psoriasis, with high rates of clinical response as compared with placebo, according to data from the phase IIb IASOS trial presented at AAD 2023.

“Orismilast demonstrated significant efficacy vs placebo at week 16 for the primary endpoint, Psoriasis Area and Severity Index (PASI) improvement, from the first measured timepoint [at] week 4,” said one of the study investigators, Dr Lars French, professor and chair of the Department of Dermatology at Ludwig Maximilian University of Munich in Munich, Germany.

“Significant improvements were seen in PASI75 and, more importantly, a deeper response as demonstrated by PASI90,” French added.

On multiple imputation analysis, the primary endpoint of PASI at week 16 decreased from baseline by a mean of 52 percent with orismilast 20 mg, 62 percent with 30 mg, and 64 percent with 40 mg vs only 17 percent with placebo (p≤0.001 for all). [AAD 2023, abstract 45528]

The respective PASI75 and PASI90 responses at week 16 were 39 percent and 24 percent in the 20-mg orismilast group, 49 percent and 22 percent in the 30-mg group, 45 percent and 28 percent in the 40-mg group, and 17 percent and 8 percent in the placebo group.

French noted that orismilast 20 and 30 mg were equally efficacious for patients who weighed <100 kg, but those who weighed more (≥100 kg) saw additional efficacy with the 30-mg dose.

Moreover, significantly more patients who received orismilast vs placebo achieved complete or near-complete clearance of involved skin areas. Investigator's Global Assessment (IGA) scale 0/1 scores were 26 percent in the 20-mg group, 25 percent in the 30-mg group, and 21 percent in the 40-mg group vs 7 percent in the placebo group (p<0.05).

“No new safety signals were identified. Infection and depression rates were similar to placebo, and no malignancy or death was reported,” French said.

Tolerability seemed to be dose dependent, with diarrhoea, nausea, and headache being the most frequent adverse events (AEs). These, according to French, were mainly seen within the first month of treatment, generally transient, and mild in severity. Most AEs did not lead to treatment discontinuation.

IASOS was a 16-week, double-blinded, placebo-controlled, dose-finding trial that included 202 adults (median age 43.5 years, 72.8 percent men, median body mass index 28.8 kg/m²) with moderate-to-severe psoriasis. Severe psoriasis was predominant in the active treatment groups, whereas moderate psoriasis was more common in the placebo group.

Of the participants, 48 received orismilast 20 mg, 50 received 30 mg, 53 received 40 mg, and 51 received placebo.

“Orismilast is a potent PDE4 -B and -D inhibitor, [with] PDE4B and PDE4D isoforms [being] overexpressed in the skin of patients with psoriasis and atopic dermatitis [than in the skin of] healthy individuals,” French said. [J Eur Acad Dermatol Venereol 2023;37:721-729; Cell Signal 2016;28:753-763]

“When compared with apremilast, orismilast is at least two to fivefold more potent on all PDE4 isoforms and up to 39 times more potent on some of the PDE4B/D isoforms. [Additionally, orismilast appears to have] a broad anti-inflammatory effect by inhibiting the secretion of Th1, Th17, and Th2 effector cytokines,” he added.

Already, the efficacy and safety of orismilast in the immediate-release tablet formulation have been shown in a phase IIa trial of moderate-to-severe psoriasis. [J Eur Acad Dermatol Venereol 2023;37:711-720]

The current data, according to French, “confirm high potency PDE4 B/D inhibition with orismilast as a potential new oral addition to the psoriasis armamentarium, for the first time offering significant PASI90 response.”