Orismilast for moderate-to-severe psoriasis: Results from the phase IIb IASOS trial

The phosphodiesterase-4 (PDE-4) enzyme regulates cyclic adenosine monophosphate signaling, involved in the inflammatory cascades responsible for causing psoriasis.^1-3 Orismilast is a novel, potent PDE-4 inhibitor with high selectivity to B and D isoforms which are overexpressed in the skin of patients with psoriasis.¹ Compared with apremilast, orismilast is at least 2–5 times more potent on all PDE-4 isoforms and up to 39 times more potent on some PDE4-B/D isoforms.¹

Orismilast displays a broad-spectrum anti-inflammatory effect by inhibiting the production of tumor necrosis factor (TNF)-α and secretion of T-helper (Th)-1 (TNF-α and interferon [IFN]-γ), Th17 (interleukin [IL]-22 and IL-23), and Th2 (IL-4, IL-5, and IL-13) effector cytokines in preclinical models.² The efficacy and safety of four different formulations of orismilast and immediate-release tablets were demonstrated in phase I (NCT03812198) and in phase IIa (NCT02888236) trials, respectively, in patients with moderate-to-severe psoriasis.³

At the 2023 American Academy of Dermatology (AAD) Annual Meeting, French presented results of phase IIb IASOS study (NCT05190419) evaluating the efficacy and safety of modified-release orismilast tablets versus placebo in adults with moderate-to-severe psoriasis.¹ Here, we summarize the key findings.

Study design¹

In this phase IIb, double-blind, placebo-controlled, parallel-group dose-ranging study, eligible patients were randomized 1:1:1:1 to receive one of three active doses of orismilast or placebo twice daily. The study design is illustrated in Figure 1.

BID, twice daily; BSA, body surface area; IGA, Investigators Global Assessment; PASI, Psoriasis Area and Severity Index.

*Adapted from Warren, et al.¹

Results¹

A total of 202 patients with moderate-to-severe psoriasis were included (Table 1). The median age was 43.5 years and the majority of patients were male (72.8%) and white (89.1%). Severe psoriasis was predominant in the active arms, whereas moderate psoriasis was predominant in the placebo arm.

Table 1. Baseline patient characteristics*

BID, twice daily; BMI, body mass index; BSA, body surface area; DLQI, Dermatology Life Quality Index; IGA, Investigator’s Global Assessment; PASI, Psoriasis Area and Severity Index; PsA, psoriatic arthritis. *Adapted from Warren, et al.1
Characteristic, % (unless otherwise stated)	Placebo (n = 51)	20 mg BID (n = 48)	30 mg BID (n = 50)	40 mg BID (n = 53)
Median age, years	42.0	42.5	47.0	44.0
Male	76.5	64.6	78.0	71.7
Median BMI, kg/m2	27.7	28.8	29.5	28.8
White	86.3	89.6	92.0	88.7
Median disease duration, years	18.0	23.0	16.5	17.0
Median PASI	17.40	19.25	16.85	20.80
PASI >20	33.3	45.8	36.0	52.8
Median BSA	20.0	26.0	21.0	22.5
IGA score	21.6	35.4	30.0	41.5
Median DLQI	13.0	12.0	13.0	15.0
Presence of PsA	2.0	4.2	10.0	11.3

Efficacy¹

The primary endpoint was met, with a significant reduction in Psoriasis Area and Severity Index (PASI) score with orismilast 20 mg (−53%; p < 0.001), 30 mg (−61%; p < 0.001), and 40 mg (−64%; p < 0.001) versus placebo (−17%) at Week 16.

PASI scores reduced up to 38% with orismilast 40 mg at Week 4 from baseline.

As per the multiple imputation (MI) and non-responder imputation (NRI) analysis, 20 mg and 40 mg doses showed significant improvement in PASI75 (≥75% reduction in PASI) and PASI90 (≥90% reduction in PASI; Figure 2).

ITT, intent-to-treat; MI, multiple imputation; NRI, non-responder imputation; PASI, Psoriasis Area and Severity Index.
*Adapted from Warren, et al.^1
†p < 0.05

In addition, 26%, 25%, and 21% of patients achieved Investigator’s Global Assessment scores of 0/1 with 20 mg, 30 mg, and 40 mg, respectively, versus 7% with placebo (p < 0.05).

Safety¹

Dose dependent adverse events (AEs) were observed with orismilast (Table 2). Infections and depression rates were similar to placebo, with no malignancies or deaths reported.

Table 2. Safety findings*

TEAE, treatment-emergent adverse event. *Adapted from Warren, et al.1 †Preferred term.
Adverse event, %	Placebo (n = 51)	Orismilast
		20 mg (n = 48)	30 mg (n = 50)	40 mg (n = 53)
Any TEAE	45.1	77.1	84	94.3
TEAE by toxicity grade
Grade 1/mild	33	52.1	72	75.5
Grade 2/moderate	19.6	37.5	38	49.1
Grade 3 or more/severe	3.9	16.7	14	15.1
TEAE leading to drug discontinuation	3.9	20.8	20	39.6
Any serious TEAE	0	2.1	2.0	0
Key TEAE
Infections	17.6	16.7	22.0	15.1
Neoplasms benign, malignant, and unspecified	0	0	0	0
Depression†	2.0	0	2.0	0
Suicidal ideation†	0	0	0	0

The most frequent AEs were diarrhea, nausea, and headache; these mainly occurred in the first month and were generally transient and mild in severity. The majority of these AEs did not lead to treatment discontinuation (Figure 3).

SOC, system organ class; PT, preferred term; TEAE, treatment-emergent adverse event.
*Adapted from Warren, et al.^1
†Orange lines depict the proportion of patients discontinuing due to TEAE.

Conclusion¹

In this phase IIb trial, orismilast modified-release tablets demonstrated significantly higher efficacy versus placebo in patients with moderate-to-severe psoriasis at Week 16. Safety and tolerability profiles were favorable and consistent with findings from other PDE-4 inhibitors. These results confirm the high potency of orismilast in inhibiting PDE4-B/D isoforms and demonstrate the potential of a new oral treatment regimen for psoriasis.