Journal of the European Academy of Dermatology and Venereology

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>There remains an unmet need for oral medications that are safe and efficacious for long‐term management of chronic inflammatory skin diseases (CISD). Inhibition of phosphodiesterase 4 (PDE4) can modulate a broad range of pro‐inflammatory cytokines that play a major role in CISD pathogenesis. Orismilast is a second generation PDE4 inhibitor in clinical development for CISD treatment.</jats:p></jats:sec><jats:sec><jats:title>Objectives</jats:title><jats:p>The objective of this study was to examine the PDE4 enzymatic activity and anti‐inflammatory effects of orismilast in vitro<jats:italic>,</jats:italic> ex vivo<jats:italic>,</jats:italic> and in vivo.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>The PDE1‐11 enzymatic activity of orismilast was tested in vitro using a single concentration of 308 nM orismilast. The PDE4 selectivity and inhibitory potency was further examined in a radiometric assay. Orismilast was tested on human whole blood and human peripheral blood mononuclear cells (PBMC) to determine effects on its cytokine secretion and inhibition profile ex vivo. Orismilast was orally administered in a murine model of chronic oxazolone‐induced ear skin inflammation. Ear thickness, a marker of inflammation, and inflammatory cytokines were analysed.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Orismilast selectively inhibited PDE4 and demonstrated potent inhibition of PDE4B and PDE4D subtype splice variants in vitro. Orismilast inhibited whole blood and PBMC production of tumour necrosis factor α (TNFα), and the secretion of T‐helper (Th)1 (TNFα and IFNγ), Th17 (IL‐22 and IL‐23), and Th2 (IL‐4, IL‐5, and IL‐13) related cytokines in PBMC. In vivo<jats:italic>,</jats:italic> 10 and 30 mg/kg doses of orismilast significantly reduced ear thickness and inflammation markers (<jats:italic>p</jats:italic> &lt; 0.0001, respectively).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Orismilast displayed selective and potent PDE4 inhibition and broad‐spectrum anti‐inflammatory activity in several pre‐clinical models. The results of the study support clinical development of oral orismilast as a novel treatment option for CISD including psoriasis, atopic dermatitis, and hidradenitis suppurativa.</jats:p></jats:sec>

publication_history

received

accepted

published

New and emerging topical therapies for psoriasis and atopic dermatitis

J Clin Aesthet Dermatol

Manifestations and management of difficult‐to‐treat psoriasis

JDNA

Cyclic adenosine monophosphate signalling in inflammatory skin disease

J Clin Exp Dermatol Res

Crisaborole 2% ointment (Eucrisa) for atopic dermatitis

Skin Therapy Lett

Roflumilast: first phosphodiesterase 4 inhibitor approved for treatment of COPD

Drug dDes Devel Ther

There remains an unmet need for oral medications that are safe and efficacious for long-term management of chronic inflammatory skin diseases (CISD). Inhibition of phosphodiesterase 4 (PDE4) can modulate a broad range of pro-inflammatory cytokines that play a major role in CISD pathogenesis. Orismilast is a second generation PDE4 inhibitor in clinical development for CISD treatment.
The objective of this study was to examine the PDE4 enzymatic activity and anti-inflammatory effects of orismilast in vitro, ex vivo, and in vivo.
The PDE1-11 enzymatic activity of orismilast was tested in vitro using a single concentration of 308 nM orismilast. The PDE4 selectivity and inhibitory potency was further examined in a radiometric assay. Orismilast was tested on human whole blood and human peripheral blood mononuclear cells (PBMC) to determine effects on its cytokine secretion and inhibition profile ex vivo. Orismilast was orally administered in a murine model of chronic oxazolone-induced ear skin inflammation. Ear thickness, a marker of inflammation, and inflammatory cytokines were analysed.
Orismilast selectively inhibited PDE4 and demonstrated potent inhibition of PDE4B and PDE4D subtype splice variants in vitro. Orismilast inhibited whole blood and PBMC production of tumour necrosis factor α (TNFα), and the secretion of T-helper (Th)1 (TNFα and IFNγ), Th17 (IL-22 and IL-23), and Th2 (IL-4, IL-5, and IL-13) related cytokines in PBMC. In vivo, 10 and 30 mg/kg doses of orismilast significantly reduced ear thickness and inflammation markers (p < 0.0001, respectively).
Orismilast displayed selective and potent PDE4 inhibition and broad-spectrum anti-inflammatory activity in several pre-clinical models. The results of the study support clinical development of oral orismilast as a novel treatment option for CISD including psoriasis, atopic dermatitis, and hidradenitis suppurativa.

Pharmacology of orismilast, a potent and selective PDE4 inhibitor.

Pharmacology of orismilast, a potent and selective PDE4 inhibitor

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Orismilast is a high‐potency phosphodiesterase 4 (PDE4) inhibitor with enhanced selectivity for the PDE4B and PDE4D subtypes.</jats:p></jats:sec><jats:sec><jats:title>Objectives</jats:title><jats:p>The objective of this phase 2a trial was to examine the efficacy and safety of orismilast for psoriasis using a first‐generation immediate‐release (IR) formulation. The objective of the subsequent phase 1 trial was to test new formulations designed to minimize the gastrointestinal (GI)‐related adverse events (AEs) observed with the first‐generation IR formulation. We examined the following: (1) pharmacokinetic (PK) properties of orismilast modified release (MR) and IR, (2) food effects on PK properties of orismilast MR or IR, (3) safety of orismilast MR compared to placebo.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>In a phase 2a prospective, randomized, double‐blind, placebo‐controlled trial, patients with moderate‐to‐severe psoriasis were randomized to receive 30 mg oral orismilast IR or placebo over 16 weeks. The single‐site phase 1 trial consisted of three parts: (1) participants received a single 30 mg dose of orismilast MR and IR (open‐label), (2) participants received 30 mg orismilast MR or IR under either fasting condition, following a high‐fat meal or low‐fat meal (open‐label) and (3) participants received up to 60 mg orismilast MR twice‐daily or a placebo for 17 days (double‐blind).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>In the phase 2a trial, treatment with orismilast IR significantly improved the mean Psoriasis Area Severity Index score at week 16 compared to placebo. The phase 1 trial revealed comparable PK properties of the orismilast MR and IR formulations, with participants in the orismilast MR group experiencing fewer GI‐related AEs than those receiving orismilast IR (16.7% vs. 33.3%).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Orismilast IR displayed higher efficacy compared to placebo in patients with moderate‐to‐severe psoriasis at week 16. Orismilast MR had similar PK properties and fewer GI disorders compared to the IR formulation in healthy participants. Future development of orismilast will be based on the MR formulation.</jats:p></jats:sec>

Novo Nordisk Fonden

The risk of depression, anxiety, and suicidality in patients with psoriasis: a population‐based cohort study

Arch Dermatol

Orismilast is a high-potency phosphodiesterase 4 (PDE4) inhibitor with enhanced selectivity for the PDE4B and PDE4D subtypes.
The objective of this phase 2a trial was to examine the efficacy and safety of orismilast for psoriasis using a first-generation immediate-release (IR) formulation. The objective of the subsequent phase 1 trial was to test new formulations designed to minimize the gastrointestinal (GI)-related adverse events (AEs) observed with the first-generation IR formulation. We examined the following: (1) pharmacokinetic (PK) properties of orismilast modified release (MR) and IR, (2) food effects on PK properties of orismilast MR or IR, (3) safety of orismilast MR compared to placebo.
In a phase 2a prospective, randomized, double-blind, placebo-controlled trial, patients with moderate-to-severe psoriasis were randomized to receive 30 mg oral orismilast IR or placebo over 16 weeks. The single-site phase 1 trial consisted of three parts: (1) participants received a single 30 mg dose of orismilast MR and IR (open-label), (2) participants received 30 mg orismilast MR or IR under either fasting condition, following a high-fat meal or low-fat meal (open-label) and (3) participants received up to 60 mg orismilast MR twice-daily or a placebo for 17 days (double-blind).
In the phase 2a trial, treatment with orismilast IR significantly improved the mean Psoriasis Area Severity Index score at week 16 compared to placebo. The phase 1 trial revealed comparable PK properties of the orismilast MR and IR formulations, with participants in the orismilast MR group experiencing fewer GI-related AEs than those receiving orismilast IR (16.7% vs. 33.3%).
Orismilast IR displayed higher efficacy compared to placebo in patients with moderate-to-severe psoriasis at week 16. Orismilast MR had similar PK properties and fewer GI disorders compared to the IR formulation in healthy participants. Future development of orismilast will be based on the MR formulation.

Oral orismilast: Efficacy and safety in moderate-to-severe psoriasis and development of modified release tablets.

Oral orismilast: Efficacy and safety in moderate‐to‐severe psoriasis and development of modified release tablets

Papers