Pharmacology of orismilast, a potent and selective PDE4 inhibitor.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

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

BACKGROUND: Orismilast is a high-potency phosphodiesterase 4 (PDE4) inhibitor with enhanced selectivity for the PDE4B and PDE4D subtypes. OBJECTIVES: 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. METHODS: 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). RESULTS: 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%). CONCLUSION: 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.

Scan-rescan measurement repeatability of 18F-FDG PET/MR imaging of vascular inflammation.

Non-invasive positron emission tomography (PET) of vascular inflammation and atherosclerotic plaque by identifying increased uptake of 18F-fluordeoxyglucose (18F-FDG) is a powerful tool for monitoring disease activity, progression, and its response to therapy. 18F-FDG PET/computed tomography (PET/CT) of the aorta and carotid arteries has become widely used to assess changes in inflammation in clinical trials. However, the recent advent of hybrid PET/magnetic resonance (PET/MR) scanners has advantages for vascular imaging due to the reduction in radiation exposure and improved soft tissue contrast of MR compared to CT. Important for research and clinical use is an understanding of the scan-rescan repeatability of the PET measurement. While this has been studied for PET/CT, no data is currently available for vascular PET/MR imaging. In this study, we determined the scan-rescan measurement repeatability of 18F-FDG PET/MR in the aorta and carotid arteries was less than 5%, comparable to similar findings for 18F-FDG PET/CT.

Good practice intervention for clinical assessment and diagnosis of atopic dermatitis: Findings from the atopic dermatitis quality of care initiative.

Atopic dermatitis (AD) is frequently misdiagnosed and undertreated, resulting in increased morbidity. In 2019, the Atopic Dermatitis Quality of Care Initiative was launched globally to investigate barriers to AD care and note good practice interventions to improve care. The initiative included a literature review to define the challenges in AD and a survey of 32 AD centers to define good practice interventions. One topic studied was best practices for clinical assessment and diagnosis. The literature review revealed the primary gaps included difficulty differentiating AD from other skin disorders, diagnosing atypical AD, staging AD severity in individual patients, and delays in assessment and treatment due to referral time lag. The best clinical practices used by leading AD centers included the use of validated diagnostic criteria, established AD scoring tools including patient-reported outcome measures and electronic health records (EHR), the formation of multidisciplinary teams (MDTs), and improved communication between health care providers (HCPs) and patients. Most centers worked with patient advocacy groups and implemented educational programs for HCPs. AD centers are overcoming issues in AD care. Educating health care providers and the public, using screening surveys, using established guidelines, and communicating with MCTs and patients through EHRs are the most frequently used strategies.

TNF-α downregulates filaggrin and loricrin through c-Jun N-terminal kinase: role for TNF-α antagonists to improve skin barrier.

Filaggrin (FLG), loricrin (LOR), and involucrin are important epidermal barrier proteins. As psoriasis is characterized by overexpression of tumor necrosis factor-α (TNF-α) and impaired skin barrier, we investigated the expression of skin barrier proteins in psoriasis patients and whether their expression was modulated by TNF-α. The expression of FLG and LOR was found to be decreased in lesional and non-lesional skin of psoriasis patients. A correlation was found between the expression of TNF-α and epidermal barrier proteins in psoriasis. TNF-α was found to modulate the expression of FLG and LOR via a c-Jun N-terminal kinase-dependent pathway. Importantly, we report that clinical treatment of psoriasis patients with a TNF-α antagonist results in significant enhancement of epidermal barrier protein expression. Our current study suggests that TNF inhibits barrier protein expression, and TNF-α antagonists may contribute to clinical improvement in patients with psoriasis by improving barrier protein expression.