Phosphodiesterase 4 Inhibitor Research Articles

Efficacy and safety profile of phosphodiesterase 4 inhibitor in the treatment of psoriasis: A systematic review and meta-analysis of randomized controlled trials.

BackgroundSystemic therapy is an important treatment for psoriasis. Phosphodiesterase 4 (PDE4) inhibitors are new candidates for psoriasis therapy.ObjectivesTo evaluate the efficacy and safety of PDE4 inhibitors in psoriasis.MethodRandomized clinical trials with PDE4 inhibitors vs placebos in patients with psoriasis were identified from MEDLINE, Embase, Cochrane Controlled Register of Trials, ClinicalTrials.gov, from inception to July 14, 2022. The study was registered in PROSPERO (CRD42022345700).Results18 studies were identified, 9 of which included moderate-to-severe plaque psoriasis, 2 mild-to-moderate plaque psoriasis, and 7 psoriatic arthritis. A total of 6036 patients were included. Only one oral PDE4 inhibitor, apremilast, met the inclusion criteria. Overall, compared with the placebo, apremilast was associated with higher response rates in PASI-75 (RR, 3.22; 95% CI, 2.59-4.01), ScPGA of 0 or 1 (RR, 2.21; 95% CI, 1.69-2.91), PPPGA of 0 or 1 (RR 2.33; 95%CI, 1.16-4.66), and a significant decrease in NPASI (SMD, -0.46; 95% CI, -0.58 to -0.33). There were no significant differences in serious adverse events. Subgroup analyses showed that significantly more patients achieved PASI-75 after 16 weeks of therapy with apremilast of 20 mg bid (RR, 2.82; 95% CI, 2.01-3.95) and 30 mg bid (RR, 4.08; 95% CI, 3.12-5.33). Heterogeneity was not significant across studies.ConclusionApremilast is a safe and effective treatment for plaque psoriasis and psoriatic arthritis, especially for difficult-to-treat sites.Systematic review registration https://www.crd.york.ac.uk/prospero, identifier (CRD42022345700).

Non-FDA-Approved Uses of Apremilast in Dermatology: A Review of Current Available literature

Introduction: Apremilast, an oral phosphodiesterase-4 inhibitor, decreases the production of pro-inflammatory cytokines including tumour necrosis factor-α, interleukin-12/23, IL-12, IL-2, and interferon-γ; while upregulating the anti-inflammatory cytokine IL-10. Its pan-immunomodulatory nature has led to its use in managing various immune-mediated dermatoses for non-FDA-approved indications. Objectives: To review and analyze the use of Apremilast in Non-FDA-approved indications in current available literature. Materials and methods: PubMed, EMBASE, SCOPUS, and Google scholar databases were searched with the parameters “Apremilast”, “Apremilast NOT Psoriasis*”, “Apremilast NOT Behçet’s*”, and “Apremilast NOT arthritis*”. A total of 45 relevant articles were chosen for review. Results: We found 22 indications in dermatology where apremilast has been used without FDA approval. The best evidence was for treatment in Atopic Dermatitis, Alopecia Areata, and Hidradenitis Suppurativa, with randomized controlled trials. Prospective open-label trials were found for Cutaneous Sarcoidosis, Lichen Planus, Rosacea, and Vitiligo. Individual case series and reports were found for Acrodermatitis Continua of Hallopeau, Dermatomyositis, Disseminated Granuloma Annulare, Erythema Nodosum Leprosum, Morphea, Pityriasis Rubra Pilaris, Hailey-Hailey Disease, Recurrent Erythema Multiforme, and Folliculitis Decalvans, Prurigo Nodularis, Perforating Dermatoses, Chronic Actinic Dermatitis, and Hand Eczema, and Epidermolysis Bullosa Simplex-Generalised Severe Type. Apremilast has shown varied efficacy despite a better safety profile and tolerability over a long duration compared to conventional immunosuppressant drugs and placebo. Conclusion: Apremilast has been used for varied non-FDA-approved indications in dermatology with variable efficacy. Better controlled, randomized studies with adequate sample size and drug comparisons are needed for better analyses.

Nanoparticle Delivery of Novel PDE4B Inhibitor for the Treatment of Alcoholic Liver Disease.

The incidence of alcoholic liver disease (ALD) is increasing worldwide while no effective treatment has been approved. The progression of ALD has proven to be related to the upregulation of phosphodiesterase 4 (PDE4) expression, and PDE4 inhibitors showed potential to improve ALD. However, the application of PDE4 inhibitors is limited by the gastrointestinal side effects due to PDE4D inhibition. Therefore, we used a novel PDE4B inhibitor KVA-D88 as the therapeutic for ALD treatment. KVA-D88 inhibited inflammatory response, promoted β-oxidation, increased the level of antioxidants in the hepatocytes, and suppressed hepatic stellate cell (HSC) activation in vitro. To improve the solubility and availability in vivo, KVA-D88 was encapsulated into mPEG-b-P(CB-co-LA) nanoparticles (NPs) by solvent evaporation, with a mean particle size of 135 nm and drug loading of 4.2%. We fed the male C57BL/6 mice with a Lieber–DeCarli liquid diet containing 5% (v/v) ethanol for 6 weeks to induce ALD. Systemic administration of KVA-D88 free drug and KVA-D88-loaded NPs at 5 mg/kg significantly improved the ALD in mice. KVA-D88 significantly ameliorated alcohol-induced hepatic injury and inflammation. KVA-D88 also markedly reduced steatosis by promoting fatty acid β-oxidation. Liver fibrosis and reactive oxygen species (ROS)-caused cellular damage was observed to be alleviated by KVA-D88. KVA-D88-loaded NPs proved better efficacy than free drug in the animal study. In conclusion, the novel PDE4B inhibitor KVA-D88-loaded NPs have the potential to treat ALD in mice

PDE4 inhibitor eliminates breast cancer stem cells via noncanonical activation of mTOR.

Ineffective cancer treatment is implicated in metastasis, recurrence, resistance to chemotherapy and radiotherapy, and evasion of immune surveillance. All these failures occur due to the persistence of cancer stem cells (CSCs) even after rigorous therapy, thereby rendering them as essential targets for cancer management. Contrary to the quiescent nature of CSCs, a gene profiler array disclosed that phosphatidylinositol-3-kinase (PI3K), which is known to be crucial for cell proliferation, differentiation, and survival, was significantly upregulated in CSCs. Since PI3K is modulated by cyclic adenosine 3',5' monophosphate (cAMP), analyses of cAMP regulation revealed that breast CSCs expressed increased levels of phosphodiesterase 4 (PDE4) in contrast to normal stem cells. In accordance, the effects of rolipram, a PDE4 inhibitor, were evaluated on PI3K regulators and signaling. The efficacy of rolipram was compared with paclitaxel, an anticancer drug thatis ineffective in obliterating breast CSCs. Analyses of downstream signaling components revealed a switch between cell survival and death, in response to rolipram, specifically of the CSCs. Rolipram-mediated downregulation of PDE4A levels in breast CSCs led to an increase in cAMP levels and protein kinase A (PKA) expression. Subsequently, PKA-mediated upregulation of phosphatase and tensin homologantagonized the PI3K/AKT/mTOR pathwayand led to cell cycle arrest. Interestingly, direct yet noncanonical activation of mTOR by PKA, circumventing the influence of PI3K and AKT, temporally shifted the fate of CSCs towardapoptosis. Rolipram in combination with paclitaxel indicated synergistic consequences, which effectively obliterated CSCs within a tumor, thereby suggesting combinatorial therapy as a sustainable and effective strategy to abrogate breast CSCs for better patient prognosis.

33537 Inhibitory effects of ME3183, a novel phosphodiesterase-4 inhibitor, on stimulants-induced production of proinflammatory cytokines and chemokines in whole blood cell cultures of patients with plaque psoriasis

Inhibition of phosphodiesterase-4 (PDE4) has been reported as a therapeutic target for inflammatory diseases. ME3183 is an orally available and selective inhibitor of PDE4, which showed various anti-inflammatory effects in nonclinical studies. We examined the inhibitory effects of ME3183 on stimulants-induced production of proinflammatory cytokines and chemokines in whole blood cell cultures of healthy volunteers and patients with plaque psoriasis (Ps). Tumor necrosis factor alpha (TNF-α), interleukin 17A, interferon-γ, monocyte chemotactic protein-1 and interferon gamma-induced protein-10 were measured in each subject’s whole blood cell cultures stimulated with lipopolysaccharide (LPS) or phytohemagglutinin (PHA) in the presence of ME3183 or apremilast. Correlation between the inhibition of TNF-α production and each clinical parameter of patients were statistically analyzed. ME3183 showed approximately 5- to 40-folds more potent inhibitory activities against production of cytokines than apremilast both in the whole blood cell cultures of Ps patients and healthy subjects. Interestingly, our correlation analysis suggested that high body surface area (%) and long-duration of psoriasis may be associated with the potency (IC50) of ME3183 against TNF-α production. ME3183 showed higher potency than apremilast in the inhibition of proinflammatory cytokines and chemokines production. ME3183 can be a new generation of PDE4 inhibitor with improved therapeutic effect, and the efficacy of ME3183 will be investigated in patients with Ps in the P2a study.

What's New in Topicals for Atopic Dermatitis?

Atopic dermatitis (AD) is a chronic inflammatory skin condition that can have tremendous impact on quality of life for affected children and adults. First-line therapy for acute management of AD includes topical therapies such as corticosteroids, calcineurin inhibitors, and, more recently, the phosphodiesterase inhibitor crisaborole. Topical agents have remained the mainstay therapy for decades; however, there has been a longstanding need for topical therapies with high efficacy and low risk of adverse effects with long-term use. Given the ongoing advances in understanding the pathogenesis of AD, there are novel targets for pharmacological intervention. We are now in an unprecedented time with more than 40 topical treatments in the pipeline for AD in addition to many developments and treatments on the horizon. This review summarizes selected therapeutic topical agents in later phases of development that target various aspects in the pathogenesis of AD such as Janus kinase inhibition (ruxolitinib and delgocitinib), phosphodiesterase-4 inhibition (roflumilast and difamilast), aryl hydrocarbon modulation (tapinarof), and modulation of the microbiome. We also review novel targeted therapies that are in early phase clinical trials, including AMTX-100, BEN-2293, and PRN473. Preliminary findings on efficacy and tolerability of most of these agents are promising, but further studies are warranted to evaluate the long-term safety and efficacy of these novel agents against the current standard of care.

33467 Long-term safety and efficacy of roflumilast cream 0.3% in patients with chronic plaque psoriasis: Interim results from a 24-week, phase 3 open-label study

Roflumilast cream is a selective, highly potent phosphodiesterase-4 inhibitor under investigation as a nonsteroidal, once-daily treatment for psoriasis. A phase 3, 24-week, open-label extension (DERMIS-OLE; NCT04286607) is being conducted in patients (aged ≥2 years) with psoriasis who successfully completed a prior roflumilast cream study (Cohort-1) and patients (aged ≥2-17 years) naïve to roflumilast/vehicle (Cohort-2). We present interim results from Cohort-1, comprising 264 patients from two 8-week phase 3 studies. As of December 2020, 84.1% of Cohort-1 completed the study, 3.8% were ongoing, and 12.1% discontinued. One (0.4%) patient discontinued due to an adverse event (AE). Overall, 69 (26.1%) patients experienced a treatment-emergent AE; most were mild or moderate. One AE was considered likely treatment-related and 3 were possibly related; none were serious. Investigator tolerability assessments demonstrated ≥96.3% of patients had “no evidence of irritation” at each visit. At Week 24 of the OLE, key efficacy results were: 50.0% of patients had Investigator Global Assessment (IGA) status of Clear/Almost Clear, >75% of patients with intertriginous-IGA of at least Mild (≥2) at Baseline achieved intertriginous-IGA Success, 43.8% of patients had 75% reduction on the Psoriasis Area and Severity Index, and 62.4% of patients achieved 4-point improvement on the Worst Itch-Numeric Rating Scale from a baseline of ≥4. With cumulative treatment up to 32 weeks (including parent study), safety and tolerability were consistent with the previous phase 2, 52-week study. In this long-term safety study, roflumilast cream demonstrated excellent tolerability with no unexpected AEs and effectively maintained Clear/Almost Clear skin.

33460 Roflumilast foam 0.3% treatment of seborrheic dermatitis is effective and safe and improves patient quality of life: Results from a phase 2 study

Seborrheic dermatitis is a chronic inflammatory skin condition that may cause discomfort, itching, and reduced quality of life. No novel treatments have been developed in decades. A phase 2, 8-week study investigated once-daily roflumilast foam 0.3%, a selective and highly potent phosphodiesterase-4 inhibitor, in patients with seborrheic dermatitis. Adult patients with seborrheic dermatitis of at least moderate Investigator Global Assessment (IGA) severity affecting ≤20% of body surface area were randomized to roflumilast foam 0.3% (n = 154) or vehicle (n = 72). For the primary endpoint, significantly more roflumilast-treated patients (73.8%) than vehicle-treated patients (40.9%; P < .0001) achieved an IGA score of clear or almost clear plus 2-grade improvement from baseline at week 8; significant differences occurred as early as the first postbaseline visit (week 2, P = .0033). Patients in the roflumilast foam 0.3% group had greater improvement in health-related quality of life (Scalpdex) scores compared with those in the vehicle group at all postbaseline assessments (P ≤ .0019). At Weeks 4 and 8, roflumilast-treated patients had greater improvement in Dermatology Life Quality Index compared with vehicle-treated patients (P ≤ .0380). Roflumilast also increased the percentage of patients achieving a 4-point response on the worst itch-numeric rating scale at all postbaseline visits (evaluated in patients with baseline score ≥4; P ≤ .0009). Rates of application site pain, treatment-related adverse events, and discontinuations due to adverse events were low and comparable to vehicle. These data indicate investigational once-daily roflumilast foam 0.3% is a promising, novel and effective topical therapy that may rapidly improve quality of life in patients with seborrheic dermatitis.

33463 Pooled efficacy and safety results from the DERMIS-1 and DERMIS-2 phase 3 trials of once-daily roflumilast cream 0.3% by baseline body surface area

Roflumilast cream 0.3% is a selective and potent phosphodiesterase-4 inhibitor under investigation as a once-daily treatment for psoriasis. Here we describe pooled efficacy and safety results from 2 identical phase 3 randomized controlled trials of roflumilast cream (DERMIS-1: NCT04211363 and DERMIS-2: NCT04211389) analyzed by baseline body surface area (BSA) affected ( 10%). Patients (≥2 years) with psoriasis involving 2-20% BSA were randomized to roflumilast (n = 576) or vehicle (n = 305) for 8 weeks.

33468 Efficacy and safety of once-daily roflumilast cream 0.3% in patients with knee/elbow involvement: Pooled results from phase 3 trials (DERMIS-1 and DERMIS-2)

Roflumilast cream 0.3% is a selective and potent phosphodiesterase-4 inhibitor under investigation as a once-daily treatment for psoriasis. Psoriatic plaques on the knees/elbows can be challenging to treat due to thicker stratum corneum, which impedes topical absorption. We present pooled efficacy results from a post hoc analysis of the subgroup of patients with knee and/or elbow involvement from two identical phase 3 randomized controlled trials of roflumilast (DERMIS-1: NCT04211363 and DERMIS-2: NCT04211389).

33356 A multinational chart review to examine gastrointestinal symptoms and their management in patients treated with apremilast for plaque psoriasis

Background: Diarrhea and nausea are the most common adverse events observed in phase 3 clinical trials and real-world studies of apremilast, an oral phosphodiesterase-4 inhibitor indicated for moderate-to-severe plaque psoriasis.

31865 Pooled efficacy and safety results from the DERMIS-1 and DERMIS-2 phase 3 trials of once-daily roflumilast cream 0.3% for treatment of chronic plaque psoriasis

Roflumilast cream 0.3% is a selective, highly potent phosphodiesterase-4 inhibitor being investigated as a nonsteroidal, once-daily treatment for psoriasis. Here we describe pooled efficacy and safety results from 2 identical Phase 3 randomized controlled trials of roflumilast cream (DERMIS-1: NCT04211363 and DERMIS-2: NCT04211389). Patients with psoriasis involving 2-20% of body surface area (aged ≥2 years) were randomized to roflumilast (n = 576) or vehicle (n = 305) for 8 weeks. Significantly greater percentages of roflumilast-treated versus vehicle-treated patients achieved the primary efficacy endpoint, Investigator Global Assessment (IGA) Success (Clear or Almost Clear IGA plus ≥2-grade improvement from baseline) at Week 8 (39.9% vs.

An Overview of PDE4 Inhibitors in Clinical Trials: 2010 to Early 2022.

Since the early 1980s, phosphodiesterase 4 (PDE4) has been an attractive target for the treatment of inflammation-based diseases. Several scientific advancements, by both academia and pharmaceutical companies, have enabled the identification of many synthetic ligands for this target, along with the acquisition of precise information on biological requirements and linked therapeutic opportunities. The transition from pre-clinical to clinical phase was not easy for the majority of these compounds, mainly due to their significant side effects, and it took almost thirty years for a PDE4 inhibitor to become a drug i.e., Roflumilast, used in the clinics for the treatment of chronic obstructive pulmonary disease. Since then, three additional compounds have reached the market a few years later: Crisaborole for atopic dermatitis, Apremilast for psoriatic arthritis and Ibudilast for Krabbe disease. The aim of this review is to provide an overview of the compounds that have reached clinical trials in the last ten years, with a focus on those most recently developed for respiratory, skin and neurological disorders.

Rolipram Rescues Memory Consolidation Deficits Caused by Sleep Deprivation: Implication of the cAMP/PKA and cAMP/Epac Pathways.

Over the last few years, the number of people suffering from sleeping disorders has increased significantly despite negative effects on cognition and an association with brain inflammation. We assessed memory deficits caused by Sleep Deprivation (SD) to determine the therapeutic effect of phosphodiesterase 4 (PDE4) inhibitors on SD-induced memory deficits and to investigate whether the modulation of memory deficits by PDE4 inhibitors is mediated by a protein kinase A (PKA)-independent pathway in conjunction with a PKA-dependent pathway. Adult male mice were divided into four groups. Three SD groups were deprived of Rapid Eye Movement (REM) sleep for 12 h a day for six consecutive days. They were tested daily in the Morris water maze to evaluate learning and memory. One of the SD groups was injected with a PDE4 inhibitor, rolipram (1 mg/kg ip), whereas another had rolipram co-administered with chlorogenic acid (CHA, 20 mg/kg ip), an inhibitor of PKA. After 6 days, the mice were sacrificed, and the hippocampi were evaluated for cyclic AMP (cAMP) and nuclear factor Nrf-2 levels. The hippocampal expression of PKA, phosphorylated cAMP Response Element-Binding Protein (CREB), and phosphorylated glycogen synthase 3β (Ser389) were also evaluated. SD caused a significant decrease in cAMP levels in the brain and had a detrimental effect on learning and memory. The administration of rolipram or rolipram+CHA resulted in an improvement in cognitive function. The present study provides evidence that restoration of memory with PDE4 inhibitors occurs through a dual mechanism involving the PKA and Epac pathways.

Roflumilast-Mediated Phosphodiesterase 4D Inhibition Reverses Diabetes-Associated Cardiac Dysfunction and Remodeling: Effects Beyond Glucose Lowering

Patients with type 2 diabetes have a substantial risk of developing cardiovascular disease. Phosphodiesterase 4 (PDE4) dysregulation is of pathophysiological importance in metabolic disorders. For determination of the role of PDE4 in diabetic cardiac dysfunction, mice fed with a high-fat diet (HFD) were treated by pharmacological inhibition of PDE4 or cardiac specific knocking down of PDE4D. Mice on HFD developed diabetes and cardiac dysfunction with increased cardiac PDE4D5 expression. PDE4 inhibitor roflumilast can reverse hyperglycemia and cardiac dysfunction, accompanied by the decrease of PDE4D expression and increase of muscle specific miRNA miR-1 level in hearts. Either cardiac specific PDE4D knockdown or miR-1 overexpression significantly reversed cardiac dysfunction in HFD mice, despite persistence of hyperglycemia. Findings of gain- and loss-of-function studies of PDE4D in cardiomyocytes indicated that inhibition of insulin-induced PDE4D protected cardiac hypertrophy by preserving miR-1 expression in cardiomyocytes through promoting cAMP-CREB-Sirt1 signaling-induced SERCA2a expression. We further revealed that insulin also induced PDE4D expression in cardiac fibroblasts, which causes cardiac fibrosis through TGF-β1 signaling-mediated miR-1 reduction. Importantly, the expression of PDE4D5 was increased in human failing hearts of individuals with diabetes. These studies elucidate a novel mechanism by which hyperinsulinemia-induced cardiac PDE4D expression contributes to diabetic cardiac remodeling through reducing the expression of miR-1 and upregulation of miR-1 target hypertrophy and fibrosis-associated genes. Our study suggests a therapeutic potential of PDE4 inhibitor roflumilast in preventing or treating cardiac dysfunction in diabetes in addition to lowering glucose.

Targeting PDE4B (Phosphodiesterase-4 Subtype B) for Cardioprotection in Acute Myocardial Infarction via Neutrophils and Microcirculation.

Timely and complete restoration of blood flow is the most effective intervention for patients with acute myocardial infarction. However, the efficacy is limited by myocardial ischemia-reperfusion (MI/R) injury. PDE4 (phosphodiesterase-4) hydrolyzes intracellular cyclic adenosine monophosphate and it has 4 subtypes A-D. This study aimed to delineate the role of PDE4B (phosphodiesterase-4 subtype B) in MI/R injury. Mice were subjected to 30-minute coronary artery ligation, followed by 24-hour reperfusion. Cardiac perfusion was assessed by laser Doppler flow. Vasomotor reactivities were determined in mouse and human coronary (micro-)arteries. Cardiac expression of PDE4B, but not other PDE4 subtypes, was increased in mice following reperfusion. PDE4B was detected primarily in endothelial and myeloid cells of mouse and human hearts. PDE4B deletion strikingly reduced infarct size and improved cardiac function 24-hour or 28-day after MI/R. PDE4B in bone marrow-derived cells promoted MI/R injury and vascular PDE4B further exaggerated this injury. Mechanistically, PDE4B mediated neutrophil-endothelial cell interaction and PKA (protein kinase A)-dependent expression of cell adhesion molecules, neutrophil cardiac infiltration, and release of proinflammatory cytokines. Meanwhile, PDE4B promoted coronary microcirculatory obstruction and vascular permeability in MI/R, without affecting flow restriction-induced thrombosis. PDE4B blockade increased flow-mediated vasodilatation and promoted endothelium-dependent dilatation of coronary arteries in a PKA- and nitric oxide-dependent manner. Furthermore, postischemia administration with piclamilast, a PDE4 pan-inhibitor, improved cardiac microcirculation, suppressed inflammation, and attenuated MI/R injury in mice. Incubation with sera from patients with acute myocardial infarction impaired acetylcholine-induced relaxations in human coronary microarteries, which was abolished by PDE4 inhibition. Similar protection against MI/R-related coronary injury was recapitulated in mice with PDE4B deletion or inhibition, but not with the pure vasodilator, sodium nitroprusside. PDE4B is critically involved in neutrophil inflammation and microvascular obstruction, leading to MI/R injury. Selective inhibition of PDE4B might protect cardiac function in patients with acute myocardial infarction designated for reperfusion therapy.

SARS-CoV-2 nucleocapsid protein triggers hyperinflammation via protein-protein interaction-mediated intracellular Cl− accumulation in respiratory epithelium

SARS-CoV-2, the culprit pathogen of COVID-19, elicits prominent immune responses and cytokine storms. Intracellular Cl− is a crucial regulator of host defense, whereas the role of Cl− signaling pathway in modulating pulmonary inflammation associated with SARS-CoV-2 infection remains unclear. By using human respiratory epithelial cell lines, primary cultured human airway epithelial cells, and murine models of viral structural protein stimulation and SARS-CoV-2 direct challenge, we demonstrated that SARS-CoV-2 nucleocapsid (N) protein could interact with Smad3, which downregulated cystic fibrosis transmembrane conductance regulator (CFTR) expression via microRNA-145. The intracellular Cl− concentration ([Cl−]i) was raised, resulting in phosphorylation of serum glucocorticoid regulated kinase 1 (SGK1) and robust inflammatory responses. Inhibition or knockout of SGK1 abrogated the N protein-elicited airway inflammation. Moreover, N protein promoted a sustained elevation of [Cl−]i by depleting intracellular cAMP via upregulation of phosphodiesterase 4 (PDE4). Rolipram, a selective PDE4 inhibitor, countered airway inflammation by reducing [Cl−]i. Our findings suggested that Cl− acted as the crucial pathological second messenger mediating the inflammatory responses after SARS-CoV-2 infection. Targeting the Cl− signaling pathway might be a novel therapeutic strategy for COVID-19.

Past, Present, and Future in Dermatomyositis Therapeutics.

This review highlights current and emerging pharmacologic therapies for the treatment of dermatomyositis (DM). Current clinical evidence, in addition to recently published and ongoing clinical trials for various drugs in development, are summarized in this review. There has been significant progress in the research and development of potential treatments in DM. The FDA recently approved Octagam® 10% Immune Globulin Intravenous (IVIg) for the treatment of DM. Several drug targets are being explored as viable therapeutic options in phase 2 and phase 3 clinical trials; at the forefront of these are JAK inhibitors (tofacitinib and baricitinib) and T-cell co-stimulation blockers (i.e. abatacept). In addition, clinical trials are currently under way for therapeutics targeting novel molecular pathways, including immunoproteasome inhibitors, anti-B cell therapy, anti-interferon drugs, complement inhibitors, and phosphodiesterase-4 inhibitors. With the large number of clinical trials, multiple novel therapeutics in development, and improved classification and outcome measures, the treatment landscape for DM will continue to rapidly evolve in the coming years as more options become available.

Can Phosphodiesterase 4 Inhibitor Therapy Be Used in Respiratory Diseases Other Than Chronic Obstructive Pulmonary Disease?

Selective phosphodiesterase 4 (PDE4) inhibitors have been extensively studied for the treatment of various respiratory diseases due to their broad anti-inflammatory and/or bronchodilator effects. Roflumilast, an oral selective PDE4 inhibitor, is currently used as a second-line treatment in patients with chronic obstructive pulmonary disease (COPD) with chronic bronchitis. Despite its proven efficacy in other respiratory disorders, including asthma, no other PDE4 inhibitor is approved for respiratory pathologies. This systematic review summarizes the therapeutic action of PDE4 inhibitors, their limitations, recent therapeutic success, and future targets for their use in respiratory diseases other than COPD. An electronic literature search was conducted on four databases, namely, PubMed, PubMed Central, Google Scholar, and ScienceDirect, to collect data on related studies done in humans and published in the English language in the last five years. After extensive analysis and quality appraisal, 11 studies were eligible and thus included in this review, consisting of two randomized controlled trials (RCT), one systematic review and meta-analysis, and eight literature reviews. Roflumilast is not approved for the treatment of asthma due to associated adverse effects and comparable efficacy to inhaled corticosteroids, which are considered the mainstay of asthma maintenance therapy. Hence, the importance of balancing the efficacy with minimizing the side effects is highlighted. Tanimilast (CHF6001), an inhalational selective PDE4 inhibitor, and ensifentrine, a combined PDE3/4 inhibitor, demonstrate the recent therapeutic success in asthma and warrant further large-scale clinical studies. Future researchers will focus on the specific endotype than the phenotype in asthma as a meaningful therapeutic approach due to the high heterogeneity noted in asthma. Current evidence suggests the possibility of PDE4 inhibitors as a novel therapeutic option for chronic cough, allergic rhinitis, and cystic fibrosis. Further evidence from new studies is eagerly anticipated to better understand the efficacy and safety of PDE4 inhibitors in these respiratory diseases.

573 ME3183, a novel phosphodiesterase-4 (PDE4) inhibitor, showed potent suppressive effects on pathogenic cytokine expression in cultures of peripheral blood mononuclear cells (PBMC) from psoriasis patients and on psoriatic features in mouse models

Introduction & Objectives: PDE4 plays an important role in the immune system. ME3183, an oral PDE4 inhibitor, has shown anti-inflammatory effects in non-clinical studies. Here, we evaluated the therapeutic potency of ME3183 for psoriasis both in vitro and in vivo and compared it with apremilast, a marketed oral PDE4 inhibitor. Methods: In the in vitro assay, cultures of PBMC from 10 psoriasis (Ps) patients were stimulated with lipopolysaccharide (LPS) in the presence of ME3183 or apremilast, and the level of tumor necrosis factor-alpha (TNF-α) was measured. In the psoriasis model, imiquimod was applied on shaved dorsal skin for 6 consecutive days. In the arthritis model, collagen antibody was injected on Day 0 and LPS on Day 3. In both models, ME3183 or apremilast was administered twice daily, and clinical score and histological findings were evaluated. Gene expression by real-time polymerase chain reaction and cell population were analyzed in the psoriasis model and paw thickness in the arthritis model. Results: In cultures of PBMC from Ps patients, ME3183 showed a 114-fold inhibitory activity against TNF-α production than apremilast. We next evaluated the effects of ME3183 on psoriasis and arthritis in vivo. In the psoriasis model, ME3183 significantly ameliorated the psoriatic score, epidermal thickness, gene expressions of interleukin (IL)-17A and IL-23p19 and skin infiltration of IL-17A+ cells. In the arthritis model, ME3183 significantly suppressed the arthritis score and paw thickness. In both models, ME3183 was effective at low doses compared to apremilast. Conclusions: Our results indicated that ME3183 had potent anti-psoriatic effects via suppression of pathogenic cytokine expression. ME3183 may have higher therapeutic effects on Ps and psoriatic arthritis compared to the current oral PDE4 inhibitor. The clinical efficacy of ME3183 will be evaluated in the P2a study with Ps patients.