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BACKGROUND & nbsp;Phosphodiesterase 4 (PDE4) inhibition is associated with antiinflammatory and antifibrotic effects that may be beneficial in patients with idiopathic pulmonary fibrosis.& nbsp;METHODS & nbsp;In this phase 2, double-blind, placebo-controlled trial, we investigated the efficacy and safety of BI 1015550, an oral preferential inhibitor of the PDE4B subtype, in patients with idiopathic pulmonary fibrosis. Patients were randomly assigned in a 2:1 ratio to receive BI 1015550 at a dose of 18 mg twice daily or placebo. The primary end point was the change from baseline in the forced vital capacity (FVC) at 12 weeks, which we analyzed with a Bayesian approach separately according to background nonuse or use of an antifibrotic agent.& nbsp;RESULTS & nbsp;A total of 147 patients were randomly assigned to receive BI 1015550 or placebo. Among patients without background antifibrotic use, the median change in the FVC was 5.7 ml (95% credible interval, -39.1 to 50.5) in the BI 1015550 group and -81.7 ml (95% credible interval, -133.5 to -44.8) in the placebo group (median difference, 88.4 ml; 95% credible interval, 29.5 to 154.2; probability that BI 1015550 was superior to placebo, 0.998). Among patients with background antifibrotic use, the median change in the FVC was 2.7 ml (95% credible interval, -32.8 to 38.2) in the BI 1015550 group and -59.2 ml (95% credible interval, -111.8 to -17.9) in the placebo group (median difference, 62.4 ml; 95% credible interval, 6.3 to 125.5; probability that BI 1015550 was superior to placebo, 0.986). A mixed model with repeated measures analysis provided results that were consistent with those of the Bayesian analysis. The most frequent adverse event was diarrhea. A total of 13 patients discontinued BI 1015550 treatment owing to adverse events. The percentages of patients with serious adverse events or severe adverse events were similar in the two trial groups.& nbsp;CONCLUSIONS & nbsp;In this placebo-controlled trial, treatment with BI 1015550, either alone or with background use of an antifibrotic agent, prevented a decrease in lung function in patients with idiopathic pulmonary fibrosis.

In a phase 3 trial involving patients with Behçet’s syndrome, the small-molecule phosphodiesterase 4 inhibitor apremilast reduced the number of oral ulcers and pain of ulcers and improved quality-of-life measures as compared with placebo over 12 weeks. Adverse events included diarrhea, nausea, and headache.

In this randomized trial involving patients with pulmonary hypertension, sildenafil (an inhibitor of phosphodiesterase type 5) was found to improve exercise capacity and pulmonary hemodynamics. The study was not powered to assess mortality, but the findings suggest that sildenafil may have a place in the treatment of symptomatic pulmonary hypertension. In patients with pulmonary hypertension, sildenafil was found to improve exercise capacity and pulmonary hemodynamics. Pulmonary arterial hypertension is defined as a group of diseases characterized by a progressive increase in pulmonary vascular resistance, leading to right ventricular failure and premature death. 1 , 2 Pathobiologic mechanisms of the disease include pulmonary endothelial dysfunction, which leads to impaired production of vasodilators, such as nitric oxide and prostacyclin, and overexpression of vasoconstrictors, such as endothelin-1. 3 , 4 Treatment includes conventional agents (anticoagulants, diuretics, digoxin, and supplemental oxygen, as well as calcium-channel blockers in selected patients), vasodilators, and antiproliferative agents such as prostanoids and endothelin-receptor antagonists, which are targeted at abnormalities of endothelial function. 5 , 6 Four agents are currently approved . . .

A cream formulation of the phosphodiesterase type 4 inhibitor roflumilast, in two concentrations, led to higher percentages of patients with clearance or near-clearance of psoriatic lesions at 6 weeks than placebo. Difficult-to-treat intertriginous areas also improved as compared with placebo.

The antiinflammatory small molecule ibudilast was tested in a phase 2 trial in patients with progressive multiple sclerosis. The rate of brain atrophy over 96 weeks was lower with ibudilast than with placebo. Side effects with ibudilast included GI symptoms and depression.

Apremilast (Otezla ® ) is an orally administered, small molecule inhibitor of phosphodiesterase 4 (PDE4). Apremilast 30 mg twice daily reduced the severity of moderate to severe plaque psoriasis in the phase 3 ESTEEM trials, as well as improving difficult-to-treat nail, scalp and palmoplantar psoriasis. Most patient-reported outcomes, including pruritus and the total Dermatology Life Quality Index, also improved to a significantly greater extent with apremilast than with placebo, with significant improvements in pruritus and skin discomfort/pain visual analogue scale scores seen as early as week 2 with apremilast. Apremilast 30 mg twice daily improved signs and symptoms in both disease-modifying antirheumatic drug (DMARD)-naïve and DMARD-experienced patients with active psoriatic arthritis in the phase 3 PALACE trials. Enthesitis, dactylitis, physical function and fatigue were also improved with apremilast, and its efficacy was sustained for up to 208 weeks. Apremilast had an early onset of efficacy in patients with active psoriatic arthritis, with significantly more apremilast 30 mg twice daily than placebo recipients achieving a ≥20% improvement in modified American College of Rheumatology response criteria at week 2 in the phase 3b ACTIVE trial. Apremilast was generally well tolerated in patients with psoriasis and psoriatic arthritis; no laboratory monitoring is required. In conclusion, orally administered apremilast is an effective, generally well tolerated and convenient option for the treatment of psoriasis and psoriatic arthritis.

Treatment options for alcohol use disorders (AUDs) have minimally advanced since 2004, while the annual deaths and economic toll have increased alarmingly. Phosphodiesterase type 4 (PDE4) is associated with alcohol and nicotine dependence. PDE4 inhibitors were identified as a potential AUD treatment using a bioinformatics approach. We prioritized a newer PDE4 inhibitor, apremilast, as ideal for repurposing (i.e., FDA approved for psoriasis, low incidence of adverse events, excellent safety profile) and tested it using multiple animal strains and models, as well as in a human phase IIa study. We found that apremilast reduced binge-like alcohol intake and behavioral measures of alcohol motivation in mouse models of genetic risk for drinking to intoxication. Apremilast also reduced excessive alcohol drinking in models of stress-facilitated drinking and alcohol dependence. Using site-directed drug infusions and electrophysiology, we uncovered that apremilast may act to lessen drinking in mice by increasing neural activity in the nucleus accumbens, a key brain region in the regulation of alcohol intake. Importantly, apremilast (90 mg/d) reduced excessive drinking in non-treatment-seeking individuals with AUD in a double-blind, placebo-controlled study. These results demonstrate that apremilast suppresses excessive alcohol drinking across the spectrum of AUD severity.

Ensifentrine, an inhaled, selective phosphodiesterase (PDE) 3 and PDE4 inhibitor, is being developed by Verona Pharma plc for the treatment of respiratory diseases, including chronic obstructive pulmonary disease (COPD). In June 2024, ensifentrine (OHTUVAYRE™) inhalation suspension was approved for the maintenance treatment of COPD in adult patients in the USA. This article summarizes the milestones in the development of ensifentrine leading to this first approval for the maintenance treatment of COPD.

The inhibition, in mice, of the phosphodiesterase PDE9A, which specifically regulates natriuretic-peptide-coupled cGMP signalling, is independent of nitric oxide and is upregulated in failing human hearts, and can reverse pre-established stress-induced heart disease. A new treatment for heart disease Work in animals has shown that inhibition of phosphodiesterase type 5A (PDE5A) with, for example, Viagra, can protect the heart from pathological stress by preventing the degradation of nitric-oxide-generated cGMP. However, nitric oxide signalling is often depressed in cardiovascular disease, potentially explaining the disappointing results of PDE5A inhibition in clinical trials. David Kass and colleagues now identify an alternative target, PDE9A, which specifically regulates natriuretic-peptide-coupled cGMP signalling, and is independent of nitric oxide. They show that PDE9A is upregulated in failing human hearts and that its inhibition in mice can reverse pre-established stress-induced heart disease. PDE9A inhibitors seem to be well tolerated in humans and are being investigated in clinical trials for neurocognitive disease. The new results suggest that these inhibitors may also find an application in heart disease. Cyclic guanosine monophosphate (cGMP) is a second messenger molecule that transduces nitric-oxide- and natriuretic-peptide-coupled signalling, stimulating phosphorylation changes by protein kinase G. Enhancing cGMP synthesis or blocking its degradation by phosphodiesterase type 5A (PDE5A) protects against cardiovascular disease 1 , 2 . However, cGMP stimulation alone is limited by counter-adaptions including PDE upregulation 3 . Furthermore, although PDE5A regulates nitric-oxide-generated cGMP 4 , 5 , nitric oxide signalling is often depressed by heart disease 6 . PDEs controlling natriuretic-peptide-coupled cGMP remain uncertain. Here we show that cGMP-selective PDE9A (refs 7 , 8 ) is expressed in the mammalian heart, including humans, and is upregulated by hypertrophy and cardiac failure. PDE9A regulates natriuretic-peptide- rather than nitric-oxide-stimulated cGMP in heart myocytes and muscle, and its genetic or selective pharmacological inhibition protects against pathological responses to neurohormones, and sustained pressure-overload stress. PDE9A inhibition reverses pre-established heart disease independent of nitric oxide synthase (NOS) activity, whereas PDE5A inhibition requires active NOS. Transcription factor activation and phosphoproteome analyses of myocytes with each PDE selectively inhibited reveals substantial differential targeting, with phosphorylation changes from PDE5A inhibition being more sensitive to NOS activation. Thus, unlike PDE5A, PDE9A can regulate cGMP signalling independent of the nitric oxide pathway, and its role in stress-induced heart disease suggests potential as a therapeutic target.