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American Journal of Respiratory and... Aug 2023Ensifentrine is a novel, selective, dual phosphodiesterase (PDE)3 and PDE4 inhibitor with bronchodilator and antiinflammatory effects. Replicate phase III trials of... (Randomized Controlled Trial)
Randomized Controlled Trial
Ensifentrine, a Novel Phosphodiesterase 3 and 4 Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease: Randomized, Double-Blind, Placebo-controlled, Multicenter Phase III Trials (the ENHANCE Trials).
UNLABELLED
Ensifentrine is a novel, selective, dual phosphodiesterase (PDE)3 and PDE4 inhibitor with bronchodilator and antiinflammatory effects. Replicate phase III trials of nebulized ensifentrine were conducted (ENHANCE-1 and ENHANCE-2) to assess these effects in patients with chronic obstructive pulmonary disease (COPD). To evaluate the efficacy of ensifentrine compared with placebo for lung function, symptoms, quality of life, and exacerbations in patients with COPD. These phase III, multicenter, randomized, double-blind, parallel-group, placebo-controlled trials were conducted between September 2020 and December 2022 at 250 research centers and pulmonology practices in 17 countries. Patients aged 40-80 years with moderate to severe symptomatic COPD were enrolled. Totals of 760 (ENHANCE-1) and 789 (ENHANCE-2) patients were randomized and treated, with 69% and 55% receiving concomitant long-acting muscarinic antagonists or long-acting β-agonists, respectively. Post-bronchodilator FEV percentage predicted values were 52% and 51% of predicted normal. Ensifentrine treatment significantly improved average FEV area under the curve at 0-12 hours versus placebo (ENHANCE-1, 87 ml [95% confidence interval, 55, 119]; ENHANCE-2, 94 ml [65, 124]; both < 0.001). Ensifentrine treatment significantly improved symptoms (Evaluating Respiratory Symptoms) and quality of life (St. George's Respiratory Questionnaire) versus placebo at Week 24 in ENHANCE-1 but not in ENHANCE-2. Ensifentrine treatment reduced the rate of moderate or severe exacerbations versus placebo over 24 weeks (ENHANCE-1, rate ratio, 0.64 [0.40, 1.00]; = 0.050; ENHANCE-2, rate ratio, 0.57 [0.38, 0.87]; = 0.009) and increased time to first exacerbation (ENHANCE-1, hazard ratio, 0.62 [0.39, 0.97]; = 0.038; ENHANCE-2, hazard ratio, 0.58 [0.38, 0.87]; = 0.009). Adverse event rates were similar to those for placebo. Ensifentrine significantly improved lung function in both trials, with results supporting exacerbation rate and risk reduction in a broad COPD population and in addition to other classes of maintenance therapies. Clinical trial registered with www.
CLINICALTRIALS
gov and EudraCT (ENHANCE-1, www.
CLINICALTRIALS
gov identifier NCT04535986, EudraCT identifier 2020-002086-34; ENHANCE-2, www.
CLINICALTRIALS
gov identifier NCT04542057, EudraCT identifier 2020-002069-32).
Topics: Humans; Bronchodilator Agents; Double-Blind Method; Forced Expiratory Volume; Phosphoric Diester Hydrolases; Pulmonary Disease, Chronic Obstructive; Quality of Life; Adult; Middle Aged; Aged; Aged, 80 and over
PubMed: 37364283
DOI: 10.1164/rccm.202306-0944OC -
Clinical Cancer Research : An Official... Jun 2023ENPP1 (ecto-nucleotide pyrophosphatase/phosphodiesterase) participates in the hydrolysis of different purine nucleotides in an array of physiologic processes. However,... (Review)
Review
ENPP1 (ecto-nucleotide pyrophosphatase/phosphodiesterase) participates in the hydrolysis of different purine nucleotides in an array of physiologic processes. However, ENPP1 is frequently overexpressed in local relapses and tumor metastases, which are associated with poor prognosis and survival in a range of solid tumors. ENPP1 promotes an immunosuppressive tumor microenvironment (TME) by tilting the balance of ATP/adenosine (Ado) in conjunction with other components (CD38, CD39/ENTPD1, and CD73/NT5E). Moreover, ENPP1 intersects with the stimulator of interferon genes (STING), impairing its robust immune response through the hydrolysis of the effector 2´,3´-cyclic GMP-AMP. Thus, ENPP1 blockade emerges as a unique target eliciting immune remodeling and leveraging the STING pathway. Several ENPP1 inhibitors have shown an immunostimulatory effect, and their combination with other therapeutic modalities, such as immune-checkpoint blockade, STING activation, DNA damage response (DDR) inhibitors, and radiotherapy (RT), represents a promising avenue to boost antitumor-immune responses and to improve current clinical outcomes in several tumors. This comprehensive review summarizes the current state of the art and opens new perspectives for novel treatment strategies.
Topics: Humans; Neoplasm Recurrence, Local; Adenosine; Phosphoric Diester Hydrolases; Tumor Microenvironment
PubMed: 36719675
DOI: 10.1158/1078-0432.CCR-22-1681 -
International Journal of Molecular... Dec 2023Vitiligo is a complex disease with a multifactorial nature and a high impact on the quality of life of patients. Although there are multiple therapeutic alternatives,... (Review)
Review
Vitiligo is a complex disease with a multifactorial nature and a high impact on the quality of life of patients. Although there are multiple therapeutic alternatives, there is currently no fully effective treatment for this disease. In the current era, multiple drugs are being developed for the treatment of autoimmune diseases. This review assesses the available evidence on the pathogenesis of vitiligo, and a comprehensive review of treatments available for vitiligo now and in the near future is provided. This qualitative analysis spans 116 articles. We reviewed the mechanism of action, efficacy and safety data of phototherapy, afamelanotide, cyclosporine, phosphodiesterase 4 inhibitors, trichloroacetic acid, basic fibroblast growth factor, tumor necrosis factor (TNF) inhibitors, secukinumab, pseudocatalase and janus kinase (JAK) inhibitors. At the moment, there is no clearly outstanding option or fully satisfactory treatment for vitiligo, so it is necessary to keep up the development of new drugs as well as the publication of long-term effectiveness and safety data for existing treatments.
Topics: Humans; Vitiligo; Quality of Life; Janus Kinase Inhibitors; Phototherapy; Treatment Outcome
PubMed: 38139134
DOI: 10.3390/ijms242417306 -
Journal of the American Academy of... Mar 2024Seborrheic dermatitis (SD) is a common skin disease with signs and symptoms that may vary by skin color, associated medical conditions, environmental factors, and... (Review)
Review
Seborrheic dermatitis (SD) is a common skin disease with signs and symptoms that may vary by skin color, associated medical conditions, environmental factors, and vehicle preference. Diagnosis of SD is based on presence of flaky, "greasy" patches, and/or thin plaques accompanied by erythema of the scalp, face, ears, chest, and groin and is associated with pruritus in many patients. The presentation may vary in different skin types and hyper- or hypopigmentation may occur, with or without erythema and minimal or no scaling. While the pathogenesis is not certain, 3 key factors generally agreed upon include lipid secretion by sebaceous glands, Malassezia spp. colonization, and some form of immunologic dysregulation that predisposes the patient to SD. Treatment involves reducing proliferation of, and inflammatory response to, Malassezia spp. Topical therapies, including antifungal agents and low potency corticosteroids, are the mainstay of treatment but may be limited by efficacy and side effects. Few novel treatments for SD are currently being studied; however, clinical trials assessing the use of topical phosphodiesterase-4 inhibitors have been completed. Improving outcomes in SD requires recognizing patient-specific manifestations/locations of the disease, including increased awareness of how it affects people of all skin types.
Topics: Humans; Dermatitis, Seborrheic; Antifungal Agents; Adrenal Cortex Hormones; Erythema; Malassezia
PubMed: 36538948
DOI: 10.1016/j.jaad.2022.12.017