Mammalian skeletal muscles consist of two main fibre types: slow-twitch (type I, oxidative) and fast-twitch (type IIa, fast oxidative; type IIb/IIx, fast glycolytic). Muscle fibre composition switch is closely associated with chronic diseases such as muscle atrophy, obesity, type II diabetes and athletic performance. Prostaglandin D2 (PGD2 ) is a bioactive lipid derived from arachidonic acid that aggravates muscle damage and wasting during muscle atrophy. This study aimed to investigate the precise mechanisms underlying PGD2 -mediated muscle homeostasis and myogenesis.
Skeletal muscle-specific PGD2 receptor DP2-deficient mice (DP2fl/fl HSACre ) and their littermate controls (DP2fl/fl ) were subjected to exhaustive exercise and fed a high-fat diet (HFD). X-linked muscular dystrophy (MDX) mice and HFD-challenged mice were treated with the selective DP2 inhibitor CAY10471. Exercise tolerance, body weight, glycometabolism and skeletal muscle fibre composition were measured to determine the role of the skeletal muscle PGD2 /DP2 signalling axis in obesity and muscle disorders. Multiple genetic and pharmacological approaches were also used to investigate the intracellular signalling cascades underlying the PGD2 /DP2-mediated skeletal muscle fibre transition.
PGD2 generation and DP2 expression were significantly upregulated in the hindlimb muscles of HFD-fed mice (P < 0.05 or P < 0.01 vs. normal chow diet). Compared with DP2fl/fl mice, DP2fl/fl HSACre mice exhibited remarkable glycolytic-to-oxidative fibre-type transition in hindlimb muscles and were fatigue resistant during endurance exercise (154.9 ± 6.0 vs. 124.2 ± 8.1 min, P < 0.05). DP2fl/fl HSACre mice fed an HFD showed less weight gain (P < 0.05) and hepatic lipid accumulation (P < 0.01), reduced insulin resistance and enhanced energy expenditure (P < 0.05) compared with DP2fl/fl mice. Mechanistically, DP2 deletion promoted the nuclear translocation of nuclear factor of activated T cells 1 (NFATc1) by suppressing RhoA/Rho-associated kinase 2 (ROCK2) signalling, which led to enhanced oxidative fibre-specific gene transcription in muscle cells. Treatment with CAY10471 enhanced NFATc1 activity in the skeletal muscles and ameliorated HFD-induced obesity (P < 0.05 vs. saline) and insulin resistance in mice. CAY10471 also enhanced exercise tolerance in MDX mice (100.8 ± 8.0 vs. 68.9 ± 11.1 min, P < 0.05 vs. saline) by increasing the oxidative fibre-type ratio in the muscles (45.1 ± 2.3% vs. 32.3 ± 2.6%, P < 0.05 vs. saline).
DP2 activation suppresses oxidative fibre transition via RhoA/ROCK2/NFATc1 signalling. The inhibition of DP2 may be a potential therapeutic approach against obesity and muscle disorders.

BACKGROUND: The prostaglandin D2 (PGD2) receptor 2 (DP2 receptor) pathway is an important regulator of the inflammatory cascade in asthma, which can be stimulated by allergic or non-allergic triggers. Fevipiprant is an oral, non-steroidal, highly selective, reversible antagonist of the DP2 receptor that inhibits the binding of PGD2 and its metabolites.
METHODS: SPIRIT, a 2-treatment period (52-week, double-blind and optional 104-week single-blind), randomised, placebo-controlled, multicentre, parallel-group study, assessed the long-term safety of fevipiprant (150 mg and 450 mg o.d.) added to standard of care in patients ≥ 12 years with uncontrolled asthma. Stratified block randomisation was used. Patients were randomised in an approximate ratio of 3:3:1 (fevipiprant 150 mg, fevipiprant 450 mg or placebo). Patients were either newly enrolled or had participated in a previous fevipiprant Phase 3 trial. Primary endpoints were: time-to-first treatment emergent adverse event (AE); serious AE; and AE leading to discontinuation from study treatment. Data from both treatment periods were combined for analyses. Data were collected during study site visits.
RESULTS: In total, 1093 patients were randomised to receive fevipiprant 150 mg, 1085 to fevipiprant 450 mg, and 360 to placebo. Overall, 1184 patients had ≥ 52 weeks\' treatment, while 163 received ≥ 104 weeks\' treatment. Both doses were well tolerated, with a safety profile similar to placebo both in new patients and in those enrolled from previous studies. In exploratory analyses, reduced rates of moderate-to-severe asthma exacerbations, increased time-to-first moderate-to-severe asthma exacerbation and improved FEV1 were observed for both doses of fevipiprant versus placebo; these were without multiplicity adjustment and should be interpreted with caution. SPIRIT was terminated early, on 16 December 2019, by the Sponsor.
CONCLUSIONS: In patients with uncontrolled asthma, the addition of fevipiprant had a favourable long-term safety profile.
BACKGROUND: Clinicaltrials.gov, NCT03052517, prospectively registered 23 January 2017, https://clinicaltrials.gov/ct2/show/NCT03052517 .

Accumulating evidence has shown that prostaglandin D2 (PGD2)-chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) pathway plays an important role in promoting eosinophilic airway inflammation in asthma. We aimed to assess the efficacy and safety of CRTH2 antagonist fevipiprant in patients with persistent asthma compared with placebo.
We identified eligible studies by searching PubMed, EMBASE, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov. The study was registered as CRD 42020221714 ( http://www.crd.york.ac.uk/PROSPERO ). Ten randomized controlled trials with 7902 patients met our inclusion criteria. A statistically significant benefit of fevipiprant compared with placebo was shown in improving forced expiratory volume in 1 s (MD 0.05 L, 95% CI: 0.02 to 0.07; p < 0.0001), Asthma Control Questionnaire score (MD -0.10, 95% CI: -0.16 to -0.04; p = 0.001), and Asthma Quality of Life Questionnaire score (MD 0.08, 95% CI: 0.03 to 0.13; p = 0.003). Fevipiprant decreased number of patients with at least one asthma exacerbation requiring administration of systemic corticosteroids for 3 days or more (RR 0.86, 95% CI: 0.77 to 0.97; p = 0.01). Some benefits were a little more pronounced in the high eosinophil population (with an elevated blood eosinophil count or sputum eosinophil percentage) and in the 450 mg dose group. Fevipiprant was well tolerated with no safety issues compared with placebo. Fevipiprant could safely improve asthma outcomes compared to placebo. However, most of the differences didn\'t reach the minimal clinically important difference (MCID), thus the clinical benefits remained to be confirmed.

Fevipiprant is an oral, non-steroidal, highly selective, reversible antagonist of the prostaglandin D2 (DP2) receptor. The DP2 receptor is a mediator of inflammation expressed on the membrane of key inflammatory cells, including eosinophils, Th2 cells, type 2 innate lymphoid cells, CD8+ cytotoxic T cells, basophils and monocytes, as well as airway smooth muscle and epithelial cells. The DP2 receptor pathway regulates the allergic and non-allergic asthma inflammatory cascade and is activated by the binding of prostaglandin D2. Fevipiprant is metabolised by several uridine 5\'-diphospho glucuronosyltransferase enzymes to an inactive acyl-glucuronide (AG) metabolite, the only major human metabolite. Both fevipiprant and its AG metabolite are eliminated by urinary excretion; fevipiprant is also possibly cleared by biliary excretion. These parallel elimination pathways suggested a low risk of major drug-drug interactions (DDI), pharmacogenetic or ethnic variability for fevipiprant, which was supported by DDI and clinical studies of fevipiprant. Phase II clinical trials of fevipiprant showed reduction in sputum eosinophilia, as well as improvement in lung function, symptoms and quality of life in patients with asthma. While fevipiprant reached the most advanced state of development to date of an oral DP2 receptor antagonist in a worldwide Phase III clinical trial programme, the demonstrated efficacy did not support further clinical development in asthma.

Diabetes is associated with disturbances in the normal levels of both insulin and glucagon, both of which play critical roles in the regulation of glycemia. Recent studies have found lipocalin-type prostaglandin D2 synthase (l-PGDS) to be an emerging target involved in the pathogenesis of type-2 diabetes. This study focused on the effect of l-PGDS on glucagon secretion from cultured pancreatic Alpha TC-1 Clone 6 cells. When cells were treated with various concentrations of l-PGDS (0, 10, 50, and 100 ug/ml) for 2 h in 1 mM glucose; glucagon secretion decreased to 670±45, 838±38, 479±11, and 437±45 pg/ml, respectively. In addition, pancreatic islets were isolated from C57BL/6 mice and stained for prostaglandin D2 receptors, DP1 and DP2, using immunohistochemistry. Our results showed that these islets express only the DP1 receptor. Pancreatic islets were then stained for alpha and beta cells, as well as DP1, to find the primary location of the receptor within the islets using immunofluorescence. Interestingly, DP1 receptor density was found primarily in alpha cells rather than in beta cells. Our study is the first to report a correlation between l-PGDS and glucagon secretion in alpha cells. Based on our obtained results, it can be concluded that higher concentrations of l-PGDS significantly reduced the secretion of glucagon in alpha cells, which may contribute to the pathogenesis of diabetes as well as offer a novel therapeutic site for the treatment of diabetes.