Effects of 1-H-indole-3-glyoxamide (A-002) on concentration of secretory phospholipase A2 (PLASMA study): a phase II double-blind, randomised, placebo-controlled trial

Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA.
The Lancet (Impact Factor: 45.22). 03/2009; 373(9664):649-58. DOI: 10.1016/S0140-6736(09)60403-7
Source: PubMed


Secretory phospholipase A(2) (sPLA(2)) enzymes, produced and secreted in human blood vessels and hepatocytes, contribute to the development of atherosclerosis through mechanisms that are both dependent and independent of lipoprotein. We examined the effects of an sPLA(2) inhibitor on enzyme concentration and on plasma lipoproteins and inflammatory biomarkers in patients with coronary heart disease.
Patients aged 18 years and older with stable coronary heart disease from the USA and Ukraine were eligible for enrolment in this phase II, randomised, double-blind, placebo-controlled, parallel-arm, dose-response study. 393 patients were randomly assigned by computer-generated sequence to receive either placebo (n=79) or one of four doses of an sPLA(2) inhibitor, A-002 (1-H-indole-3-glyoxamide; 50 mg [n=79], 100 mg [n=80], 250 mg [n=78], or 500 mg [n=77] twice daily), for 8 weeks. The primary endpoint was the change in sPLA(2) group IIA (sPLA(2)-IIA) concentration or activity from baseline to week 8. Analysis was by modified intention to treat (ITT). The ITT population consisted of all patients who received one dose of study treatment; data for patients who dropped out before the end of the study were carried forward from last observation. This trial is registered with, number NCT00455546.
All randomised patients received at least one dose and were included in the ITT population. Data for 45 patients were carried forward from last observation (36 in the A-002 group and nine in the placebo group); the main reason for dropout before completion was because of adverse events. 348 patients reached the primary endpoint (A-002 n=278, placebo n=70). Mean sPLA(2)-IIA concentration fell by 86.7%, from 157 pmol/L to 21 [corrected] pmol/L, in the overall active treatment group, and by 4.8%, from 157 pmol/L to 143 [corrected] pmol/L, in the placebo group (p<0.0001 treatment vs placebo). The reductions in sPLA(2)-IIA concentration in the A-002 groups were dose dependent (ranging from 69.2% in the 50 mg group to 95.8% in the 500 mg group) and differed significantly from placebo (p<0.0001 for all doses). In the 500 mg A-002 treatment group, there was one serious adverse event (exacerbation of underlying chronic obstructive pulmonary disease), but the proportion of patients reporting treatment-emergent adverse events did not differ from placebo. The main side-effects of the drug included headache (n=20), nausea (n=17), and diarrhoea (n=12).
The reductions in sPLA(2)-IIA concentration suggest that A-002 might be an effective anti-atherosclerotic agent.

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    • "We identified 4 randomized clinical trials (RCTs) of the sPLA2 inhibitor varespladib in a total of 1,300 individuals (Online Fig. 6, Online Table 12) (9,20–22). A meta-regression suggested varespladib treatment produced a dose-dependent reduction in sPLA2-IIA mass (p for meta-regression = 0.06) (Online Fig. 7). "
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    ABSTRACT: To investigate the role of secretory phospholipase A2-(sPLA2)-IIA in cardiovascular disease. Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase-III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy. We conducted a Mendelian randomization meta-analysis of 19 general population studies (8021 incident, 7513 prevalent major vascular events (MVE) in 74,683 individuals) and ten acute coronary syndrome (ACS) cohorts (2520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable. PLA2G2A rs11573156 C-allele associated with lower circulating sPLA2-IIA mass (38-44%) and sPLA2 enzyme activity (3-23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C-allele was 1.02(95%CI:0.98,1.06) in general populations and 0.96(95%CI:0.90,1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1 log unit lower sPLA2-IIA mass was 1.04(95%CI:0.96,1.13), and differed from the non-genetic observational estimate (OR0.69;95%CI:0.61,0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
    Full-text · Article · Jul 2013 · Journal of the American College of Cardiology
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    • "Nowadays, this is the sPLA2 inhibitor with more available pharmacologic data: varespladib has been intravenously administered in adults with septic shock [15], [16] and is presently under advanced clinical investigation for sickle cell disease-induced acute chest syndrome (IMPACTS trial, NCT00434473) [17]. Varespladib methyl is the oral pro-drug of varespladib sodium and it has been studied for chronic and acute cardiovascular disease in two trials (PLASMA [18], FRANCIS [19]). "
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    ABSTRACT: Secretory phospholipase A2 (sPLA2) plays a pivotal role in acute respiratory distress syndrome (ARDS). This enzyme seems an interesting target to reduce surfactant catabolism and lung tissue inflammation. Varespladib is a specifically designed indolic sPLA2 inhibitor, which has shown promising results in animals and adults. No specific data in pediatric ARDS patients are yet available. We studied varespladib in broncho-alveolar lavage (BAL) fluids obtained ex vivo from pediatric ARDS patients. Clinical data and worst gas exchange values during the ARDS course were recorded. Samples were treated with saline or 10-40-100 µM varespladib and incubated at 37°C. Total sPLA2 activity was measured by non-radioactive method. BAL samples were subjected to western blotting to identify the main sPLA isotypes with different sensitivity to varespladib. Results was corrected for lavage dilution using the serum-to-BAL urea ratio and for varespladib absorbance. Varespladib reduces sPLA2 activity (p<0.0001) at 10,40 and 100 µM; both sPLA2 activity reduction and its ratio to total proteins significantly raise with increasing varespladib concentrations (p<0.001). IC(50) was 80 µM. Western blotting revealed the presence of sPLA2-IIA and -IB isotypes in BAL samples. Significant correlations exist between the sPLA2 activity reduction/proteins ratio and PaO(2) (rho = 0.63;p<0.001), PaO(2)/FiO(2) (rho = 0.7; p<0.001), oxygenation (rho = -0.6; p<0.001) and ventilation (rho = -0.4;p = 0.038) indexes. Varespladib significantly inhibits sPLA2 in BAL of infants affected by post-neonatal ARDS. Inhibition seems to be inversely related to the severity of gas exchange impairment.
    Full-text · Article · Oct 2012 · PLoS ONE
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    • "Several indole-based inhibitors of sPLA2 have been developed to treat various inflammatory conditions such as pancreatitis, allergic rhinitis, rheumatoid arthritis, gout and atherosclerosis. For example, the indole derivative varespladib 24 (s-PLA2 IC50 = 15 nM, Figure 6) was developed as a treatment for rheumatoid arthritis and atherosclerosis [66,67,68]. A recent phase II trial showed that oral varespladib was able to reduce progression of atherosclerosis and associated cardiovascular events, without any evidence of adverse effects [67]. "
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    ABSTRACT: Ever since the discovery of aspirin, small molecule therapeutics have been widely prescribed to treat inflammation and pain. Aspirin and several small molecule NSAIDs are known to inhibit the enzymes cyclooxygenase-1 (COX-1) and -2 (COX-2). Despite the success of NSAIDs to treat inflammatory disorders, the development of a clinically useful small molecule NSAIDs with decreased side effect profiles is an ongoing effort. The recent discovery and development of selective COX-2 inhibitors was a step toward this direction. Emerging trends are represented by the progress in the development of hybrid agents such as nitric oxide donor-NSAIDs (NO-NSAIDs) and dual COX/lipoxygenase (LOX) inhibitors. This review focuses on the recent advances in the rational design of small molecule NSAIDs in therapy.
    Full-text · Article · May 2010 · Pharmaceuticals
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