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    • As cytosolic acetyl CoA levels

    2023-04-06

    As cytosolic acetyl-CoA levels in hepatocytes descend, cellular production and concentration of cholesterol go down, a change that is known to be sensed by the Sterol response element binding protein (SREBP)/Cleavage-Activating Protein system, leading to SREBP escort to the Golgi apparatus, cleavage, and nuclear translocation. In the nucleus, SREBPs binds to sterol response elements in several target genes, regulating their transcription. One of those genes is the LDL receptor (LDLR) gene, whose increased expression leads to increased uptake of circulating LDL and lowering of plasma LDL-C. Expression of the gene for HMG-CoA is also stimulated, but in the context of low cytosolic acetyl CoA, this does not impact cholesterol production. Activation of AMPK via liver kinase B1 (LKB1) by ETC-1002 leads to inhibition of ACC and HMG-CoA reductase (Fig. 2) and could potentially increase nitric oxide production and reduce inflammatory and oxidative stress. The pharmacokinetics of ETC-1002 seem to make it suitable for once-daily administration. MacDougall et al reported in a phase I study that used doses between 20 and 220 mg/d, a directly proportional increase in the maximum plasma concentration and 24-hour area under the curve with increasing doses of ETC-1002. The mean half-life of the drug ranged between 16 and 33 hours across the dosing range. Given that ETC-1002 would be used in patients with comorbidities, many of which may also be receiving a statin, a clinical trial was undertaken, aimed at evaluating the safety and pharmacokinetic interactions of ETC-1002 in patients with hypercholesterolemia who were concomitantly receiving atorvastatin 10 mg (clinicaltrials.govNCT01779453). According to preliminary results announced by the manufacturer, ETC-1002 showed only a small pharmacokinetic interaction with atorvastatin. Several other compounds have proven capable of inhibiting ACL in vitro, including (−), (−), 2,2 difluorocitrate, several benzonesulfonamides, and the naturally occurring compound hydroxycitrate. Nevertheless, their development as pharmacologic agents has been limited by issues related to poor ability to cross cell membranes, poor affinity for ACL requiring too high tissue concentrations, or, as in the case of hydroxycitrate, poor specificity leading to undesirable inhibition of other essential enzymes (isocitrate dehydrogenase). The compound bb'-methyl-substituted a,w-dicarboxylic BAY 87-2243 of 16-carbon length (MEDICA 16) was identified as a potent inhibitor of neutral lipid synthesis in the rat, with additional direct inhibitory activity over acyl-CoA carboxylase. However, MEDICA 16 did not continue its development into the clinical phase. Yet, other studies have evaluated ACL inhibitor precursors that can penetrate the plasma membrane, including SB-204990, the lactone prodrug of the ACL inhibitor SB-201076. In HepG2 cells, SB-204990 strongly inhibited both cholesterol and fatty acid synthesis. In rats, the compound also reduced plasma cholesterol and very low–density lipoprotein production, albeit to a smaller extent than in vitro. In dogs, the effect of SB-204990 on plasma triglycerides and cholesterol was still more modest, yet still significant.
    Clinical efficacy of ACL inhibition There is currently a quite efficacious and extensively used family of LDL-lowering medications, the HMG-CoA reductase inhibitors, commonly referred to as statins. Despite their efficacy, many patients do not reach LDL treatment goals because titration of statin doses may lead to dose-dependent adverse effects.4, 5, 6, 7, 8 Against the backdrop of this unmet need, a number of studies have evaluated the ACL inhibitor ETC-1002 as a lipid-lowering agent in humans. Table 1 recapitulates the key features and results of clinical phase I and phase II studies involving ETC-1002. The lowest dose of ETC-1002 with a significant LDL-C reducing effect has been 60 mg/d, and the maximum dose tested so far for clinical efficacy is 240 mg/d (Table 1). In adult patients with hypercholesterolemia, ETC-1002 has induced dose-dependent LDL-C reductions between 16% and 25%, regardless of plasma triglycerides. Non–HDL-C (18%-27%) and plasma apolipoprotein B (15%-22%) were reduced to a similar degree, whereas plasma triglycerides were reduced nonsignificantly and only by the 40 mg (15%) and 80 mg (12%) doses. Levels of lipoprotein(a) were completely unaltered with any of the doses of ETC-1002 in this study. An even more marked hypocholesterolemic effect was observed in a study that included only patients with type 2 diabetes and hypercholesterolemia; a 4-week treatment course reduced LDL-C levels by 39% on average, with a simultaneous reduction of circulating high-sensitivity C-reactive protein of 41%. Non–HDL-C was reduced by 20%, with no significant changes in HDL-C or triglycerides. This increased efficacy in the context of insulin resistance and/or type 2 diabetes may be related to activation of the AMPK pathway by ETC-1002.