tak-475 and Hypercholesterolemia

Mevalonate Kinase Deficiency (MKD, OMIM #610377) is a rare autosomal recessive metabolic and inflammatory disease. In MKD, defective function of the enzyme mevalonate kinase, due to a mutation in the MVK gene, leads to the shortage of mevalonate- derived intermediates, which results in unbalanced prenylation of proteins and altered metabolism of sterols. These defects lead to a complex multisystem inflammatory and metabolic syndrome.. Although biologic therapies aimed at blocking the inflammatory cytokine interleukin- 1 can significantly reduce inflammation, they cannot completely control the clinical symptoms that affect the nervous system. For this reason, MKD can still be considered an orphan drug disease. The availability of MKD models reproducing the MKD-systematic inflammation, is crucial to improve the knowledge on its pathogenesis, which is still unknown. New therapies are also required in order to improve pateints' conditions and their quality of life.. MKD-cellular models can be obtained by biochemical inhibition of mevalonatederived isoprenoids. Of note, these cells present an exaggerated response to inflammatory stimuli that can be reduced by treatment with zaragozic acid, an inhibitor of squalene synthase, thus increasing the availability of isoprenoids intermediates upstream the enzymatic block.. A similar action might be obtained by lapaquistat acetate (TAK-475, Takeda), a drug that underwent extensive clinical trials as a cholesterol lowering agent 10 years ago, with a good safety profile.. Here we describe the preclinical evidence supporting the possible repositioning of TAK-475 from its originally intended use to the treatment of MKD and discuss its potential to modulate the mevalonate pathway in inflammatory diseases.

Topics: Acyl Coenzyme A; Cholesterol; Drug Repositioning; Farnesyl-Diphosphate Farnesyltransferase; Humans; Hypercholesterolemia; Mevalonate Kinase Deficiency; Oxazepines; Phosphotransferases (Alcohol Group Acceptor); Piperidines

Lapaquistat acetate is a squalene synthase inhibitor investigated for the treatment of hypercholesterolemia.. This report summarizes the phase 2 and 3 results from the lapaquistat clinical program, which was halted at an advanced stage as a result of potential hepatic safety issues. Efficacy and safety data were pooled from 12 studies (n=6151). These were 6- to 96-week randomized, double-blind, parallel, placebo- or active-controlled trials with lapaquistat monotherapy or coadministration with other lipid-altering drugs in dyslipidemic patients, including a large (n=2121) 96-week safety study. All studies included lapaquistat 100 mg daily; 5 included 50 mg; and 1 included 25 mg. The main outcome measures were the percent change in low-density lipoprotein cholesterol, secondary lipid/metabolic parameters, and overall safety. Lapaquistat 100 mg significantly decreased low-density lipoprotein cholesterol by 21.6% in monotherapy and by 18.0% in combination with a statin. It also reduced other cardiovascular risk markers, such as C-reactive protein. Total adverse events were higher for lapaquistat than placebo, although individual events were generally similar. At 100 mg, there was an increase in alanine aminotransferase value ≥3 times the upper limit of normal on ≥2 consecutive visits (2.0% versus 0.3% for placebo in the pooled efficacy studies; 2.7% versus 0.7% for low-dose atorvastatin in the long-term study). Two patients receiving lapaquistat 100 mg met the Hy Law criteria of alanine aminotransferase elevation plus increased total bilirubin.. Squalene synthase inhibition with lapaquistat acetate, alone or in combination with statins, effectively lowered low-density lipoprotein cholesterol in a dose-dependent manner. Elevations in alanine aminotransferase, combined with a rare increase in bilirubin, presented potential hepatic safety issues, resulting in termination of development. The lapaquistat experience illustrates the current challenges in lipid-altering drug development.. URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00487994, NCT00143663, NCT00143676, NCT00864643, NCT00263081, NCT00286481, NCT00249899, NCT00249912, NCT00813527, NCT00256178, NCT00268697, and NCT00251680.

Topics: Adult; Aged; Anticholesteremic Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Farnesyl-Diphosphate Farnesyltransferase; Female; Humans; Hypercholesterolemia; Liver Diseases; Male; Middle Aged; Oxazepines; Piperidines; Randomized Controlled Trials as Topic

There remains an unmet need to reduce elevated low-density lipoprotein cholesterol (LDL-C) in patients who are maximized on current therapy or intolerant to statins. Several novel agents have been developed to lower LDL-C, either as monotherapy or in combination with statins. These novel therapies include squalene synthase inhibitors, microsomal triglyceride transfer protein inhibitors, and antisense apolipoprotein B. Although each of these novel therapies effectively lowers LDL-C, challenges remain in the clinical development to assess long-term safety.

Topics: Animals; Anticholesteremic Agents; Azetidines; Benzimidazoles; Carrier Proteins; Cholesterol, LDL; Ezetimibe; Farnesyl-Diphosphate Farnesyltransferase; Humans; Hypercholesterolemia; Indoles; Oligonucleotides; Oxazepines; Piperidines; Proprotein Convertase 9; Proprotein Convertases; Pyridines; Serine Endopeptidases; Serine Proteinase Inhibitors

Inhibition of squalene synthesis could transform unstable, macrophage/lipid-rich coronary plaques into stable, fibromuscular plaques. We have here treated WHHLMI rabbits, a model for coronary atherosclerosis and myocardial infarction, with a novel squalene synthase inhibitor, lapaquistat acetate (TAK-475).. Young male WHHLMI rabbits were fed a diet supplemented with lapaquistat acetate (100 or 200 mg per kg body weight per day) for 32 weeks. Serum lipid levels were monitored every 4 weeks. After the treatment, lipoprotein lipid and coenzyme Q10 levels were assayed, and coronary atherosclerosis and xanthomas were examined histopathologically or immunohistochemically. From histopathological and immunohistochemical sections, the composition of the plaque was analysed quantitatively with computer-assisted image analysis. Xanthoma was evaluated grossly.. Lapaquistat acetate decreased plasma cholesterol and triglyceride levels, by lowering lipoproteins containing apoB100. Development of atherosclerosis and xanthomatosis was suppressed. Accumulation of oxidized lipoproteins, macrophages and extracellular lipid was decreased in coronary plaques of treated animals. Treatment with lapaquistat acetate increased collagen concentration and transformed coronary plaques into fibromuscular plaques. Lapaquistat acetate also suppressed the expression of matrix metalloproteinase-1 and plasminogen activator inhibitor-1 in the plaque and increased peripheral coenzyme Q10 levels. Increased coenzyme Q10 levels and decreased very low-density lipoprotein cholesterol levels were correlated with improvement of coronary plaque composition.. Inhibition of squalene synthase by lapaquistat acetate delayed progression of coronary atherosclerosis and changed coronary atheromatous plaques from unstable, macrophage/lipid accumulation-rich, lesions to stable fibromuscular lesions.

Topics: Animals; Apolipoprotein B-100; Cholesterol; Collagen; Coronary Artery Disease; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Enzyme Inhibitors; Farnesyl-Diphosphate Farnesyltransferase; Hypercholesterolemia; Hypolipidemic Agents; Image Interpretation, Computer-Assisted; Immunohistochemistry; Lipid Metabolism; Lipoproteins, LDL; Macrophages; Male; Matrix Metalloproteinase 1; Oxazepines; Piperidines; Plasminogen Activator Inhibitor 1; Rabbits; Triglycerides; Ubiquinone; Xanthomatosis