title: Lapaquistat acetate: development of a squalene synthase inhibitor for the treatment of hypercholesterolemia.
abstract: BACKGROUND
  Lapaquistat acetate is a squalene synthase inhibitor investigated for the treatment of hypercholesterolemia.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00487994, NCT00143663, NCT00143676, NCT00864643, NCT00263081, NCT00286481, NCT00249899, NCT00249912, NCT00813527, NCT00256178, NCT00268697, and NCT00251680.
authors.affiliation: Metabolic and Atherosclerosis Research Center, Cincinnati, OH 45212, USA. esteinmrl@aol.com
authors.forename: Evan A
authors.initials: EA
authors.lastname: Stein
authors.forename: Harold
authors.initials: H
authors.lastname: Bays
authors.forename: Dennis
authors.initials: D
authors.lastname: O'Brien
authors.forename: Jim
authors.initials: J
authors.lastname: Pedicano
authors.forename: Edward
authors.initials: E
authors.lastname: Piper
authors.forename: Andrea
authors.initials: A
authors.lastname: Spezzi
mesh_terms: D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy*; D008107:Liver Diseases / Q000209:etiology; D008297:Male; D008875:Middle Aged; D010077:Oxazepines / Q000008:administration & dosage / Q000009:adverse effects*; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects*; D016032:Randomized Controlled Trials as Topic
chemical_list: C466644:1-((1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl)acetyl)piperidine-4-acetic acid; D000924:Anticholesteremic Agents; D010077:Oxazepines; D010880:Piperidines; D013186:Farnesyl-Diphosphate Farnesyltransferase