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.

METHODS AND 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.

CLINICAL TRIAL REGISTRATION:

URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00487994, NCT00143663, NCT00143676, NCT00864643, NCT00263081, NCT00286481, NCT00249899, NCT00249912, NCT00813527, NCT00256178, NCT00268697, and NCT00251680.

• Authors: Evan A Stein, Harold Bays, Dennis O'Brien, Jim Pedicano, Edward Piper, Andrea Spezzi
• Journal: Circulation (Circulation) Vol. 123 Issue 18 Pg. 1974-85 (May 10 2011) ISSN: 1524-4539 [Electronic] United States
• PMID: 21518985 (Publication Type: Journal Article, Meta-Analysis, Research Support, Non-U.S. Gov't)

Chemical References

• 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
• Anticholesteremic Agents
• Oxazepines
• Piperidines
• Farnesyl-Diphosphate Farnesyltransferase

Topics

• Adult
• Aged
• Anticholesteremic Agents (administration & dosage, adverse effects)
• Clinical Trials, Phase II as Topic
• Clinical Trials, Phase III as Topic
• Farnesyl-Diphosphate Farnesyltransferase (antagonists & inhibitors)
• Female
• Humans
• Hypercholesterolemia (drug therapy)
• Liver Diseases (etiology)
• Male
• Middle Aged
• Oxazepines (administration & dosage, adverse effects)
• Piperidines (administration & dosage, adverse effects)
• Randomized Controlled Trials as Topic