Cholesterol lowering agent – alirocumab

Statins do not work for everybody, and the pharma industry continues to work on drugs that act at alternative targets that can reduce cholesterol levels

Statins are now widely prescribed because of their ability to lower levels of ‘bad’ low density lipoprotein cholesterol. However, they don’t work for everybody, and the pharma industry continues to work on drugs that act at alternative targets that can reduce cholesterol levels.

One of these is the gene PCSK9, which is attracting a good deal of attention. Both antibodies and small molecule drugs that inhibit PCSK9 synthesis are under development. This mode of action has the potential to produce very large decreases in LDL-C, to the point that the FDA has imposed a bottom limit for LDL-C reduction because of safety concerns.

One such antibody is being developed by Regeneron and Sanofi. Alirocumab is a fully human monoclonal antibody that targets and blocks PCSK9.1 In a double blind, parallel group, placebo-controlled trial, 183 patients with LDL-C levels above 100mg/dl and who were taking a stable dose of atorvastatin, were given subcutaneous placebo every two weeks; 50, 100 or 150mg subcutaneous doses of alirocumab every two weeks; or 200 or 300mg doses of the antibody every four weeks, alternating with placebo.2 The trial lasted for 12 weeks.

Both active treatment schedules gave a dose-related percentage lowering of LDL-C across both dosing schedules, with the highest reduction (72%) seen with the biweekly 150mg doses, and the lowest (40%) with the 50mg biweekly dose; a 5% reduction occurred with placebo. It was generally well tolerated, although one patient given the antibody experienced leukocytoclastic vasculitis.

A randomised, placebo-controlled Phase II trial has also been carried out in patients with heterozygous familial hypercholesterolaemia on stable statin doses, with or without ezetimbe.3

In all, 77 patients with this condition, which causes very high cholesterol levels, were given 150, 200 or 300mg doses of the antibody every four weeks, 150mg every two weeks, or placebo. Again, good LDL-C reductions were seen: from 29% in the 150mg/four weekly dose group to 68% in those on the two-weekly schedule. The reduction was 11% with placebo. Again, it was well tolerated.

Late last year, the companies announced top line results of a Phase III study via press release, the first of 12 Phase III trials that are being run. In the 24 week study, 103 patients with primary hyper-cholesterolaemia and modest cardiovascular risk were given 10mg of ezetimibe daily or 75mg alirocumab every two weeks, which was uptitrated at week 12 to 150mg if the LDL-C measurement at week eight was above 70mg/dl.

Most remained on the low dose. Of the antibody-dosed patients, 47% achieved the target reduction, compared with 16% of the ezetimibe group.

References

1. E.A. Stein et al. N. Engl. J. Med. 2012, 366, 1108

2. J.M. McKenney et al. J. Am. Coll. Cardiol. 2012, 59, 2344

3. E.A. Stein et al. Lancet 2012, 380, 29

Companies