A pivotal Phase III trial with mipomersen, under development by Genzyme Corp and Isis Pharmaceuticals for high-risk cardiovascular patients who cannot achieve target cholesterol levels with statins and/or other lipid-lowering therapies, has shown the drug can reduce LDL cholesterol levels by 25%.

However, safety concerns about elevated liver enzyme levels, and the news that mipomersen will be filed for approval nearly a year later than was previously indicated, took the edge off the favourable efficacy outcomes, pushing Isis’ shares down by as much as 18%.

Data from the Phase III study with mipomersen in 51 patients with the very rare condition homozygous familial hypercholesterolaemia (hoFH) were presented at the American Heart Association’s Scientific Sessions in Orlando, Florida. The estimated one in a million people with hoFH can have cholesterol levels higher than 600mg/dL, exposing them to acute risk of early coronary events and sudden death.

In the trial conducted at 10 sites in North America, Europe, Asia, South America and Africa, patients were randomised 2:1 to either 200mg mipomersen or placebo via weekly injections for 26 weeks. All but one of the patients, whose average LDL cholesterol levels were above 400mg/dL at baseline, were already on lipid-lowering therapy. Of those, 11 were taking a statin alone and 39 a statin in combination with at least one other lipid-lowering agent – mostly ezetimibe (Zetia, 37 patients).

The reductions in LDL cholesterol seen in the trial were in addition to those achieved with the patients’ existing regimen. The study met its primary endpoint, with an intent-to-treat analysis showing that mipomersen lowered LDL cholesterol by an average of 25%, or more than 100mg/dL, versus a 3% reduction in patients on placebo.

The trial also met all of its secondary and tertiary endpoints, suggesting that mipomersen might offer potential benefits beyond lowering LDL cholesterol, Genzyme and Isis said.

For example, patients treated with mipomersen showed a 27% reduction in apolipoprotein B versus 3% on placebo; a 21% fall in total cholesterol versus 2% on placebo; and a 25% reduction in non-HDL cholesterol versus 3% on placebo. HDL cholesterol levels in the mipomersen patients were up by 15% and LDL/HDL ratios decreased by 34%.

Liver enzymes

But analysts warned that elevated liver enzymes – suggesting potential liver damage – could be a limiting factor as Genzyme and Isis pursue clinical development and approvals in broader populations of high-cholesterol patients.

In the Phase III trial, four patients had elevations in liver transaminases of more than three times the upper limit of normal (ULN), while in three patients these levels reached between five and eight times the ULN. None of these patients showed changes indicating hepatic dysfunction in other laboratory tests, and in all cases transaminases returned to entry-criteria levels by the end of planned clinical observations, the companies noted.

Genzyme now expects to file for approval of mipomersen, indicated initially for hoFH, in the US and the EU by mid-2011, whereas the previous expectation was for the second half of 2010. Results from a Phase III trial of mipomersen in patients with heterozygous familial hypercholesterolaemia should be out in the first quarter of 2010, Genzyme and Isis added.

Data from Phase III trials in patients with severe hypercholesterolaemia and patients at high risk of coronary heart disease are expected in the middle of next year.