Genzyme/Isis’ Long-Awaited Kynamro NDA May Allay Liver Toxicity Fears

Sanofi’s Genzyme business unit and Isis submitted an NDA for mipomersen, a first-in-class cholesterol-lowering antisense drug, in an orphan population of high-risk patients with a rare genetic cardiovascular disease – with an assist from three Phase III clinical trials from other, larger, high-risk populations, to help inform regulators.

Sanofi/Genzyme Corp. and Ionis Pharmaceuticals Inc.’s NDA for Kynamro (mipomersen) includes data demonstrating that liver toxicity, a safety concern that has dogged development of the cholesterol-lowering antisense agent, does not appear to be a long-term problem for the orphan drug.

Results of a two-year, ongoing, open extension study incorporating patients from the mipomersen Phase III program found that metrics measuring liver function were consistent with the much shorter randomized, controlled Phase III studies, which had six months duration. The positive results from the extension study were presented on March 29, the same day the companies submitted an NDA for management of severe high cholesterol in patients with a rare inherited genetic disease.

While the NDA seeks approval for a rare disease, its dataset is larger than for most orphan drugs, including three Phase III trials in other high-risk severe high cholesterol settings.

The latest data are important because liver safety has been a chief concern surrounding the first-in-class apolipoprotein B-100 inhibitor, which demonstrated strong efficacy in four of four Phase III trials – but also was four for four in showing elevated liver enzymes (Also see "Genzyme/Isis On Track To Submit Cholesterol Drug Mipomersen In 1H 2011" - Pink Sheet, 1 Sep, 2010.). The potential for liver toxicity contributed to the drawn-out development of the drug; when Genzyme won a bidding war for rights to mipomersen in 2008, the drug was projected for filing in 2009.

The NDA seeks an indication for homozygous familial hypercholesterolemia (HoFH), which occurs because of a genetic mutation that triggers overproduction of all atherogenic lipoproteins, which transport cholesterol through the bloodstream. Patients who inherit the mutation from both parents (homozygous) have increased risk of premature heart disease, even in childhood, and heart-related death; about one to four in a million, or 20,000 people in the U.S. and Europe, are affected, said Paula Soteropoulos, VP and general manager of Genzyme’s cardiovascular business.

The drug reduces levels of LDL cholesterol by preventing the formation of the lipoproteins. Cholesterol-lowering treatments, notably statins, don’t work well in these patients and, currently, the only alternative treatments are LDL-apheresis, which is a process that routinely clears cholesterol buildups from the blood, or liver transplants, she said.

The HoFH submission is supported by data from a randomized, double-blind, placebo-controlled, multi-center study, which found patients taking Kynamro and the maximum tolerated dose of statin therapy over a six-month period had significant reductions in all atherogenic lipoproteins measured, including LDL-C, Apo B and Lp(a). LDL-C levels, the primary endpoint, fell by 25%, while Lp(a) levels declined 31%, compared to patients on maxim-tolerated doses of statins alone. Three patients, or 12% of subjects, withdrew from the study because of side effects, which included mild injection-site irritation and elevation in liver enzymes.

The NDA also includes data from the extension study. Two-year data from the Phase III extension were presented at the International Symposium on Atherosclerosis in Sydney, Australia March 29, based on 141 patients who had completed a six-month Phase III trial in either HoFH, severe hypercholesterolemia, or HeFH. In addition to showing sustained reductions in LDL-C, the extension study also found that liver fat may increase, but then stabilizes and declines in some patients: the median percent liver fat in the extension study patients increased from 5% at 26 weeks to 13% at 52 weeks, and then returned to 5% at 104 weeks. Changes in liver fat returned “towards normal” upon treatment discontinuation.

The sponsors rounded out the NDA with the results of the three other Phase III studies of Kynamro in different high-risk patient populations, Soteropoulos said. These are not part of the pivotal trial for this indication, but will help inform regulators.

The trials enrolled different high-risk patient groups: patients with severe heterozygous FH (HeFH), who have inherited the disease from one parent and who have LDL-C greater than 300 mg/dl without coronary artery disease; a group of patients with HeFH with coronary artery disease; and patients with high cholesterol at high risk for coronary heart disease. All patients were already taking maximally tolerated doses of statins and additional lipid-lowering drugs. All trials met their primary, secondary and tertiary endpoints.

A submission for EU marketing authorization was made in July 2011 for both HoFH and severe HeFH. The partners opted not to file for severe HeFH in the U.S. at this time because while FDA accepted six-month data for the more severe and rarer HoFH, it wants studies showing 12 months of treatment duration for HeFH.

Genzyme initiated a trial to support broadening the familial hypercholesterolemia label to heterozygous patients in late 2011. The FOCUS FH trial in severe HeFH patients is being conducted under a special protocol assessment, and is also designed to support an alternative three-times-a-week dosing schedule.