Long-term liver toxicities do not appear to be a significant problem for Kynamro, a second-generation anti-sense drug that manages severe high cholesterol in patients with a rare inherited genetic disease, the companies sponsoring the drug, Sanofi/Genzyme Corp. and partner Ionis Pharmaceuticals Inc. say.

Results of a two-year, ongoing, open extension study incorporating patients from a Phase III program for the drug found that metrics measuring liver function were consistent with the much shorter randomized, controlled Phase III studies, which had six months duration. Researchers supported by the sponsors presented the positive results from the extension study to analysts on March 29, the same day the companies submitted an NDA for the drug.

The latest data are important because liver safety has been a chief concern surrounding Kynamro (mipomersen), which demonstrated strong efficacy in its clinical development program Also see "Genzyme/Isis On Track To Submit Cholesterol Drug Mipomersen In 1H 2011" - Pink Sheet, 1 September, 2010.. Genzyme and Isis see the drug as a cornerstone of their cardiovascular programs.

The indication they are pursuing initially is 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, a first-in-class inhibitor of apolipoprotein B-100, 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 treatment is LDL-apheresis, which is a process that routinely clears cholesterol buildups from the blood, or liver transplants, she said.

The 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.

Data from the open-extension study will be included in the submission package, along with results of three other Phase III studies of Kynamro in different high-risk patient populations, said Soteropoulos. These are not part of the pivotal trial for this indication, but will help inform regulators.

Efficacy data have been good throughout Kynamro’s development program, but elevated liver enzymes and dropout rates have been problematic, raising uncertainties over the years about the drug’s approvability. Such concerns were considered a handicap by analysts in 2010 and early 2011, when they set out to evaluate Genzyme’s R&D portfolio in light of Sanofi’s offer to buy the rare disease pioneer for more than $20 billion Also see "Genzyme’s Risky Pipeline Isn’t A Value Driver In The Sanofi Deal" - Pink Sheet, 14 March, 2011. and Also see "Sanofi Claims Genzyme With $20.1 Billion Upfront And CVRs" - Pink Sheet, 21 February, 2011..

But liver function ultimately was not found to be a problem in the Phase III trials, or in the long-term extension study, which consisted of 141 patients, researchers said on a call with investors on March 29 to review data from the extension trial. The latter found that while median liver-fat levels rose incrementally for the first year, they plateaued, then fell to baseline as the liver adapted and remodeled in response to changes in its environment due to the medication, said Soteropoulos.

Injection-site reactions were the most frequent adverse event, but these were mild, and there were no changes in liver synthetic function or bilirubin levels, researchers said. Liver enzyme levels rose to worrisome levels (three times the upper limit of normal) in approximately 13% of patients in the extension study but this occurred mainly in the first year and vanished with time, Raul Santos, director of the lipid clinic at the Heart Institute of the University of Sao Paulo in Brazil, explained during the investor call.

Genzyme To Lead Commercialization, Not Sanofi

Kynamro, if approved, will be sold by Genzyme’s cardiovascular business, not the parent company, because HoFH is the kind of inherited orphan disease with which Genzyme has expertise. It is treated by a sub-group of specialists in lipid-lowering disease, who have close ties to patients, and would benefit from a more scientific, educational commercial strategy than is typically the case with lipid-lowering drugs aimed at more common forms of lipid disease.

And Genzyme’s interest brings another benefit to the field: patients with the disease did not have an organized advocacy group until December 2011, when they formed one with the company’s support.

Sanofi also has a cardiovascular sales force, aimed at broader groups of cardiologists, and now devoted to selling its anti-arrhythmia drug Multaq (dronedarone). It will be responsible for commercializing a PCSK9 antibody, which was the subject of attention at the American College of Cardiology meeting on March 26 and is likely to be the first of a new class of antibodies to go into Phase III clinical trials. That drug is being developed for statin-resistant patients with elevated LCL-C levels, a much larger patient population than Kynamro’s initial indication, with a broader base of treating physicians.

Isis, which partnered with Genzyme on the drug in 2008, will receive a $25 million milestone payment once FDA accepts the NDA. Mipomersen has orphan drug status for treatment of patients with HoFH.

The Phase III program around the drug included three other trials in 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 MTDs 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.

Sanofi/Genzyme And Isis Submit Kynamro For Lowering Cholesterol

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