Genzyme, a Sanofi company and Isis Pharmaceuticals Inc. have submitted a New Drug Application (NDA) to the US Food and Drug Administration (FDA) seeking approval for Kynamro (mipomersen sodium) for the treatment of patients with homozygous familial hypercholesterolemia (HoFH).
“HoFH patients have aggressive, life-threatening cardiovascular disease starting at birth because of genetic mutations which severely impair LDL clearance and also trigger an overproduction of all atherogenic lipoproteins,” said Christie M Ballantyne, MD, Chief of the Sections of Cardiology and Cardiovascular Research, and Professor of Medicine and Genetics, Baylor College of Medicine. “Currently available therapies work on clearance whereas Kynamro uniquely targets Apo B production and production of all Apo B-containing, atherogenic lipoproteins, including VLDL, LDL, and Lp(a). Current options reserved for these patients are mechanical procedures such as LDL-aphereis or liver transplant.”
“This submission marks the second of two key milestones for the Kynamro programme including the submission of the EU marketing authorization application last year,” said Paula Soteropoulos, vice president and general manager of Genzyme’s Cardiovascular Business. “These are important steps toward our goal of bringing an innovative solution to patients in great need of a novel, targeted therapy.”
The FDA submission for Kynamro is supported by the largest clinical trial conducted to date in the HoFH patient population. In the randomized, double-blind, placebo controlled, multi-centre trial, significant reductions were observed in all atherogenic lipoproteins evaluated (including LDL-C, Apo B and Lp(a)) for patients receiving Kynamro who are already receiving a regimen of maximally tolerated lipid-lowering therapies including statins. Three patients (12 per cent) treated with Kynamro withdrew due to adverse events. Consistent with other studies evaluating Kynamro, commonly observed adverse events included mild to moderate injection site reactions and flu-like symptoms, as well as elevations in liver transaminases.
Isis will receive a $25 million milestone payment from Genzyme following FDA acceptance of the NDA submission. Provided the necessary approvals are granted, mipomersen would be marketed under the brand name Kynamro, the name that has been submitted to health authorities for the investigational agent. The FDA has granted mipomersen Orphan Drug designation for the treatment of patients with HoFH.
“The last twelve months have been very successful for the Kynamro programme,” said B Lynne Parshall, JD, chief operating officer, chief financial officer and secretary of Isis. “We look forward to working with the US and EU regulatory authorities to bring this treatment to patients in need.”
Kynamro is a first-in-class apo-B synthesis inhibitor currently in late-stage development for patients with homozygous familial hypercholesterolemia (HoFH) and severe heterozygous familial hypercholesterolemia (Severe HeFH) to further reduce LDL cholesterol (LDL-C) in patients already maintaining a stable regimen of maximally tolerated lipid lowering therapies, and who require additional, significant lipid lowering therapy. It is intended to reduce LDL-C by preventing the formation of atherogenic lipoproteins, the particles that carry cholesterol through the bloodstream. Kynamro acts by blocking the production of, apolipoprotein B (apo B), the protein that provides the structural core for these atherogenic particles, including LDL and lipoprotein-a (Lp(a)).
FH is a genetic disease that results in elevated LDL-C levels and family patterns of increased risk of premature heart disease and heart disease-related death. FH patients have inherited abnormalities in liver cells that are responsible for clearing LDL particles from the blood. FH is autosomal dominant, which means that all first-degree relatives of FH patients have a 50 percent chance of having the disease as well, making early detection through family screening critically important.
The most severe FH patients have LDL-C levels that are two to four times higher than recommended levels, even when taking multiple cholesterol-lowering medications. These people, who are characterized as having severe FH, include: those who have inherited the disease from both parents (HoFH) and those who have inherited it from only one parent, and have a particularly severe form of the disease (Severe HeFH) defined as those people who are maximally treated and still have LDL-C greater than 200 mg/dL (5.1 mmol) with coronary heart disease or greater than 300 mg/dL (7.1 mmol) without coronary heart disease. People with HoFH may have aggressive heart disease beginning in childhood, and even with today’s therapies remain at significant risk of cardiovascular events.
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