Mipomersen Lowers MACE in FH Patients, Analysis Shows

Marlene Busko

May 25, 2015

AMSTERDAM, THE NETHERLANDS—The antisense oligonucleotide mipomersen (Kynamro, ISIS Pharmaceuticals/Genzyme), which inhibits atherogenic lipoproteins, "dramatically and significantly" reduced major adverse cardiac events (MACE) in patients with familial hypercholesterolemia (FH) who were treated for more than a year, report investigators at the International Symposium on Atherosclerosis 2015.[1]

Led by Dr P Barton Duell (Oregon Health and Science University, Portland), the researchers analyzed data from three phase 3 randomized placebo-controlled trials of 104 patients with homozygous, heterozygous, or severe FH. The 2-year rate of MACE—a composite that included MI, stroke, unstable angina, or revascularization (PCI/CABG)—fell from 61% in patients not treated with mipomersen to 8.7% in those who received the drug.

Cardiologists "need to know that [mipomersen] is available and it appears to be associated with a reduction in cardiovascular events, although right now the approval is only for homozygous FH," Duell told heartwire for Medscape. Further studies are needed to verify these data, "but from what we have right now, it looks very impressive," he added.

Session cochair Dr John Chapman (National Institute for Health and Medical Research, Paris, France) agreed. To heartwire , he noted that the study has two critical clinical implications: first, mipomersen has "a totally different mechanism of action" from statins and ezetimibe (Zetia, Merck), and second, "that mechanism facilitates a reduction in major cardiac events."

Does Effect on Lipids Alter Cardiac Events?

Although some clinicians may not be familiar with mipomersen, it was approved by the US Food and Drug Administration in January 2013 for a specific narrow indication—patients with homozygous FH, explained Duell. Unlike the statins and ezetimibe, which upregulate LDL-receptor activity, mipomersen decreases the production of apolipoprotein B and also significantly reduces plasma concentrations of atherogenic lipoproteins, specifically very-low-density-lipoprotein (VLDL) cholesterol, LDL cholesterol, and lipoprotein(a).

Patients with FH are a particularly high-risk group, added Duell, with a 10- to-20-fold higher rate of cardiovascular events than the general population. The researchers hypothesized that treatment with mipomersen would reduce the incidence of cardiovascular events in patients with FH who were taking maximally tolerated lipid-lowering therapy. They compared rates of MACE before and during treatment with mipomersen.

Patients in the analysis were middle-aged (mean 50 years) and overweight (mean body-mass index 28.6 kg/m2), and the majority were men. About three-quarters of patients had elevated LDL-cholesterol levels despite receiving maximum doses of a statin or statin plus ezetimibe. Mean baseline LDL-cholesterol levels in the homozygous FH patients were significantly elevated, ranging from 400 to 439 mg/dL. In those with severe FH, LDL-cholesterol levels ranged from 249 to 276 mg/dL, while those with heterozygous FH had LDL-cholesterol levels of approximately 150 mg/dL.

A third of patients (n=34) received placebo for 6 months followed by mipomersen for at least 1 year. The other two thirds (n=70) received blinded mipomersen for 6 months followed by at least 6 months of open-label treatment. Patients were followed for a maximum of 4 years beyond the initial 6 months of treatment with placebo or mipomersen.

During the 24 months prior to mipomersen treatment, 64 patients (63%) had 146 events: 39 had MIs, 99 had PCI/CABG, five had unstable angina, and three had a stroke. During a mean 24.4 months after starting mipomersen therapy, nine patients (9%) had 12 events: two had an MI, six had PCI/CABG, and four had unstable angina.

The rate of MACE per 1000 patient-months was 25.7 before mipomersen vs 3.6 during mipomersen treatment (odds ratio 0.035; 95% CI 0.009–0.144; P<0.0001). The marked reduction in MACE coincided with the absolute mean reductions in LDL-cholesterol levels (–49 to –113 mg/dL) reported in phase 3 clinical trials of FH.

"Results from this limited analysis suggest that treatment with mipomersen may reduce cardiovascular events in patients with FH," the researchers summarize. The company is conducting a trial in patients with heterozygous FH, which is expected to be completed later this year, Duell said.

The study was derived from data from studies funded by ISIS Pharmaceuticals and Genzyme, a Sanofi company.

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