Mipomersen Shows Large LDL Reduction, Side Effects an Issue

November 28, 2011

November 25, 2011 (Orlando, Florida) Weekly subcutaneous injection of the investigational lipid-lowering agent mipomersen (Genzyme) was associated with a 47% reduction in low-density lipoprotein (LDL) levels and similar large reductions in most other lipid parameters in a small Phase 2 study in high-risk patients intolerant to statins.

The drug is, however, also associated with flu-like symptoms, liver enzyme increases, and intrahepatic fat accumulation, which may limit its use.

Mipomersen is an antisense oligonucleotide designed to inhibit the synthesis of apolipoprotein B (apoB), which is essential for the synthesis of all atherogenic lipoproteins.

In the current study, presented at last week's American Heart Association 2011 Scientific Sessions, 34 statin-intolerant patients at high-risk of cardiovascular disease were randomized (2:1) to receive 26 weekly doses of 200 mg mipomersen (n=22) or placebo (n=12).

At the end of the study period, LDL levels had decreased from 242 mg/dL to 128 mg/dL in the treatment group--a reduction of 114 mg/dL. Presenting the data, Dr Erik Stroes (Academic Medical Center, Amsterdam, the Netherlands) said this would translate into a >50% reduction in events. All other atherogenic lipid parameters showed similar impressive reductions.

Mean Change in Lipid Parameters With Mipomersen

Lipid parameter Mean change from baseline, %
LDL-cholesterol –47.3
ApoB –46.2
Total cholesterol –36.9
NonHDL-cholesterol –45.6
Triglycerides –27.0
HDL-cholesterol +8.1
Lp(a) –27.1
VLDL-cholesterol –27.1

ApoB=apolipoprotein B; HDL=high-density lipoprotein; Lp(a)=lipoprotein (a); VLDL = very low-density lipoprotein

Small LDL particles showed the greatest reductions, with more modest reductions in large LDL particles.

In terms of adverse events, 19 patients (90%) in the mipomersen group experienced flu-like symptoms and 20 (95%) had injection-site reactions, although only four patients discontinued treatment.

Hepatic steatosis (fatty liver) occurred in 11 mipomersen patients (54%). Liver needle biopsies performed in two patients showed severe hepatic steatosis "with minimal inflammation and minimal-to-no fibrosis." Transaminase levels were raised to more than twice the upper limit of normal in 12 patients.

Stroes concluded that "future studies with mipomersen need further monitoring of long-term hepatic effects, but interim results suggest that liver fat stabilizes or improves with more than 12 months of continued dosing."

May Have a Role in Very High-Risk Patients

Commenting on the study for heartwire , session cochair Dr Amit Khera (UT Southwestern Medical Center, Dallas, TX) described mipomersen as "exciting, as it is a completely novel agent," but added, "the challenge will be where and when to use it."

He said he thought it could have a role in patients with very-high LDL who can't get to goal on statins, and in those who can't tolerate statins.

Khera said the side effect of fatty liver was "potentially worrisome." He commented: "The consequences of this are not clear at the moment. Fatty liver can be accompanied by inflammation, in which case it is more serious. The presenter was trying to build a case that the fatty liver seen with this drug was the noninflammation, benign type, but this was a very short-term study in only a small number of patients. Larger studies are needed to give more information on this."

Even with all the side effects, Khera still believes the drug may find a niche. "If people are very high risk--ie, they have FH and very-high LDL levels--there certainly could be a role for a drug like this. I don't think that the fact it is an injection is a complete negative. Several new drugs for diabetes are injectable, but are still being used. I think if the patient is at sufficient risk, they would tolerate an injection."

The other cochair, Dr Melvyn Rubenfire (University of Michigan, Ann Arbor) had similar opinions. He said he was impressed with the degree of LDL and apoB lowering, and pointed out that it was the only drug--apart from niacin--that lowers lipoprotein a. On the issue of hepatic steatosis, he noted that mipomersen mimics the heterozygote genetic condition of hypobetalipoproteinemia, in which patients have fatty livers, which "seems relatively innocent compared to the protective effect of the very low apoB and LDL- and VLDL-cholesterol." He added: "The mipomersen data on fatty liver by MRI has been previously published to be reversible when the drug is stopped. I've heard it said that the fat decreases over time while treatment is continued, but have not seen published data."

Rubenfire pointed out that patients with familial hypercholesterolemia often do not adequately respond to statins, even in combination with other lipid-lowering agents, and many will have cardiovascular events in middle age or even childhood if homozygous. "In these patients, the major treatment is LDL apheresis, which is very costly, has major complications, and fails to get many patients to target. Mipomersen will be a welcome drug for these very high-risk patients. As a lipidologist, I'm hopeful the safety data will be adequate to allow FDA approval with limited indications and careful monitoring postapproval."

The study was sponsored by Genzyme. Stroes acts as a consultant for Genzyme on mipomersen.