November 12, 2012

LOS ANGELES — Initial clinical trials with the novel apolipoprotein A1 (apoA1) formulation CSL-112 (CSL Laboratories, Victoria, Australia) have shown that it rapidly enhances key biomarkers of the early stages of reverse cholesterol transport. It is thus being positioned as a new therapeutic approach to quickly lower the atherosclerosis burden in an attempt to reduce cardiovascular events in the initial days after an ACS.

CSL-112 is a reconstituted formulation of apoA1, the main component of HDL, derived from human plasma and reconstituted to form HDL particles suitable for infusion. As the natural function of HDL is to promote cholesterol efflux (the removal of cholesterol from tissue such as the arterial wall and subsequent transport to the liver for clearance from the body), the hope is that by rapidly raising HDL levels, CSL-112 will quickly reduce cholesterol-loaded plaques that contribute to cardiovascular events.

Phase 2 trials of CSL-112 are currently under way in stable coronary artery disease patients, and a phase 2b study in ACS patients is now planned.

"Speed Is a Big Deal"

Dr Samuel Wright (CSL Laboratories, King of Prussia, PA) commented to heartwire : "The idea is to give a series of two-hour IV infusions of CSL-112 soon after an ACS event. This is an acute therapy for an acute condition in a period of very high risk." He added: "In the first 30 days after an ACS, there is a very high risk of a subsequent MI. Speed is a big deal. We need therapies that act quickly. A two-hour infusion of CSL-112 starts to work immediately, giving a 100% increase in apoA1 within two hours. In comparison, niacin raises apoA1 by only 3% after eight weeks."

At last week's American Heart Association (AHA) 2012 Scientific Sessions, researchers from CSL presented two phase 1 studies of CSL-112 demonstrating that the product induces cholesterol efflux from macrophages into the plasma, the initial step in reverse cholesterol transport.

Although there are now doubts surrounding the HDL field following the failure of initial HDL-raising therapies to show any reduction in cardiovascular events, CSL suggests that that not all forms of HDL are equally effective in promoting reverse cholesterol transport and that the HDL formed by the cholesteryl ester transfer protein (CETP) inhibitors so far tested (torcetrapib and dalcetrapib) may not promote cholesterol efflux as effectively as CSL-112.

Nissen: "A Very Reasonable Hypothesis"

Commenting on CSL-112 for heartwire , Dr Steve Nissen (Cleveland Clinic, OH) explained: "This is a very different approach from the other HDL-raising drugs we have seen before, in that it is the smaller prebeta-HDL that is being infused. Unlike the alpha HDL, which is raised with niacin and the CETP inhibitors, prebeta-HDL is not already heavily laden with cholesterol, so the theory is that it has more potential to load up with cholesterol from atherosclerotic plaques."

The road to hell is paved with biological plausibility.

While Nissen believes this is "a very reasonable hypothesis," he also cautions that "the road to hell is paved with biological plausibility." He points out that the current phase 1 studies show substantial changes in measures of reverse cholesterol transport, which is encouraging, but that "these are still surrogate end points and do not predict the ultimate success of a drug." However, he adds, "You need a lot of different shots at goal to get one in the back of the net, and this novel approach is certainly worth pursuing further in a large clinical trial."

HDL Raised "Higher and Faster"

Speaking at an AHA press conference, Dr Andreas Gille (CSL, Victoria, Australia) noted that increased cholesterol-efflux capacity has recently been shown to be associated with reduced MI risk. He added: "We have previously shown CSL-112 to be an efficient acceptor of cholesterol in in vitro studies. Now we have also shown that it is effective in humans, raising HDL to higher levels and faster than any other previous therapy."

In one trial presented at the AHA meeting, 57 healthy volunteers were given a single infusion of CSL-112 at dose levels of 5 to 135 mg/kg. Blood samples taken from the volunteers were then tested and showed dose-proportional increases in HDL cholesterol, prebeta1-HDL, and cholesterol-efflux capacity from macrophages. The top dose of CSL-112 increased prebeta1-HDL by 3600% and global cholesterol efflux by 270%. There were no changes in levels of apoB, non-HDL cholesterol, and non-HDL triglycerides.

In a second placebo-controlled study in 36 healthy subjects, three dose regimens were studied: four once-weekly infusions of 3.4 g, four once-weekly infusions of 6.8 g, and eight twice-weekly infusions of 3.4 g. Results showed that infusions of CSL-112 caused immediate large increases in cholesterol-efflux capacity, prebeta1-HDL, and HDL in serum or plasma. Prebeta1-HDL were elevated up to 20-fold. For all three regimens, all biomarker responses were dose dependent and had a similar magnitude and time course after the first and last infusions. Increases in HDL peaked at 24 to 48 hours after infusion, but levels remained elevated after 72 hours. The results suggested that when compared with a single infusion of CSL112, multiple infusions may provide greater efflux of cholesterol, the researchers said.

Safety Data

Safety data with CSL-112 will be scrutinized closely, because a previous version of the product, CSL-111, was discontinued due to liver toxicity. The company says it has reformulated the product (to produce CSL-112) to be less likely to cause liver problems.

In the 36-patient study, there where were no treatment-related serious adverse events reported. Overall, a similar proportion of subjects in the placebo group and CSL-112-treatment groups reported at least one adverse event, and none were reported as product-related. The most common adverse event was vessel puncture-site hematoma (seen in 18 of 36 subjects), which was reported by similar proportions of subjects administered CSL-112 or placebo. In the CSL-112-treatment group, no clinically significant abnormalities were observed in serum biochemistry, hematology, and urine parameters. In addition, there were no remarkable changes seen in platelet function, vital signs, or ECG and no evidence of immunogenicity to CSL-112.

The researchers concluded: "This first clinical trial evaluating repeat dosing of CSL-112 demonstrated that once- or twice-weekly infusions in healthy subjects had acceptable safety and pharmacokinetic profiles that are sufficiently robust to warrant further testing in patients."

A third study presented at the AHA meeting was reported to show anti-inflammatory properties of CSL-112, which may also be beneficial in reducing cardiovascular events. In the in vitro study using human blood, CSL-112 caused a strong inhibition of the expression of intracellular adhesion molecule-1 (ICAM-1) (CD54) on both monocytes and neutrophils and inhibited the secretion of proinflammatory cytokines (TNF{:alpha:}, IL-1{:beta:}, and IL-6) and chemokines (IL-8, RANTES, and macrophage inflammatory protein 1{:beta:} [Mip-1{:beta:}]).