Results of a Phase 2a trial of CSL112, sponsored by CSL Limited, demonstrated favorable safety and tolerability when administered to patients with stable atherothrombotic disease. The trial data for CSL112 also showed a dramatic and rapid increase in key biomarkers of reverse cholesterol transport, a process by which cholesterol is removed from arteries and transported to the liver for clearance.
“We are encouraged by the positive safety profile observed in the trial which supports progression of the CSL112 clinical development program,” said Pierluigi Tricoci, MD, PhD, MHS, Duke Clinical Research Institute, and lead study author. “We know there is a need for novel approaches to reduce the high risk of early recurrent ischemic events after acute coronary syndrome. CSL112 is a promising treatment targeting coronary atherosclerotic plaques causing these events and deserves further investigation.”
Three separate analyses of data from the CSL112 Phase 2a study were presented at the American Heart Association 2013 Scientific Sessions. The presentations examined the safety and tolerability, pharmacokinetics and lipid biomarker profile, and potential antiplatelet effects of CSL112 on top of dual antiplatelet therapy.
Study Design and Key Findings
The CSL112 Phase 2a study was a randomized, multicenter, double-blind, placebo-controlled trial (n=44) that evaluated the safety and pharmacokinetics/pharmacodynamics (PK/PD) of a single-dose administration of CSL112 in patients with stable atherothrombotic disease. Patients were randomized to a single infusion of either CSL112 at 1.7, 3.4 or 6.8g doses or masked placebo. PK and PD were assessed up to 7 days after the infusion during the active treatment period. Safety was assessed for up to 90 days after the infusion.
No treatment-emergent serious adverse events (AE) were reported during the active treatment period except for one case of atrial fibrillation which occurred in the placebo group. Assessments of liver function and other key biochemical, hematologic and immunogenic measurements over time were similar across all CSL112 and placebo groups.
PK and PD analyses showed that CSL112 caused immediate and robust increases in apoA-I, the active component of high density lipoprotein (HDL). Blood levels of apoA-I rose in a dose-proportional fashion with elevations approaching three-fold baseline levels at the top dose. The highly anti-atherosclerotic form of HDL known as PreBeta1 showed an even greater elevation, with increases up to 17-fold. CSL112 also enhanced key biomarkers of the early steps of reverse cholesterol transport with strong elevations in cholesterol efflux capacity observed across all CSL112 regimens. Changes were maintained for up to 72 hours after infusion of CSL112 at the higher doses.
Potential antiplatelet effects of CSL112 were also evaluated in this population of patients who were receiving chronic dual antiplatelet therapy. CSL112 did not significantly influence platelet aggregation in response to AA, ADP and collagen. Based on these data, it is anticipated that CSL112 will not affect hemostasis when administered with concomitant antiplatelet therapies.
“Patients who experience an ACS event have a great unmet need to reduce the risk of suffering another heart attack, stroke or other cardiovascular event, particularly within the first 30 days,” said Chuck Shear, CSL Cardiovascular Therapeutic Area Head. “The results of this third clinical study of CSL112 support our continued enthusiasm for its development as a novel approach to address this important therapeutic void.”
CSL112 is a novel formulation of apolipoprotein A-I (apoA-I), the active component of high-density lipoprotein (HDL). It is purified from human plasma and reconstituted to form HDL particles suitable for intravenous infusion. Studies have shown the infusion of CSL112 rapidly elevates markers of reverse cholesterol efflux, a process by which cholesterol is removed from arteries and transported to the liver for clearance. CSL112 may offer a novel option for rapidly stabilizing atherosclerotic lesions and is being studied for reduction in the risk of early atherothrombotic events in acute coronary syndrome (ACS) patients.
Headquartered in Melbourne, Australia, CSL Limited is a global biopharmaceutical company that develops, manufactures and markets biotherapies to prevent and treat rare and serious human diseases. CSL owns major facilities in Australia, Germany, Switzerland and the United States, and employs over 11,000 people in more than 25 countries. Visit www.csl.com.au for more information.
Sheila A. Burke
Director, Communications & Public Relations
Worldwide Commercial Operations
MCS Healthcare Public Relations