LOS ANGELES, Nov. 5, 2012 /PRNewswire/ -- Infusions of a novel formulation of apolipoprotein A-I (apoA-I) – the main component of high-density lipoprotein (HDL) – rapidly increased the presence of key biomarkers associated with reverse cholesterol transport, a process by which cholesterol is removed from arteries and transported to the liver for clearance, according to data from a Phase 1 study sponsored by CSL Limited. Rapid removal of cholesterol following a heart attack may play a role in stabilizing vulnerable plaque lesions and lowering the high risk of subsequent attacks.
"In our study, CSL112 dramatically elevated measures of cholesterol efflux capacity, a newly recognized marker of HDL function, and rapidly raised blood levels of apoA-I," said Andreas Gille, MD, PhD, CSL Head of Clinical and Translational Science Strategy, and lead study author. "This is a very exciting early finding when viewed in the context of reducing the risk of recurrent heart attacks. We look forward to further developing CSL112 with the goal of meeting a significant unmet medical need in the acute coronary syndrome patient population."
Data from two CSL112 Phase 1 studies presented at the American Heart Association (AHA) meeting demonstrated a positive safety and pharmacokinetic (PK) profile for CSL112, warranting progression to Phase 2 development. CSL112 will be studied for the early reduction of recurrent cardiovascular events in acute coronary syndrome (ACS) patients.
Study Design and Key Findings
Biomarkers of cholesterol movement following infusions of CSL112 were observed in 36 healthy subjects. Three dosing regimens were studied, including 4 once-weekly infusions of 3.4g, 4 once-weekly infusions of 6.8g, and 8 twice-weekly infusions of 3.4g. Subjects were randomized to CSL112 or placebo (3:1, respectively). All biomarker responses were dose dependent and showed similar magnitude and time course after the first and last infusions.
An overall elevation in cholesterol efflux capacity, PreBeta1-HDL, and HDL in serum or plasma was observed among all dosing regimens. PreBeta1-HDL was increased 20-fold among dosing regimens. Cholesterol efflux capacity and PreBeta1-HDL peaked immediately following infusion and returned to near baseline at 24 hours. HDL level increased following PreBeta1-HDL, peaked at 24 to 48 hours, and sustained elevation 72 hours after infusion.
Safety and PK profiles were separately evaluated in the 36 healthy patients receiving the three dosing regimens of CSL112. No treatment-emergent serious adverse events (AE) were reported, no abnormalities were observed in serum biochemistry, hematology and urine parameters, and no significant changes were seen in platelet function, vital signs or ECG associated with CSL112 treatment. The most common AE reported was vessel puncture site hematoma (18 of 36), which was reported by similar proportions of patients receiving either CSL112 or placebo.
"Development of products that increase cholesterol efflux from the artery wall represents an emerging area in atherosclerosis discovery," said Dr. Samuel Wright, PhD, Global Strategic Director for Cardiovascular Therapeutics at CSL Limited and study co-author. "Prior approaches have centered on addressing only HDL cholesterol levels. CSL112 holds promise as a new therapy that may be used in addition to other treatments, such as anti-platelet agents, to provide early event reduction."
Additional CSL112 Research
Data from a randomized single ascending dose study of 57 healthy subjects were also presented at the AHA 2012 Scientific Sessions and demonstrated that a single infusion of CSL112 at dose levels of 5 to 135 mg/kg immediately caused dose-proportional elevation in apoA-I and changes to key biomarkers of the early steps in reverse cholesterol transport. These changes from baseline occurred in a dose- and time-dependent manner and were maintained for at least 72 hours after infusion of CSL112 at 40 mg/kg and higher. Notable biomarker changes included elevations in PreBeta1-HDL (maximum=3,600%) and global cholesterol efflux capacity from macrophages (maximum=270%).
In another study presented at the meeting, CSL112 was observed to have strong anti-inflammatory properties in human blood ex vivo. This property of CSL112 may prove to be beneficial in the reduction of inflammation associated with cardiovascular events.
"We are very encouraged by the early experience with CSL112 in the clinic and are looking forward to completing the mid-stage studies that are now in progress or being planned to start next year," said Chuck Shear, CSL Senior Director and Therapeutic Area Head.
CSL112 is a novel formulation of apolipoprotein A-I (ApoA-I), the chief component of high-density lipoprotein (HDL). It is purified from plasma and reconstituted to form HDL suitable for intravenous infusion. As demonstrated in pre-clinical and Phase 1 studies, CSL112 elevates cholesterol efflux capacity, as well as additional steps in reverse cholesterol transport. CSL112 demonstrates strong anti-inflammatory activity, as well.
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.
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