A Multiple Ascending Dose Study of CSL112 in Healthy Volunteers

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Objective

• To measure the biomarkers of cholesterol movement following a single and multiple infusions of CSL-112 in healthy subjects.

• To evaluate role of CSL-112 in decreasing cholesterol-loaded plaques that contribute to cardiovascular disease.

Timeline

Start Date

June 2010

                                                                       ===Final Data Collection for Primary Outcomes End Date====

December 2010

Study Completion Date

January 2011

Study Completion Date

January 2011

Methods

• Phase I study

• Adaptive, randomized, placebo-controlled, double-blinded, sponsor-unblinded, multiple ascending dose study

• Patients enrolled: 36 healthy subjects
• Inclusion criteria: Age 18-55 yo, healthy, weight ≥ 5 kg, and BMI between 18-42 kg/m2

• Exclusion criteria: Clinically significant medical condition or disease or abnormal lab test result, history of alcohol or other substance abuse.

• 2 study arms: Intravenous placebo infusions composed of 0.9% normal saline and single escalating intravenous doses of CSL112 composed of reconstituted HDL.

• There Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 are 3 dosing groups: 4 once-weekly infusions of 3.4 g, 4 once-weekly infusions of 6.8 g, and 8 twice-weekly infusions of 3.4 g

• Biomarkers of cholesterol movement - cholesterol efflux capacity, serum preBeta1-HDL and HDL were measured.

Outcomes

• Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 Primary Outcomes: Safety and tolerability defined as rate of clinically associated adverse events that occur within 14 days of CSL112 infusion.
• Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 Secondary Outcomes: Evaluation of lipoprotein pharmacokinetics during a time frame of 10 days following CSL112 infusion and measurement of plasma levels of lipoprotein.

P==Results==

• Infusions of CSL-112 caused immediate and profound elevation in all the biomarkers.

• Serum preBeta1-HDL elevation was up to 20-fold.

• Serum preBeta1-HDL and cholesterol efflux capacity peaked after infusion and returned to baseline at 24 hour while there was a 72 hour sustained response for serum HDL following its peak at 24-48 hours after infusion.
• Multiple infusions of CSL112 causes a greater efflux of cholesterol from tissues to HDL when compared with a single infusion.
• No observed changes in the baseline of other lipoproteins.

Conclusion

Single and multiple infusions of CSL-112 in healthy subjects rapidly initiates the reverse cholesterol transport, and this is beneficial in rapidly lowering the risk of recurrent cardiovascular events following acute coronary syndromes.