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

End Date for Final Data Collection for Primary Outcomes

December 2010

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

• Healthy individual
• Age: 18-55 year old
• Weight ≥ 5 kg
• BMI between 18-42 kg/m2

Exclusion Criteria

• Clinically significant medical condition or disease
• Abnormal lab test result
• History of alcohol or other substance abuse

Study Arms

• Intravenous placebo infusions composed of 0.9% normal saline
• Single escalating intravenous doses of CSL112 composed of reconstituted HDL. There 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

Primary Outcomes

Safety and tolerability defined as rate of clinically associated adverse events that occur within 14 days of CSL112 infusion.

Secondary Outcomes

Evaluation of lipoprotein pharmacokinetics during a time frame of 10 days following CSL112 infusion and measurement of plasma levels of lipoprotein.

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.