Results of the CARAT Study Effect of Serial Infusions of CER-001, a Pre-Beta High-Density Lipoprotein Mimetic on Coronary Atherosclerosis Stephen J Nicholls, Jordan Andrews, John JP Kastelein, Bela Merkely, Steven E Nissen, Kausik Ray, Gregory G Schwartz, Stephen G Worthley, Connie Keyserling, Jean-Louis Dasseux, Liddy Griffith, Susan Kim and Julie Butters. Disclosure Consulting: AstraZeneca, Amgen, Anthera, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Merck, Takeda, Roche, Kowa, LipoScience, Novartis, Sanofi-Regeneron. Clinical Trials: Amgen, Anthera, AstraZeneca, Eli Lilly, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, LipoScience. The CARAT study was sponsored by Cerenis Therapeutics.
Background • Epidemiological studies suggest that high-density lipoproteins (HDL) protect against cardiovascular disease. • However, HDL-cholesterol raising agents have not proven to reduce cardiovascular events in recent clinical trials. • CER-001 is a negatively charged, engineered pre-beta HDL mimetic containing apoA-I and sphingomyelin with favorable effects on measures of lipid transport. • Early studies demonstrated potential coronary plaque regression infusing low dose CER-001 in high plaque burden ACS patients and on carotid plaque in genetic dyslipidemia.
Objective of Study To perform a proof of concept study to determine whether ten infusions of a negatively charged HDL mimetic containing ApoA-I and sphingoymelin (CER-001) at a dose of 3 mg/kg would provide a signal suggesting an impact on coronary atherosclerosis in patients with a recent acute coronary syndrome and higher plaque burden.
Trial Leadership Stephen J. Nicholls MBBS PhD Study Chair Executive Committee John Kastelein MD PhD (Netherlands) Bela Merkely MD (Hungary) Steven E Nissen MD (USA) Kausik Ray MBBS PhD (UK) Gregory G Schwartz MD (USA) Stephen G Worthley MBBS PhD (Australia) Jean-Louis Dasseux (France)* * Sponsor representative
724 patients screened at 33 global centers with an acute coronary syndrome. Baseline percent atheroma volume >30% in proximal 10-mm in a target vessel. Intravascular ultrasound via motorized pullback at 0.5 mm/sec through >40 mm segment 301 patients underwent randomization stratified by country Standard of care Standard of care 9 weeks plus placebo (n=150) plus CER-001 (n=151) treatment 13 patients did not complete 16 patients did not complete 137 placebo completers 135 CER-001 completers Follow-up IVUS of originally imaged “ target ” vessel (n=272)
Baseline Demographics and Statin Usage Characteristic Placebo (N=137) CER-001 (n=135) P value Age 59.1 60.6 0.18 Male Gender 82.5% 77.0% 0.26 BMI kg/m 2 29.3 28.4 0.04 Hypertension 68.6% 64.4% 0.47 Diabetes 23.4% 15.6% 0.10 Smoking 34.3% 38.5% 0.47 Baseline statin use 28.5% 28.1% 0.95 Baseline LDL-C 81.2 mg/dL 85.1 mg/dL 0.07 Baseline HDL-C 38.7 mg/dL 38.7 mg/dL 0.61
Percent Change in Biochemical Parameters Characteristic Placebo CER-001 P Value LDL cholesterol -6.4% -7.0% 0.75 HDL cholesterol +5.4% +7.1% 0.72 Triglycerides +5.7% -1.9% 0.81 Apolipoprotein B -2.0% -5.1% 0.62 Apolipoprotein A-I +7.7% -4.0% 0.69 hsCRP -56.6% -60.0% 0.98 HDL: high-density lipoprotein; hsCRP: high-sensitivity C-reactive protein; LDL: low-density lipoprotein
Primary Endpoint: Percent Atheroma Volume 0 P =0.15 -0.09 (-1.8, 0.5) P=0.67 Median Change -0.41 (-1.6, 0.8) in Percent -0.5 P=0.01 Atheroma Volume (%) -1 Placebo CER-001 Results expressed as median (interquartile range)
Change in Total Atheroma Volume Entire Vessel Length Most Diseased 10-mm Segment 0 0 -1 Median Change Volume (mm 3 ) P = 0.64 P = 0.51 Median Change Volume (mm 3 ) -2 -2 -4 -3 -3.0 (-6.9, 1.5) P <0.001 -6 -5.6 (-12.4, 1.7) -3.5 (-7.7, 1.8) -4 P <0.001 P <0.001 -6.6 (-13.7, 1.7) P <0.001 -8 -5 Placebo CER-001 Placebo CER-001 Results expressed as median (interquartile range)
Percent of Patients Showing Regression PAV TAV 100% 100% P = 0.49 for comparison P = 0.50 for comparison to placebo group to placebo group 80% 80% Percentage of Patients (%) Percentage of Patients (%) 70.8% 67.4% 57.7% 60% 60% 53.3% 40% 40% 20% 20% 0% 0% Placebo CER-001 Placebo CER-001
Subgroup Analysis Subgroup Placebo CER-001 P Value -0.41 -0.11 0.29 <59 years Age -0.38 -0.04 0.63 >59 years -0.46 -0.03 0.16 Males Gender +0.27 -0.23 0.99 Females -0.92 -0.02 0.12 Diabetes Diabetes -0.37 -0.11 0.44 No diabetes -0.70 -0.70 0.83 <70 mg/dL -0.43 -0.09 0.26 LDL-C 70-100 mg/dL -0.03 +0.20 0.52 >100 mg/dL +0.02 -0.06 0.77 <38.1% PAV -0.86 -0.09 0.04 >38.1% -0.41 0.08 0.045 No Prior statin -0.41 -0.37 0.43 Yes
Adverse Clinical Events and Safety Findings Placebo CER-001 Event P Value (N=146) (n=147) ALT/AST >2x ULN 4.8% 4.1% 0.77 Total Bilirubin >2x ULN 0.7% 0.7% 0.99 CK >5x ULN 3.4% 0.7% 0.10 Serious adverse events 8.9% 8.2% 0.82 Allergic and infusion reactions 6.8% 8.2% 0.67 ALT: alanine transaminase; AST: aspartate transaminase; CK: creatine kinase; ULN: upper limit of normal
Conclusions • Short term treatment with CER-001 3 mg/kg did not produce a significant effect on coronary disease progression measured by IVUS. • Ten infusions of CER-001 were well tolerated. • These results occurred on a background of contemporary therapy in the post ACS setting. • Whether CER-001 impacts other settings remains to be determined.
Some Final Thoughts • Early imaging studies demonstrated favorable effects of HDL infusions on coronary atherosclerosis. • This provided support for development of HDL targeted agents as potential anti-atherosclerotic therapies • However, the lack of benefit with short term therapy with CER-001 3 mg/kg in CARAT suggests that this is not a promising strategy for ACS patients. • Whether HDL therapy can impact plaque or clinical events in the setting of contemporary therapy remains to be determined, although with each disappointing study result the considerable challenge remains.
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