1. 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.

2. 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.

3. 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.

4. Stephen J. Nicholls MBBS PhD
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

5. 301 patients underwent randomization stratified by country
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
plus placebo (n=150)
Standard of care
plus CER-001 (n=151)
9 weeks 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)

6. 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/m2
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%
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
0.61

7. 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

8. Primary Endpoint: Percent Atheroma Volume
P =0.15
-0.09 (-1.8, 0.5) P=0.67
Median Change in Percent Atheroma Volume (%)
-0.41 (-1.6, 0.8) P=0.01
-0.5 -1
Placebo
Results expressed as median (interquartile range)
CER-001

9. Change in Total Atheroma Volume
Entire Vessel Length Most Diseased 10-mm Segment -1
Median Change Volume (mm3)
P = 0.64
P = 0.51 -2
Median Change Volume (mm3) -2 -4 -3
-3.0 (-6.9, 1.5)
P <0.001 -6
-5.6 (-12.4, 1.7)
P <0.001
-3.5 (-7.7, 1.8)
P <0.001 -4
-6.6 (-13.7, 1.7)
P <0.001
Placebo CER-001 -8 -5
Placebo
CER-001
Results expressed as median (interquartile range)

10. Percent of Patients Showing Regression
PAV TAV
100% 100%
P = 0.49 for comparison to placebo group
P = 0.50 for comparison
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

11. Subgroup Analysis Subgroup Placebo CER-001 P Value Age <59 years
-0.41
-0.11
0.29
>59 years
-0.38
-0.04
0.63
Gender
Males
-0.46
-0.03
0.16
Females
+0.27
-0.23
0.99
Diabetes
-0.92
-0.02
0.12
No diabetes
-0.37
0.44
LDL-C
<70 mg/dL
-0.70
0.83
mg/dL
-0.43
-0.09
0.26
>100 mg/dL
+0.20
0.52
PAV
<38.1%
+0.02
-0.06
0.77
>38.1%
-0.86
0.04

12. Subgroup Analysis: Effect of Prior Statin Use
No Prior Statin (N=195)
Prior Statin (N=77)
0.2
0.2
0.08
Median Change Percent Atheroma Volume (%)
Median Change Percent Atheroma Volume (%)
P = 0.045
-0.2
-0.2
P = 0.43
-0.4
-0.4
-0.37
-0.41
-0.41
P = 0.02
P = 0.52
P = 0.12
P = 0.06
-0.6
-0.6
Placebo CER-001
Randomisation not stratified according to prior statin use
Placebo
CER-001

13. Adverse Clinical Events and Safety Findings
Placebo (N=146)
CER (n=147)
P Value
ALT/AST >2x ULN
4.8%
4.1%
0.77
Total Bilirubin >2x ULN
0.7%
0.99
CK >5x ULN
3.4%
0.10
Serious adverse events
8.9%
8.2%
0.82
Allergic and infusion reactions
6.8%
0.67
ALT: alanine transaminase; AST: aspartate transaminase; CK: creatine kinase; ULN: upper limit of normal

14. Conclusions
Short term treatment with CER 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.

15. 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 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.