Results of the CARAT Study Effect of Serial Infusions of CER-001, a - - PowerPoint PPT Presentation

Results of the CARAT Study

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.

Effect of Serial Infusions of CER-001, a Pre-Beta High-Density Lipoprotein Mimetic on Coronary Atherosclerosis

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

Executive Committee

Stephen J. Nicholls MBBS PhD Study Chair 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

137 placebo completers 135 CER-001 completers

13 patients did not complete

Follow-up IVUS of originally imaged “target” vessel (n=272) 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. Standard of care plus placebo (n=150) Standard of care plus CER-001 (n=151) 9 weeks treatment

16 patients did not complete

Intravascular ultrasound via motorized pullback at 0.5 mm/sec through >40 mm segment

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% 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

• 1
• 0.5

Median Change in Percent Atheroma Volume (%)

Placebo CER-001

P =0.15

• 0.09 (-1.8, 0.5)

P=0.67

• 0.41 (-1.6, 0.8)

P=0.01

Results expressed as median (interquartile range)

Change in Total Atheroma Volume

• 8
• 6
• 4
• 2

Median Change Volume (mm3)

Placebo CER-001 Placebo CER-001

Entire Vessel Length Most Diseased 10-mm Segment

• 5
• 4
• 3
• 2
• 1

Median Change Volume (mm3)

• 6.6 (-13.7, 1.7)

P <0.001

• 5.6 (-12.4, 1.7)

P <0.001

• 3.0 (-6.9, 1.5)

P <0.001

• 3.5 (-7.7, 1.8)

P <0.001 P = 0.51 P = 0.64 Results expressed as median (interquartile range)

Percent of Patients Showing Regression

57.7% 53.3%

0% 20% 40% 60% 80% 100%

Percentage of Patients (%)

Placebo CER-001 Placebo CER-001

PAV TAV

70.8% 67.4%

0% 20% 40% 60% 80% 100%

Percentage of Patients (%)

P = 0.50 for comparison to placebo group P = 0.49 for comparison to placebo group

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 Diabetes

• 0.92
• 0.02

0.12 No diabetes

• 0.37
• 0.11

0.44 LDL-C <70 mg/dL

• 0.70
• 0.70

0.83 70-100 mg/dL

• 0.43
• 0.09

0.26 >100 mg/dL

• 0.03

+0.20 0.52 PAV <38.1% +0.02

• 0.06

0.77 >38.1%

• 0.86
• 0.09

0.04 Prior statin No

• 0.41

0.08 0.045 Yes

• 0.41
• 0.37

0.43

Adverse Clinical Events and Safety Findings

Event Placebo (N=146) CER-001 (n=147) P Value 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.