1. Effect of the PCSK9 Inhibitor, Evolocumab, on the Composition of Coronary Atherosclerosis: Insights from the GLAGOV Trial
SJ Nicholls, H Kassahun, DM Brennan, K Wolski, J Yang, R Somaratne, SM Wasserman and SE Nissen

2. Disclosures
Research support: AstraZeneca, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron and LipoScience
Consulting and honoraria: AstraZeneca, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, Boehringer Ingelheim

3. Amgen Proprietary - Confidential
Background
The PCSK9 inhibitor, evolocumab, lowers LDL-C, induces plaque regression on IVUS and reduces CV events in statin-treated ASCVD patients
The impact of PCSK9 inhibition on the composition of coronary atheroma has not been investigated.
Virtual histology is an experimental technique which characterizes plaque composition and may have utility in assessing effects of anti-atherosclerotic therapies.

4. GLAGOV Trial Schematic
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GLAGOV Trial Schematic
968 patients with angiographic CAD, stable statin dose and LDL-C
≥80 mg/dL OR mg/dL and 1 major or 3 minor risk factors
Screening, placebo run-in period
Coronary Angiogram
Baseline IVUS
Up to 4 week lipid stabilization period
Placebo SC monthly
Randomization
End of Study IVUS
Evolocumab 420 mg SC monthly
2-4 weeks
Max. 6 weeks
Week 4 12 24 36 52 64 70 76 80

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GLAGOV VH Substudy
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Determine if evolocumab produced changes in VH- derived plaque components (dense calcium, fibrous, fibrofatty, necrotic core) compared with placebo in 331 patients with evaluable VH imaging.
The prespecified statistical plan sought to compare changes in volumetric measures, adjusting for baseline values and multiple comparisons.
The primary endpoint was the absolute change in dense calcium volume from baseline to week 78.

6. Baseline Demographics and Statin Usage
Characteristic
Placebo (n=167)
Evolocumab (n=164)
Age
59.7
59.3
Male Gender
76.0%
70.7%
BMI (kg/m2)
29.5
29.7
Diabetes
16.2%
18.9%
Smoking
22.2%
29.9%
Baseline statin use
99.4%
98.8%
High intensity
57.5%
59.8%
Moderate intensity
41.3%
37.8%
Baseline LDL-C (mg/dL)
92.0
90.9
Baseline CRP (mg/L)
1.5
1.7

7. Percent Change in Biochemical Parameters
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Percent Change in Biochemical Parameters
Characteristic
Placebo (n=167)
Evolocumab (n=164)
P Value
LDL Cholesterol
+0.6%
-62.8%***
<0.0001
HDL Cholesterol
+7.5%***
+11.6%***
0.02
Triglycerides
+2.7%*
-11.5%**
0.0002
CRP
-21.4%
-6.7%**
0.11
Lp(a)
-2.5%
-22.7%***
* P<0.05, ** P<0.01 and *** P< compared with baseline

8. Change in Measures of Plaque Burden
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Characteristic
Placebo (n=167)
Evolocumab (n=164)
P Value
PAV (%)
+0.17
-1.20*
<0.0001
TAV (mm3)
-0.8
-3.6*
0.04
PAV regressors (%)
46.1
68.3
TAV regressors (%)
53.3
64.6
PAV: percent atheroma volume; TAV: total atheroma volume. * P< compared with baseline

9. Primary Endpoint: Change in Normalized Dense Calcium Volume
0.6*
1.0**
P=0.49***
Statin Monotherapy
Statin + Evolocumab
* P<0.05 and ** P<0.001 compared with baseline (exploratory analysis). *** Hochberg adjusted p value

10. Secondary Endpoint: Change in Volume of Other VH Parameters
-3.0*
P=0.49***
-5.0**
-2.4**
-3.0**
-0.6
-0.1
Statin Monotherapy
Statin + Evolocumab
Fibrofatty
Necrotic Core
Fibrous
* P<0.01 and ** P<0.001 compared with baseline (exploratory analysis). *** Hochberg adjusted p value

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Secondary Endpoint: Absolute Change in VH-Derived Percentage Plaque Measures
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Characteristic
Placebo (n=167)
Evolocumab (n=164)
P Value**
Dense calcium (%)
+1.00.4*
+2.20.4*
0.10
Fibrofatty (%)
-0.91.1
-1.61.1
0.67
Fibrous (%)
-0.60.8
-1.40.8
Necrotic core (%)
+0.40.5
+0.90.6
* P<0.01 compared with baseline (exploratory analysis) **Hochberg adjusted

12. Correlation Between Change in VH Measures and Biochemical Parameters
Characteristic
Change LDL-C
Change CRP
Dense calcium
r = -0.15
r = 0.07
Fibrofatty
r = 0.03
r = -0.04
Fibrous
r = 0.06
r = -0.01
Necrotic core

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Exploratory Analysis: Change in VH-Derived Plaque Measures and Regression
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Characteristic
Tertiles of Change PAV (%)
P Value
<-1.57
-1.57 – 0.57
>0.57
Dense calcium (mm3)
0.50.3
0.90.3**
1.00.3**
0.65
Fibrofatty (mm3)
-6.31.2**
-3.71.2**
-2.01.2
0.03
Fibrous (mm3)
-6.30.7**
-2.30.7**
0.50.8
<0.001
Necrotic core (mm3)
-2.60.6**
0.10.6
1.30.6*
* P<0.05 and ** P<0.01 compared with baseline

14. Exploratory Analysis: Baseline LDL-C <70 mg/dL
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Characteristic
Placebo (n=26)
Evolocumab (n=35)
P Value
Dense calcium (mm3)
+0.40.8
-0.31.7
0.54
Fibrofatty (mm3)
-6.03.1
-6.72.6**
0.87
Fibrous (mm3)
-0.82.0
-3.41.7*
0.32
Necrotic core (mm3)
+0.41.4
-2.91.2*
0.08
* P<0.05 and ** P<0.01 compared with baseline

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Conclusion
Evolocumab on a background of optimal statin therapy produced robust lowering of LDL cholesterol and plaque regression by conventional IVUS.
However, VH imaging failed to detect any difference between treatment groups for individual plaque components.
These findings further fuel uncertainty regarding the utility of VH imaging in drug development to assess the effect of anti-atherosclerotic therapies.

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Final Thoughts
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The inverse correlation between changes in LDL cholesterol and plaque calcium supports prior reports in studies of high intensity statins.
While the underlying mechanism remains uncertain, it questions the use of serial calcium scoring to monitor responses to lipid lowering interventions.
VH yields predictable, but not incremental information, in the setting of plaque regression. It will be of interest to see if other modalities can provide better insights.