1. Are the PCSK9 Inhibitors the Panacea of Atherosclerosis Treatment?
Slim Jim Revise
5/9/2018
Are the PCSK9 Inhibitors the Panacea of Atherosclerosis Treatment?
Effects on Lipid Lowering and Beyond
Evan A Stein MD PhD
Director Emeritus, Metabolic & Atherosclerosis Research Center
Disclosures
Have received consulting fees related to development of PCSK9 inhibitors from Amgen, Regeneron/Sanofi, Genentech/Roche and BMS and other LDL drugs from AstraZeneca, Catabasis, CymaBay and Gemphire.
Lipid Advisory Panel for CVS/Caremark 1

2. Potential Role of the PSCK9 Inhibitors in Routine Clinical Practice
What we know
Extensive clinical trials with two mAbs, evolocumab and alirocumab, resulted in FDA marketing approval in late summer of 2015 for use as follows; along with diet and maximally tolerated statin therapy in adults with heterozygous FH or ASCVD, who need additional lowering of LDL cholesterol
Both drugs have shown maximal and stable 60% reductions in LDL-C once all PCSK9 is bound (140 to 150 mg Q2W or 420 mg Q4W) and less reduction and more variability with incomplete suppression at lower doses
Same reduction when added to diet alone, low and maximal dose statin or statin plus ezetimibe; in patients with HeFH and nonFH; pts adverse to statins
Homozygous FH patients respond about half as well to evolocumab, with mean reductions in LDL-C of 31% to high doses, 420 mg Q4W
In addition to LDL-C reductions there is robust 25-30% decrease in Lp(a)
Preliminary and exploratory analysis of CVD events are encouraging

3. Heterozyg Fam Hyperchol
OSLER Program
Mono- therapy
Hyperchol on a statin
Statin- Intol
Heterozyg Fam Hyperchol
Other
Phase 2 trials
MENDEL-1
(n=406)
LAPLACE-TIMI 57
(n=629)
GAUSS-1
(n=157)
RUTHERFORD-1
(n=167)
YUKAWA-1
(n=310)
4465 patients (74%) elected to enroll into OSLER extension study program
1324 from Ph2 trials into OSLER from Ph3 trials into OSLER-2
Eligible if medically stable and on study drug
Phase 3 trials
MENDEL-2
(n=614)
LAPLACE-2
(n=1896)
GAUSS-2
(n=307)
RUTHERFORD-2
(n=320)
DESCARTES
(n=901)
THOMAS-1
(n=149)
THOMAS-2
(n=165)
Evolocumab plus standard of care (n=2976)
Standard of care alone (n=1489)
Randomized 2:1
Irrespective of treatment assignment in parent study
Median follow-up of 11.1 months (IQR )
7% discontinued evolocumab early
96% completed follow-up

4. Evolocumab OSLER Trial: Cumulative Incidence of Cardiovascular Events¶1 2 30 60 90
120
150
180
210
240
270
300
330
365
HR 0.47
95% CI
P=0.003
Composite Endpoint: Death, MI, UA  hosp, coronary revasc, stroke, TIA, or CHF  hosp 3
Days since Randomization
Cumulative Incidence (%)
Evolocumab plus standard of care
(N=2976)
Standard of care alone (N=1489)
0.95%*
2.18%**
*29/2976
**31/1489
Figure 2 Cumulative Incidence of Cardiovascular Events. Included among the cardiovascular events were death, myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, stroke, transient ischemic attack, and hospitalization for heart failure. Cardiovascular events were reported in 29 of 2976 patients in the evolocumab group (Kaplan–Meier 1-year event rate, 0.95%) and in 31 of 1489 patients in the standard-therapy group (Kaplan–Meier 1-year event rate, 2.18%). The inset shows the same data on an expanded y axis. The P value was calculated with the use of a log-rank test.
¶CVD clinical outcomes (prespecified, exploratory): adjudicated by TIMI Study Group CEC, blinded to treatment
Included death, myocardial infarction, unstable angina requiring hospitalization, revascularization, stroke or transient ischemic attack and Heart failure requiring hospitalization
Sabatine MS et al. N Engl J Med 2015;372:

5. ODYSSEY LONG TERM Study Design
Follow-up (8 weeks)
Double-blind treatment (18 months)
Adults with HeFH or at high CV-risk
On maximally tolerated statin  other LLT
LDL-C ≥70 mg/dL (1.81 mmol/L)
N=1553
Alirocumab 150 mg Q2W SC (single 1 mL injection using prefilled syringe for self-administration) R
N=788
Placebo Q2W SC W4
W12
W24
W52
W64
W78
Assessments W0 W8
W16
W36
Primary
efficacy endpoint
[Adapted from Figure S1. Study Design – see online Supplementary Appendix – permission may be required depending on use of this slide set]
This slide set describes ODYSSEY LONG TERM, a multinational, phase 3, randomized, double-blind, placebo-controlled, parallel-group study conducted in 320 centers located in 27 countries in Africa, Europe, Canada, USA and South America.
Adult patients (aged ≥18 years) were eligible if they had heterozygous familial hypercholesterolemia (diagnosis by genotyping or clinical criteria) or established coronary heart disease or a coronary heart disease risk equivalent and LDL-C level ≥70 mg/dL (1.8 mmol/L) or more at the time of screening.
In addition, all patients were required to be receiving a maximally tolerated dose of statin (that is either high-dose statin [40‒80 mg of atorvastatin, 20‒40 mg of rosuvastatin, or 80 mg of simvastatin daily] or a lower statin dose or less potent statin if high-dose statin was not tolerated), with or without other LLT, for ≥4 weeks before screening (6 weeks for fenofibrate).
Following a screening period of 3 weeks, eligible patients were randomized (2:1 ratio) to receive either alirocumab 150 mg or placebo Q2W for 78 weeks (as well as their baseline statin therapy ±other LLT).
Alirocumab and placebo injections were given subcutaneously in a 1 mL injection volume provided as a pre-filled syringe. A Therapeutic Lifestyle Changes diet (as per Adult Treatment Panel III of the National Cholesterol Education Program or equivalent) was to be maintained for the duration of the study.
[[Source for slide: Robinson JG et al. N Eng J Med : : Supplementary Appendix Figure S1 (page 51)
Source for slide notes: Main publication, page 2, column 1 ‘Study Design and Oversight’; column 2, highlighted text in ‘Study Population’ and ‘Study Procedures’ sections]]
CV, cardiovascular; HeFH, heterozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy; Q2W, every 2 weeks; SC, subcutaneous; W, week.
ClinicalTrials.gov identifier: NCT
Robinson JG et al. NEJM 2015; 372:

6. Cumulative Probability of Event
Alirocumab: ODYSSEY Long-term Cumulative Incidence of Cardiovascular Events¶
Time (weeks)
0.06
0.02
0.04 52 78 86
0.03
0.05
0.01
Placebo
Alirocumab*
Cumulative Probability of Event 64 12 24 36
Cox model analysis HR = 0.52 (95% CI, ) Nominal P-value = .02
*27/1550
**26/788
3.3%**
1.7%*
Figure 2 Cumulative Incidence of Cardiovascular Events. Included among the cardiovascular events were death, myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, stroke, transient ischemic attack, and hospitalization for heart failure. Cardiovascular events were reported in 29 of 2976 patients in the evolocumab group (Kaplan–Meier 1-year event rate, 0.95%) and in 31 of 1489 patients in the standard-therapy group (Kaplan–Meier 1-year event rate, 2.18%). The inset shows the same data on an expanded y axis. The P value was calculated with the use of a log-rank test.
¶post-hoc analysis not specified in the study protocol - included cardiovascular event categories which comprise the endpoint in ODYSSEY Outcomes (Study to Evaluate the Effect of Alirocumab on the Occurrence of Cardiovascular Events in Patients Who Have Experienced an Acute Coronary Syndrome).
Robinson JG et al. N Engl J Med 2015;372:

7. RELATIONSHIP BETWEEN MACE AND ACHIEVED LDL-C IN PHASE 3 ODYSSEY TRIALS OF ALIROCUMAB VERSUS CONTROL*
HR 0.76, [95% CI: ] per 39 mg/dL reduction; p=0.0025
Conclusion: a continuous relationship between 24% lower MACE risk and 39 mg/dL lower on-Rx LDL-C was observed without limit, even down to mean level of 25 mg/dL
*ODYSSEY FH I, FH II, HIGH FH, LONG TERM, COMBO I, COMBO II, OPTIONS I, OPTIONS II, ALTERNATIVE and MONO studies: median time to events 36 wks 4974 patients treated with ALI, placebo or EZE experienced a total of 104 CVD events
Ray et al Originally published October 24, 2016

8. RELATIONSHIP BETWEEN MACE AND ACHIEVED LDL-C IN PHASE 3 ODYSSEY TRIALS OF ALIROCUMAB VERSUS CONTROL*
LDL-C % reduction was inversely correlated with CVD rates (HR 0.71 [0.57 to 0.89] per additional 50% LDL-C reduction; p=0.003
Conclusion: a continuous relationship between lower MACE risk and Percent reductions in LDL-C from baseline were inversely correlated with MACE rates (HR 0.71 [0.57 to 0.89] per additional 50% reduction from baseline; P=0.003)
*ODYSSEY FH I, FH II, HIGH FH, LONG TERM, COMBO I, COMBO II, OPTIONS I, OPTIONS II, ALTERNATIVE and MONO studies: median time to event 36 wks patients treated with ALI, placebo or EZE experienced a total of 104 CVD events
Ray et al Originally published October 24, 2016

9. GLAGOV: Post Hoc Relationship Between Achieved LDL-C Level and Change in Percent Atheroma Volume
Shaded area represents 95% confidence intervals
Curve truncated at 20 and 110 mg/dL owing to the small number of values outside that range.
Nicholls SJ et al JAMA Published online November 15, 2016 doi: /jama

10. GLAGOV: Cardiovascular Events*
*adjudicated by clinical events committee blinded to treatment assignment
a Total number of cardiovascular events included 2 events occurring
during the period between the last scheduled visit and the end of safety
assessment period.
Nicholls SJ et al JAMA Published online November 15, 2016 doi: /jama

11. Potential Role of the PSCK9 Inhibitors in Routine Clinical Practice
What remains to be known
Confirmation of CVD benefit – 2 large outcome trials in progress with first and largest to report out at ACC March 17, 2017
Long term safety of both drug and low/very low LDL-C

12. PCSK9 Inhibitor CVD Outcomes Trials
Evolocumab
Alirocumab
Sponsor
Amgen
Sanofi / Regeneron
Trial
FOURIER
ODYSSEY Outcomes
Sample size
27,500
18,000
Patients
MI, stroke or PAD
4-52 wks post-ACS
Statin
Atorva ≥20 mg or equiv
Evid-based med Rx
Dose mAb
420 mg QM or 140 mg Q2W
75 mg Q2W (titrate to 150mg)
LDL-C mg/dL(mmol/L)
≥70 (≥1.8)
Baseline LDL-C
91.5 mg/dL (2.37 mmol/L) ?
PCSK9i Dosing
Q2W or Q4W
Q2W
Endpoint
1: CV death, MI, stroke, revasc or hosp for UA,
*Key 2: CV death, MI, or stroke
CHD death, MI, ischemic stroke, or hosp for UA
Recruitment Status
Completed June 2015
Completed Nov 2015
Completion
2016
1/2018
*The trial is planned to continue until 1630 patients experience the secondary endpoint
[accessed September 6, 2016]

13. FOURIER CVD Outcomes Trial: Meets Primary and Key Secondary Endpoint*
Feb 2, 2017:
FOURIER CVD Outcomes Trial:
Meets Primary and Key Secondary Endpoint*
*planned to terminate when 1630 patients achieve the 2ndary endpoint

14. Evolocumab: Rapid Progress in Humans from proof-of-concept in humans to regulatory approval and confirmation of CVD reduction
Phase 3 trials complete for 2 mAbs, BLA* filed and CVD outcome trials started
First subjects treated with PCSK9 mAb in SAD studies
1st MAD phase 1b trials with PCSK9 mAb started including FH, nonFH, statin Rx
1st publications MAD POC in FH, nonFH on statin or diet
Phase 2 trials published for alirocumab and evolocumab; phase 3 started
Early data on CVD benefit
Marketing approval USA/Europe
FOURIER CVD outcome POSITIVE
*BLA – Biologics licensing application
Stein: PCSK9 Clinical Development Timeline 2017

15. Potential Role of the PSCK9 Inhibitors in Routine Clinical Practice
What remains to be known
Confirmation of CVD benefit – 2 large outcome trials in progress with first and largest to report out at ACC March 17, 2017
Long term safety of both drug and low/very low LDL-C

16. Osler: Adverse Events by Achieved LDL-C
Evolocumab subjects stratified by minimum achieved LDL-C
All
EvoMab (n=2976)
SOC Alone
(n=1489)
<25 mg/dL (n=773)
25 to <40 mg/dL (n=759)
<40 mg/dL (n=1532)
≥40 mg/dL (n=1426)
Adverse Events (%)
Any
70.0
68.1
69.1
70.1
69.2
64.8
Serious
7.6
6.9
7.2
7.8
7.5
Muscle-related
4.9
7.1
6.0
6.4
Neurocognitive
0.5
1.2
0.8
1.0
0.9
0.3
Lab results (%)
ALT/AST >3×ULN
1.3
CK >5×ULN
0.4
0.7
0.6
Sabatine MS et al. N Engl J Med 2015;372:

17. ODYSSEY LONG TERM Study: Neurocognitive TEAEs: Safety Analysis
 Alirocumab (N=1550)
 Alirocumab with 2 consecutive LDL-C <25 mg/dL (N = 575)
 Placebo (N=788)
Neurocognitive disorders - no. of patients (%)*
18 (1.2)
3 (0.5)
4 (0.5)
Amnesia
5 (0.3)
Memory impairment
4 (0.3)
1 (0.1)
Confusional state
1 (0.2)
Confusion postoperative
1 (<0.1)
Dementia
Disorientation
Disturbance in attention
Frontotemporal dementia
Reading disorder
Transient global amnesia
Vascular encephalopathy
Robinson JG, et al. N Engl J Med. 2015;372: – appendix Table S6.

18. Feb 2, 2017:
The EBBINGHAUS cognitive function trial conducted in FOURIER patients also achieved its primary endpoint, demonstrating that Repatha was non-inferior to placebo for the effect on cognitive function.

19. Adverse Experience Summary in Patients with LDL-C values <25 mg/dL, <15 mg/dL and >25 mg/dL in Global Safety Pool
Alirocumab Briefing Document: Endocrine & Metabolic Advisory Committee Meeting [accessed Sept 14, 2015]

20. Adjusted rate of any TEAE by average LDL-C during treatment period: From pool of phase 3 ODYSSEY TRIALS OF ALIROCUMAB VERSUS CONTROL*
Conclusion: “The present Phase 3 clinical trial analyses provide further data regarding the overall safety of alirocumab and lower LDL-C levels not being associated with an increase in total adverse events”
*ODYSSEY FH I, FH II, HIGH FH, LONG TERM, COMBO I, COMBO II, OPTIONS I, OPTIONS II, ALTERNATIVE and MONO studies: 4974 patients treated with ALI, placebo or EZE. Median time to event 36 weeks
Ray et al Originally published October 24, 2016

21. Potential Role of the PSCK9 Inhibitors in Routine Clinical Practice
Conclusion:
Patients achieving very low LDL-C levels (<25 mg/dL and even <15 mg/dL) do not show any increase in clinical or laboratory side effects compared to those with higher LDL-C or control groups
The CVD event and IVUS data shows potential additional benefit from low (~40 mg/dL; 1 mmol/L) and very low LDL-C (25 mg/dL;0.4 mmol/L) and increased CVD events when LDL-C remains elevated
Based on current evidence the real safety concern is under treatment of LDL-C, not too low LDL-C!
Safety and benefit data for very low LDL-C based on increased LDL clearance via upregulation of the LDL receptor (statins, ezetimibe and PCSK9 inhibition), plus unreliability of Friedewald LDL-C when LDL-C <50 mg/dL suggest eliminating lower limit for LDL-C (as for hsCRP).

22. How low should we reduce LDL-C?
Brown MS, Goldstein JL: Science 1986; 232: 34–47