PCSK9 INHIBITORS

Dr Dilzith
Lipid Disorders
Familial Hypercholesterolemia
 FH is a genetically modulated clinical syndrome
characterized by:
●Elevated low-density lipoprotein cholesterol (LDL-
C) level from birth
●Xanthomata in untreated adults and patients with
homozygous FH
●Early onset coronary heart disease (CHD)
 In patients with a negative or unknown family

history, a LDL-C level of ≥190 mg/dL (4.9

mmol/L) suggests FH
Cntd.,
 FH is most commonly caused by mutations in the
LDL receptor gene (LDLR). The phenotype of FH
can also be seen with mutations in the genes that
code for proprotein convertase subtilisin kexin 9
(PCSK9) and apolipoprotein B (APOB).

 Homozygous FH – Less common but more severe

 Heterozygous FH - More common and less severe
compared to Homozygous
Familial Hypercholesterolemia
Relation between LDL cholesterol and CVD event rate

30
4S - Placebo

25 Rx - Statin therapy
PRA – pravastatin Secondary Prevention
ATV - atorvastatin
Event rate (%)

4S - Rx
20

LIPID - Placebo
15
LIPID - Rx CARE - Placebo
TNT CARE - Rx
Primary Prevention
HPS - Rx TNT – ATV10 HPS - Placebo
10 PROVE-IT - PRA
TNT – ATV80 WOSCOPS – Placebo
PROVE-IT – ATV AFCAPS - Placebo
6
5 AFCAPS - Rx WOSCOPS - Rx
JUPITER ASCOT - Placebo
ASCOT - Rx
0
40 60 80 100 120 140 160 180 200
(1.0) (1.6) (2.1) (2.6) (3.1) (3.6) (4.1) (4.7) (5.2)
LDL-C achieved mg/dL (mmol/L)

Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279

LaRosa JC et al. N Engl J Med 2005;352:e-version
 Residual CVD Risk in Statin vs Placebo Trials
Many CHD Events Still Occur in Statin-Treated Patients

25-40% CVD Reduction Leaves High Residual Risk

Major CHD Events, %

28.0
Patients Experiencing

Placebo
Statin
19.4
15.9
12.3 13.2
11.8 10.9
10.2
8.7 7.9
5.5 6.8

4S1 LIPID2 CARE3 HPS4 WOSCOPS5 AFCAPS/TexCAPS6

N 4444 9014 4159 20 536 6595 6605
 LDL -35% -25% -28% -29% -26% -25%
Secondary High Risk Primary
1
4S Group. Lancet. 1994;344:1383-1389. 4
HPS Collaborative Group. Lancet. 2002;360:7-22.
2
LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 5
Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
3
Sacks FM et al. N Engl J Med. 1996;335:1001-1009. 6
Downs JR et al. JAMA. 1998;279:1615-1622.
 What Next?
 To date, attempts to reduce that residual risk with
additional lipid therapies have failed.
 AIM-HIGH Trial- Niacin
 ACCORD Trial- Fenofibrate
 Both these trials showed no additional benefit rather
harmful effects especially with Niacin
 statins increase the expression of proprotein convertase
subtilisin kexin 9 (PCSK9). PCSK9 promotes hepatic
LDL receptor degradation, thereby reducing LDL
receptor density and clearance of LDL particles.
 What is PCSK9

 Role of long term low level of LDL levels because of a

genetic mutation seen in 2-3% of general population
 People with absence of function of the proprotein convertase
substilisin/kexin type 9 gene (PCSK9) , had 15% to 30%
lower LDL cholesterol than persons with a functioning
PCSK9 gene.
 they were also found to have 50% to 80% lesser CHD events
than the general population over a 15 year follow up.
 The realization that a genetic flaw in PCSK9 activity could
be tolerated by the human body, with reduction in heart
disease, triggered aggressive efforts to develop a monoclonal
antibody against PCSK9.
Breakthrough Studies
What Happens?
Role of PCSK 9
What does mAb’s Do??
PCSK9 Monoclonal Antibodies

 Alirocumab (Praluent) – 24th July 2015

 Evolocumab (Repatha) – 27th Aug 2015

 Becocuzimab
Pharmacology
 Onset: Peak effect: Proprotein convertase subtilisin kexin type
9 (PCSK9) suppression: 4 to 8 hours

 Metabolism: Expected to undergo proteolysis and be degraded

to small peptides and amino acids

 Bioavailability: ~85%

 Half-life elimination: Steady-state: 17 to 20 days; reduced to

12 days when administered with a statin

 Time to peak: 3 to 7 days

Indications

 Alirocumab: “...as adjunct to diet and maximally

tolerated statin therapy for the treatment of adults
with heterozygous familial hypercholesterolemia
(HeFH) or clinical atherosclerotic cardiovascular
disease, who require additional lowering of LDL-
C.”
 Indications
 Evolocumab: “Indicated as an adjunct to diet and
maximally tolerated statin therapy for the treatment of
adults with heterozygous familial
hypercholesterolemia (HeFH) or clinical
atherosclerotic CVD, who require additional lowering
of LDL-C.”
 “Indicated as an adjunct to diet and other LDL-
lowering therapies (eg, statins, ezetimibe, LDL
apheresis) for the treatment of patients with
homozygous familial hypercholesterolemia (HoFH)
who require additional lowering of LDL-C”
Contraindications

 History of Hypersensitivity reaction to components

or drug
Adverse Effects
 Gastrointestinal: Diarrhea (5%)
 Hepatic: Liver enzyme disorder (3%), increased
serum transaminases (>3 X ULN; 2%)
 Immunologic: Immunogenicity (5%; neutralizing:
1%; efficacy effected: <1%)
 Infection: Influenza (6%)
 Local: Injection site reaction (7%)
 Neuromuscular & skeletal: Myalgia (4%), muscle
spasm (3%)
 Respiratory: Cough (3%)
Trials
 PCSK9 Monotherapy
 Both Evolocumab and Alirocumab have been studied
as monotherapies versus Ezetimibe
 Evolocumab reduced LDL-C at 12 weeks by 55% to
57% on average compared with placebo, whereas
Ezetimibe achieved an 18% to 19% reduction.
 Similarly, in a study of Alirocumab monotherapy
versus Ezetimibe in 103 patients with a 1% to 5% 10-
year risk of fatal cardiovascular events, Alirocumab
reduced LDL-C by 47% (66 mg/dl) at 24 weeks,
compared with only 16% (22 mg/dl) for Ezetimibe
LAPLACE 2 Trial
LAPLACE 2 Results
ODYSSEY Trial- Alirocumab
ODYSSEY Trial
In HeFH
OSLER Trial
 Open-label Study of Long-tERm Evaluation
Against LDL-C (OSLER) trial of evolocumab 420
mg Q4W + SOC or SOC alone.
 OSLER Study Design
31
Year 1 Years 2–5
12-week studies:

Randomization 2:1
MENDEL
Standard of Care
(monotherapy)

End of Study
N = 368
LAPLACE-TIMI 57 Evolocumab +
(patients on statins) Standard of Care
Evolocumab +
GAUSS Standard of Care
(statin intolerance) N = 736
RUTHERFORD
(Familial hyper- Blinded Unblinded
cholesterolemia) Stabilization Lipid
Period Treatment

Visits*
End of parent 4 8 12 Q4W 52 Q4W
study / Day 1 OSLER Week
Primary • Effects on LDL-C over 1 year
Objectives: • Safety and Tolerability
Q4W, every 4 weeks. * Patients in the evolocumab + SOC group had in-person visits every 4 weeks. Patients in the
SOC group had in-person visits at week 4, then every 3 months, with telephone visits every 4 weeks.
 OSLER: Safety and Tolerability
32
Evolocumab
SOC
Adverse events, % + SOC
N = 368 N = 736
Any adverse event 73.1 81.4
Serious 6.3 7.1
Possibly treatment-related (none serious) NA 5.6*
Leading to discontinuation of evolocumab NA 3.7
Deaths 0.5 0.1
Most common adverse events
Nasopharyngitis 9.8 12.2
Upper respiratory tract infection 7.6 7.7
Arthralgia 4.3 6.9
Back pain 5.4 6.5
Muscle-related 9.8 9.2
Injection-site reactions NA† 5.2

NA, not applicable; SOC, standard of care. *Percentage of adverse events. †Patients in the SOC group did not
receive injections.
OSLER Results (Once in 2wks
dose)
OSLER Results (Once in 4wks
dose)
Bococizumab
Outcome Trial
ODYSSEY Outcome Trial
FOURIER Trial
FOURIER Trial
Recommendations
Price
THANK YOU!!!