Effect of a Monoclonal
Antibody to PCSK9 on
LDL Cholesterol
George Ngo
March 22, 2012
University of Georgia
College of Pharmacy
Class of 2012
The Basics


Monoclonal antibodies bind to a specific epitope (part of an
antigen) that the body recognizes
The body's immune system recognizes the substance and
elicits a response to eliminate it

1) Hepatic LDL receptors → “The Victim”

2) PCSK9 → “The Bad Guy”
– An enzyme that binds to hepatic LDL receptors
– 1) accelerates their degradation
– 2) DECREASES LDL cholesterol intake into liver cells
(liver cannot bind and remove LDL cholesterol)
– 3) INCREASES LDL cholesterol levels
What's Our Hero's Name?

3) REGN727 → “The Hero”
– An investigational, fully human monoclonal
antibody that is highly specific for human
PCSK9
– Blocks PCSK9's interaction with the LDL
receptor


Primary Endpoint – Occurrence of adverse
effects
Secondary Endpoint – Effect on lipid profile
Single-Dose Studies

40 pts received IV

32 pts received SQ

Inclusion

Men and women

18-65 years old

BMI 18-30

LDL >100mg/dL

Prohibited use of
other lipid drugs
•
•
IV group
•
Dose ↑ from 1 → 3 →
6 → 12 mg/kg
•
Placebo
SQ group
•
Dose ↑ from 50 →
100 → 150 → 250mg
•
Placebo
•
Safety assessments:
•
Vital signs, physical exam,
blood tests, EKG
Multiple-Dose Studies


51 pts → received
atorvastatin with LDL
>100mg/dL
10 pts → modified diet
only with LDL
>130mg/dL
–
Pts randomly
assigned to receive
SQ REGN727 (50,
100, or 150 mg) or
placebo given on
days 1, 29, and 43
• Safety assessments
taken:
•
vital signs
•
physical
examination
•
blood tests
•
echocardiography
Results: Safety
• 2 pts in single-dose studies
had ADEs (adverse drug
events):
–
–
33 yr-old w/ abd pain +
rectal bleeding on day
83
19 yr-old w/ hx of
appendectomy rec'ving
50 mg of SQ
REGN727...had small
bowel obstruction on
day 75
• Lab effects seen:
–
↑ total bilirubin (1 pt)
–
↑ creatinine kinase (1 pt)
•
No pts in multipledose studies had
serious ADEs
•
All pts completed all
visits
•
No pt had an ↑ in AST
or ALT >3 ULN or ↑ in
SCr to > 1.7mg/dL
•
Headache was the
most common ADE
Results: LDL Response




Single-dose studies
↓ in baseline LDL up
to 65% compared to
placebo
Dose-dependent
decrease
Higher dose → more
decrease


Multiple-dose studies
Compared with
placebo, REGN727
doses w/ atorvastatin
↓ baseline LDL by:



50 mg → ↓ 39.2%
100 mg → ↓
53.7%
150 mg → ↓
61.0%
Results: Single-dose IV
Results: Single-dose SQ
Conclusions


REGN727 is a monoclonal antibody that blocks
PCSK9 from binding to LDL receptors
REGN727 significantly reduced LDL cholesterol
levels compared to placebo


In pts w/ familial or nonfamilial
hypercholesterolemia
Also significant in pts also taking Lipitor
Conclusions




MOA: both ↓ LDL by ↑ hepatic LDL receptor
activity
***Key difference: Lipitor enhances production
of receptors, REGN727 decreases degradation
of receptors
REGN727 takes 2 weeks for max effect, statins
can take longer
REGN727 significantly ↓ apolipoprotein B levels
Limitations
- Small number of subjects
- Short duration of exposure
- Rates of infection or malignancy as possible
ADEs not mentioned
- Supported by Regeneron Pharmaceuticals and
Sanofi
Level of Evidence: IIa-B
References
Gary D Swergold, et al. "Effect Of A Monoclonal
Antibody To PCSK9 On LDL Cholesterol." The New
England Journal Of Medicine 366.12 (2012): 11081118. MEDLINE with Full Text. Web. 29 Mar. 2012.