George NgoMarch 22, 2012

University of GeorgiaCollege of Pharmacy

Class of 2012

Effect of a Effect of a Monoclonal Antibody Monoclonal Antibody

to PCSK9 on LDL to PCSK9 on LDL CholesterolCholesterol

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 multiple-dose 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): 1108-1118. MEDLINE with Full Text. Web. 29 Mar. 2012.