George Ngo March 22, 2012 University of Georgia College of Pharmacy Class of 2012

1. George Ngo March 22, 2012 University of Georgia College of Pharmacy Class of 2012 Effect of a Monoclonal Antibody to PCSK9 on LDL Cholesterol

2. 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

3. 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

4. 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

5. 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

6. 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: 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)

7. 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: LDL Response • Single-dose studies • ↓ in baseline LDL up to 65% compared to placebo • Dose-dependent decrease • Higher dose → more decrease

8. Results: Single-dose IV

9. Results: Single-dose SQ

10. 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

11. 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

12. 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

13. Level of Evidence: IIa-B

14. 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.