mRNA Inhibition of ApoB Synthesis:

An Alternative to LDL-Receptor

Upregulation?

Prof. John J.P. Kastelein, MD PhD FESC

Dept. of Vascular Medicine

Academic Medical Center / University of Amsterdam

The Netherlands

2

Mipomersen: Apo B-100 as a Target

Cholesterol

Apo B Triglyceride

VLDL

VLDLIDL

LDL1LDL2 LDL3

Lp(a)

Apo A

Apo B-100 is an important structural and functional component of lipoproteins

Blocking Apo B-100 production blocks VLDL and LDL production

Mipomersen

3

A 20-mer phosphorothioate antisense oligonucleotide that is complementary in sequence to a segment of the human Apo B mRNA

Overview of Mipomersen

Kastelein JJ, et al. Circulation. 2006;114(16):1729-1735.

G C C T C A G T C T G C T T C G C A C C

Phosphorothioate

Backbone

2′ MOE2′ MOE2′ Deoxy

(Supports RNase H Activity)

4

Mechanism of Action

DNA mRNA Disease-Associated Protein

Transcription Translation

Antisense Drug(Oligonucleotide)

Transcription

No Disease-Associated

Proteins Produced

No Translation

Traditional

Drug

Crooke R, et al. Adapted from: Crooke ST, ed. Antisense drug technology: principles,

strategies and applications. 2nd ed. Boca Raton, FL: CRC Press, 2007:601-639.

5

OB

O

O

B

O

O

B

O

O

B

O

O

OP

O

S

O

OP

S

O

OP

S

O

OP

S

OO

CH3

OO

CH3

5'

3'

Antisense: A Novel Approach to Drug Discovery by

Inhibition of Translation of a Specific Targeted Protein

Antisense Strand

Sense-Antisense Duplex

RNase H

DNA

mRNA

Nucleus Cytoplasm

Cell Membrane

2nd Generation Antisense Drugs

~20X more potent

1X/week to 1X/quarter dosing

Better tolerated

Lower cost of therapy

RNase H Dependent Mechanism of Action

Mipomersen Phase 3 Study Design

Four Randomized Placebo-Controlled Trials

Randomized, double-blind, placebo-controlled, multi-center

All patients on stable maximally tolerated LLT (statin +/-)

Weekly subcutaneous injections of mipomersen 200 mg or placebo for 26 weeks (option to self-administer)

Primary efficacy endpoint: % change in LDL-C from baseline to week 28, or 2 weeks after the last dose

All Studies

Enroll

Patients

Mipomersen 200 mg/wk

Placebo

R 2:1 mipomersen:placebo

Screening

≤ 4 weeks

Treatment Period

26 weeks

Safety Follow-up

24 weeks

Safety Follow-up

Primary

efficacy

timepoint

MipomersenConsistent Efficacy Across the Phase 3 Program

in patients with FH

Baseline % Change

Patient Population

LDL-C

(mg/dL)

LDL-C

(mean absolute

reduction)

ApoB

(mean absolute

reduction)

Lp(a)

(mean absolute

reduction)

Homozygous FH

(MIPO 5 / n= 51)

Raal, et al. Lancet, 2010

426-24.7%

(-106 mg/dL)

- 27%

(-77.7 mg/dL )

-31%

(-20.5 mg/dL)

Severe Heterozygous FH

(MIPO 35 / n=58)

McGowan, et al. PLoS ONE, 2012

276 -36%

(-101.2 mg/dL)

-36%

(-75.3 mg/dL )

-33%

(-18 mg/dL)

Heterozygous FH

(MIPO 7 / n= 124)

Stein, et al. Circulation, 2012

153-28%

(-46 mg/dL)

- 26%

(-37.8 mg/dL)

- 21%

(- 14.4 mg/dL)

Average LDL-C Reduction > 100 mg/dL

Average LDL-C Reduction > 100 mg/dL

45% Patients Achieved LDL-C Levels < 100 mg/dL

Randomized Controlled Phase 3 Trials in FH PatientsSignificant Reduction in LDL-C, vs Placebo

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Phase 3: Homozygous FH LDL-C % Change From Baseline for Individual Patients

Raal FJ, et al. Lancet. 2010:375(9719):998-1006.

Phase 3: Safety

On-Treatment Adverse Events & Clinical Findings

Adverse Events

Most common AEs were mild to moderate injection site reactions & flu-like symptoms

• Less than 5% discontinued due to these AEs

Clinical Findings

Transaminase increases

• 8.4% mipomersen-treated patients had ALT ≥ 3x ULN on two consecutive measures 7 days apart

No effect on liver synthetic function, i.e. total bilirubin, albumin, PT

Modest median increase in hepatic fat, which was reversible after cessation of dosing

Sustained Reductions in LDL-C, ApoB, and Lp(a)

with Long-term Mipomersen Treatment

Santos et al, European Heart Journal, 2013

Change from Baseline in Liver Fat Fraction Over Time

Suggestion of Adaptation that Attenuates Hepatic Fat

Accumulation

Santos et al, European Heart Journal, 2013

MACE Rate in FH Patients

Treated for One Year with Mipomersen

The MACE rate during 2 years prior to mipomersentreatment was compared to the MACE after 1 year of mipomersen treatment in 104 patients with FH who

participated in one of three phase 3 blinded randomized placebo-controlled 6-month trials and an open-label

extension study

MACE were defined as non-fatal MI, stroke, unstable angina, and revascularization procedures (PCI/CABG)

MACE occurring before randomization were identified in medical history

On-study MACE, including those for placebo-treated patients who received active drug in the open label extension, were adjudicated post-hoc by an independent committee 13

The MACE rate was significantly lower in 104 FH patients treated with mipomersen for 1 year versus the rate 24 months prior to treatment

MACE Rate Reduced in FH Patients

One Year of Treatment with Mipomersen

14

Prior (Med

Hx)

One Year on

Treatment

# events 146 6

# patients w/event 64 (61.5%) 6 (5.8%)

OR 0.033 [95% CI 0.004-0.126]

P-value <0.0001

Mean Time, months 23.9 (0.1) 11.9 (0.6)

Total Time, months 2488 1236

Rate/1000 * 25.72 4.85

Summary of Benefit Versus Liver Effects

Benefit

• Sustained reductions in all atherogenic apoB-containing

lipoproteins, including LDL-C, apoB and Lp(a)

• No drug-drug interactions identified between mipomersen and

other drug therapies

• No clinical effect on other cardiovascular risk markers in

association with mipomersen treatment, including blood

pressure, fasting glucose, markers of chronic inflammation and

renal function

• MACE rate significantly lower in FH patients after one year of

mipomersen treatment compared to rate prior to treatment

Liver effects

• Elevated transaminases in some patients, but without clinically

significant changes in other measures of liver fx, e.g. bilirubin

• Stabilization or decrease in fat content with continued treatment