Antisense drugs to lower LDL-c & TGs: Where are we now?

John Kastelein, MDAmsterdam, The Netherlands

Presented - August 30, 2014

ApoC-III mRNA inhibition

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Apolipoprotein C-III

Key Regulator of Serum Triglyceride Levels

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Phase II, Multicenter, Randomised, Double-Blind, Placebo-

Controlled Trials in High to Very High TG Patients

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Isis-ApoC-IIIRx Monotherapy

Significantly Reduced ApoC-III

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Isis-ApoC-IIIRx Monotherapy

Significantly Reduced TG Levels

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Isis-ApoC-IIIRx Monotherapy

Significantly Increased HDL-C

Isis-ApoC-IIIRx Added to Fibrate

Improved Overall Lipid Profile

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Isis-ApoC-IIIRx Phase II Open-Label Cohort

FCS Patients

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Isis-ApoC-IIIRx in FCS Patients

Reduced Fasting Plasma ApoC-III and TG Levels

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Isis-ApoC-IIIRx in FCS Patients

Reduced Fasting Plasma Chylomicron-TG and ApoB-48

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Isis-ApoC-IIIRx Phase II Summary

Across Four Patient Populations

ApoB mRNA inhibition

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Human ApoB-100 is an Ideal Target

for a 2nd Generation Antisense Drug

• Expressed in the liver

• Essential for the synthesis and

transport of VLDL and LDL-C

• Plays a crucial role in lipid

management

• Biologically validated, but

undruggable target for small

molecules

• An apoB-100 inhibitor is predicted

to have a unique lipid lowering

profile affecting all atherogenic

lipids

• Complementary mechanism with

potential for additive effects when

co-administered with statins

• Fills an unmet medical need

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

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Phase 3: Homozygous FH Distribution of LDL-C % Change From Baseline

% c

han

ge i

n L

DL

-C f

rom

baselin

e t

o P

ET

Raal FJ, et al. Lancet. 2010:375(9719):998-1006. PET, primary efficacy time point, 2 weeks after final dose.

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 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 17

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

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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

* The number of patients with at least one event divided by the total follow-up time x 1000

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

Change from Baseline in Liver Fat Fraction Over Time

Suggestion of Adaptation that Attenuates Hepatic Fat

Accumulation

Santos et al, European Heart Journal, 2013

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