mRNA Inhibition of ApoB Synthesis: An Alternative to LDL ... · Antisense Drug (Oligonucleotide)...
Transcript of mRNA Inhibition of ApoB Synthesis: An Alternative to LDL ... · Antisense Drug (Oligonucleotide)...
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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
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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
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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)
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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.
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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
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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
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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
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Randomized Controlled Phase 3 Trials in FH PatientsSignificant Reduction in LDL-C, vs Placebo
8
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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.
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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
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Sustained Reductions in LDL-C, ApoB, and Lp(a)
with Long-term Mipomersen Treatment
Santos et al, European Heart Journal, 2013
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Change from Baseline in Liver Fat Fraction Over Time
Suggestion of Adaptation that Attenuates Hepatic Fat
Accumulation
Santos et al, European Heart Journal, 2013
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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
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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
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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