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3:10 PM – 3:20 PM
Lipoprotein(a): Genes, Biological Role,
Predictive Value and Drug
Interventions
Evan A Stein MD PhD
Director Emeritus
Metabolic & Atherosclerosis Research Center
Cincinnati
Disclosure Statement of Financial Interest
Have received consulting fees related to development of PCSK9 inhibitors from Amgen,
Regeneron/Sanofi, Genentech/Roche and BMS and other LDL drugs from AstraZeneca,
Catabasis, CymaBay and Gemphire.
Lipid Advisory Panel for CVS/Caremark
Lp(a): Structure
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Discovered by Kara Berg 1963
Consists of LDL plus apoplioprotein(a) in a 1:1 ratio
Apo (a) synthesized in hepatocyte and probably links to LDL at cell surface
Clearance not well understood; ? Renal or ? Hepatic receptor
Carries ~5 to 15% of serum cholesterol
Modified from Koschinsky and Marcovina Curr Opinion Lipidol 2004:15;167-174
Lipoprotein(a)
Unique risk factor for Atherothrombotic disease
Atherogenesis
Thrombosis
Cholesterol rich
Apo B particle
Inhibits activation of
Plasminogen by tPA
- Fibrinolysis
Prothrombotic State
Plasma concentrations of Lp(a) are highly heritable
(>90%) mostly determined by variation in Lp(a)
gene, specifically the kringle IV repeats
The intra-individual variability is small (<15%)
The inter-individual variability is large (1000-fold)
‘Optimal’ Lp(a) level <30 mg/dl
<75 nmol/L
If Lp(a) is markedly elevated, measurement of
LDL-C should be corrected for Lp(a)
Corrected LDL-C = LDL-C - [Lp(a) x 0.3]
Elevated Lp(a) levels appear to be an
independent risk factor for CAD
2-3 fold increased risk with Lp(a) > 50 mg/dl
 Cross sectional studies
 Prospective studies
Physicians Health Study (n=14 916)
Quebec Cardiovascular Study (n=2 156)
Helsinki Heart Study
 Meta-analysis
Elevated Lp(a) is also associated with:
 Aortic stenosis
 Restenosis of carotid, cerebral
vessels and stroke
 Venous graft occlusion post CABG
Current Therapy for Lp(a)
Lowering LDL cholesterol appears to remove a
substantial risk of atherogenicity from Lp(a).
Therefore in patients with high plasma levels of Lp(a),
aggressive management of LDL-cholesterol is
currently the best option
Therapeutic options to reduce Lp(a)
 Neomycin
 Nicotinic acid (15% reduction)
 Anabolic steroids e.g. danazol
 Estrogen replacement therapy (15-20%)
 Omega-3 fatty acids
 Hepatic thyromimetic receptor agonists
 Apheresis
 Apo B synthesis inhibitor (mipomersen)
 MTP inhibitor (lomitapide)
 CETP inhibitors
 PCSK9 inhibitors (25-30%)
 (a) antisense
Reduction in Lipoprotein(a) With PCSK9 Monoclonal
Antibody Evolocumab (AMG 145):a Pooled Analysis of
More Than 1,300 Patients in 4 Phase II Trials
Error bars represent standard error.
* P < 0.001
Raal et al JACC 2014;():. doi:10.1016/j.jacc.2014.01.006 Online First
Antisense therapy targeting apolipoprotein(a):
Mechanism of Action
Tsimikas S et al. Lancet July 23, 2015 online DOI: (10.1016/S0140-6736(15)61252-1)
Antisense therapy targeting apolipoprotein(a):
Randomised, double-blind, placebo-controlled phase 1 study – Effect on Plasma Lp(a)
Tsimikas S et al. Lancet July 23, 2015 online DOI: (10.1016/S0140-6736(15)61252-1)
Phase 2 trial to assess the effect of IONIS-APO(a)Rx
 Randomized, double-blind, placebo-controlled, dose-titration study
 2 Cohorts
 Cohort A: High Lp(a) (≥ 50 (125 nmol/L) and < 175 mg/dL (438 nmol/L)) – 52
patients Randomized 1:1
 Cohort B: Very high Lp(a) (≥ 175 mg/dL) – 13 patients Rand 4:1
 Intra-patient dose titration every 4 weeks with weekly dosing (100mg300mg)
 Objectives
 Evaluate activity of ISIS-APO(a)Rx in lowering Lp(a): Primary endpoints were
mean percentage change in fasting plasma Lp(a) concentration at day 85 or
99
 Evaluate the safety & tolerability of ISIS-APO(a)Rx
Viney NJ et al Lancet 2016;388:2239-2253
Phase 2 trial to assess the effect of IONIS-APO(a)Rx
Viney NJ et al Lancet 2016;388:2239-2253
Phase 2 trial to assess the effect of IONIS-APO(a)Rx
Safety
 Generally well tolerated
 12% of injections associated
with injection-site reactions
Viney NJ et al Lancet 2016;388:2239-2253
Phase phase 1/2a trial of IONIS-APO(a)-LRx;
A LICA oligonucleotide targeting apolipoprotein(a)
 Ligand Conjugation Antisense (LICA) technology is GalNacconjugated antisense oligonucleotides which targets liver
hepatocytes, and reduces the therapeutic dose needed for
liver targets by approximately 10-fold.
 Compared to the nonLICA Apo(a)Rx Apo(a)-LRx is >30 times
more potent
Viney NJ et al Lancet 2016;388:2239-2253
Phase phase 1/2a trial of IONIS-APO(a)-LRx;
A LICA oligonucleotide targeting apolipoprotein(a)
Viney NJ et al Lancet 2016;388:2239-2253
Phase phase 1/2a trial of IONIS-APO(a)-LRx;
A LICA oligonucleotide targeting apolipoprotein(a)
Single Ascending Dose Study
Viney NJ et al Lancet 2016;388:2239-2253
Phase phase 1/2a trial of IONIS-APO(a)-LRx;
A LICA oligonucleotide targeting apolipoprotein(a)
Viney NJ et al Lancet 2016;388:2239-2253
Phase phase 1/2a trial of IONIS-APO(a)-LRx;
A LICA oligonucleotide targeting apolipoprotein(a)
-66%
-80%
-92%
Viney NJ et al Lancet 2016;388:2239-2253
Phase phase 1/2a trial of IONIS-APO(a)-LRx;
A LICA oligonucleotide targeting apolipoprotein(a)
Conclusion:
 >30 fold more potency than Apo(a)Rx allowing for very small injection doses
 Dose-dependent, durable, statistically significant reductions in Lp(a)
 Good tolerability profile: no ISRs or flu-like-symptoms (FLS)
 Supports increased dosing flexibility: weekly, monthly, quarterly, or less
frequently
Viney NJ et al Lancet 2016;388:2239-2253