Novel strategies to lower Lp(a) What are the emerging insights & - - PowerPoint PPT Presentation

Novel strategies to lower Lp(a) What are the emerging insights & therapies?

Sotirios Tsimikas, MD, FACC, FAHA, FSCAI Director of Vascular Medicine Professor of Medicine University of California San Diego

EBAC Accredited symposium

Lp(a), a new lipid frontier in CV risk management & target for therapy August 29, 2020

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Disclosures

Named as co-inventor and receives royalties from patents owned by the University of California San Diego

• n oxidation-specific antibodies

Co-Founder Oxitope Inc and Kleanthi Diagnostics LLC Dual appointment at UCSD and Ionis Pharmaceuticals

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Genetics of LPA gene, Relationship to Plasminogen, Composition and Clinical Phenotypes of Lp(a)

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Tsimikas JACC 2017;69:692-711 Emdin et al JACC 2016;68:2761-72

There are over 40 isoforms of Lp(a) ranging from 1 to > 40 KIV2 repeats. Each person has 2 isoforms derived from each parent

Schmidt et al JLR 2016;57:1339-59

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Lp(a) Metabolism

Tsimikas et al JACC 2018;71:177-192

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Isis Pharmaceuticals Confidential

ASO (RNase H1) and siRNA Mechanisms for Lp(a) Therapy

◼ siRNA Mechanism ◼ RNase H1 Mechanism

Antisense Strand mRNA-Antisense Duplex RNase H1

DNA mRNA

Nucleus Cytoplasm Cell Membrane Cell Membrane Cytoplasm Nucleus Antisense Strand RNase H like nuclease DNA mRNA RISC Sense Strand siRNA Duplex

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Ionis/Akcea/Novartis – TQJ230 Phase 3 Arrowhead/Amgen – AMG 890 Phase 1 Silence Therapeutics – pre-clinical

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Antisense Drugs Target RNA Via Watson-Crick Base Pairing

RNase H1-mediated Degradation is One Antisense Mechanism

RNA Destruction

mRNA

ANTISENSE DRUG

TRANSCRIPTION

Gene

Prevents Formation of All Types of Protein

Less RNA = Less PROTEIN

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Early Insights into Antisense Mediated Lp(a) Lowering

Reduction in Lp(a) levels with ASO to apoB or apo(a)

Merki E et al. Circulation 2008;118:743–53 Merki E et al. JACC 2011;57:1611–2

ApoB ASO Apo(a) ASO

Apo(a) Mice saline Apo(a) Mice ASO control Apo(a) Mice ASO 144367 40 20

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• 40
• 60
• 80
• 100

Apo(a), % change from baseline

Weeks

**=P<0.004 ANOVA 2 4

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• 86

Lp(a), mg/dL

120 100 80 60 40 20 5 7 11 1 3 +2 +6 +10 9 *=P<0.001 ASO control Mipomersen

Lp(a), Mice On therapy

Off therapy

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Apo(a)

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IONIS-APO(a)Rx Phase 2 trial in Patients with Lp(a) > 50 mg/dL

Effects on Lp(a), OxPL and transendothelial migration

Placebo Cohort A (50-175 mg/dL) Cohort B (>175 mg/dL) Viney et al, Lancet 2016;388:2239-2253

Lp(a) OxPL-apoB OxPL-apo(a)

Transendothelial monocyte migration

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GalNAc Conjugated ASO to Apo(a) to Increase Potency

▪ Asialoglycoprotein Receptor (ASGPR) is abundantly expressed by hepatocytes

▪ 500,000 – 1 million copies per cell ▪ ASGPRs in all mammals share their specificity for Galactose and N-acetyl-galactosamine (GalNAc) terminated oligosaccharides

▪ ASGPR clears glycoproteins from circulation through receptor mediated endocytosis

▪ Ligand and receptor are taken up in clathrin- coated vesicles ▪ Upon endosome acidification, ligand is released and the receptor is recycled back to the cell surface ▪ Single ASGPR can internalize up to 250 ligand molecules during its lifetime

Prakash et al Nucleic Acids Res 2014 42:8796-807

Lp(a) ASO ED50 122 mg vs 4 mg 30-fold more potent

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Viney et al, Lancet 2016;388:2239-2253

IONIS-APO(a)-LRx (GalNac) Phase 1 trial is Subjects with Elevated Lp(a)

Dose-dependent Significant Reductions in Lp(a)

Up to 97% Reduction in Lp(a), with Mean Reduction of 85% Up to 99% Reduction in Lp(a), with Mean Reduction of 92%

Single Ascending Dose Multiple Ascending Dose

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Well tolerated with no safety concerns

Lp(a) (nmol/L) Mean % Change from Baseline (+/- SEM) Study Day

20 mg Placebo 80 mg 10 mg 40 mg 120 mg

Lp(a) (nmol/L) Mean % Change From Baseline (+/- SEM) Study Day

20 mg Placebo 10 mg 40 mg

Mean Lp(a) reductions: 10 mg= ↓ 68% 20 mg= ↓ 80% 40 mg= ↓ 92%

Viney et al Lancet 2016;388:2239-53

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AKCEA-APO(a)-LRx (TQJ230) Phase 2 Trial

Study Design and Endpoints

QW = every week; Q2W = every 2 weeks; Q4W = every 4 weeks; R = randomization; SC = subcutaneous.

*Cohorts (SC administration): 20 mg or placebo Q4W 40 mg or placebo Q4W 60 mg or placebo Q4W 20 mg or placebo Q2W 20 mg or placebo QW Treatment duration: 6-12 months

Five cohorts*, N per cohort=54, randomized 5:1 (45 active, 9 placebo)

≤4 weeks Screenin g 16 weeks follow up R The primary endpoint was the mean percent change in Lp(a) from baseline to week 25–27 depending on dose regimen Secondary endpoints included:

• Mean percent change in OxPL-apoB, OxPL-apo(a),

LDL-C, apoB and the percentage of patients reaching Lp(a) <50 mg/dL (<125 nmol/L)

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Tsimikas et al N Engl J Med 2020;382:244-55

AKCEA-APO(a)-LRx (TQJ230) Phase 2 Trial

98% of patients reached goals of <50 mg/dL (<125 nmol/L) at highest dose

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Tsimikas et al N Engl J Med 2020;382:244-55

Conclusions

• AKCEA-APO(a)-LRx Phase 2 Trial achieved its primary

endpoint and all of its secondary endpoints

• AKCEA-APO(a)-LRx significantly reduced Lp(a), OxPL-

apoB, OxPL-apo(a), LDL-C and apoB levels

• 98% of patients achieved Lp(a) levels ≤50 mg/dL at

the highest dose

• There were no safety concerns related to platelet

counts, liver function or renal function

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CVOT Targeting Lp(a) – HORIZONS

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Effect of various drugs on Lp(a) levels

Tsimikas JACC 2017;69:692-711

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Conclusion

• Since the discovery of Lp(a) in 1963, no specific therapeutic agents have

been approved, due to the difficulty in targeting hepatic production of apo(a)

• RNA therapeutics are ideally suited to reduce production of apo(a) in

hepatocytes and prevent assembly of Lp(a)

• Antisense oligonucleotides to apo(a) are highly effective in reducing Lp(a)

to non-atherogenic levels, with no safety signals in a phase 2 trial of treatment duration up to 1 yr

• The phase 3 HORIZONS trial with test the hypothesis that lowering Lp(a)

will lead to clinical benefit