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 1

Disclosures 2 Named as co-inventor and receives royalties from patents owned by the University of California San Diego on oxidation-specific antibodies Co-Founder Oxitope Inc and Kleanthi Diagnostics LLC Dual appointment at UCSD and Ionis Pharmaceuticals 2

Genetics of LPA gene, Relationship to Plasminogen, Composition and Clinical Phenotypes of Lp(a) 3 There are over 40 isoforms of Lp(a) ranging from 1 to > 40 KIV 2 repeats. Each person has 2 isoforms derived from each parent Schmidt et al JLR 2016;57:1339-59 Tsimikas JACC 2017;69:692-711 Emdin et al JACC 2016;68:2761-72 3

Lp(a) Metabolism Tsimikas et al JACC 2018;71:177-192 4

ASO (RNase H1) and siRNA Mechanisms for Lp(a) Therapy Arrowhead/Amgen – AMG 890 Phase 1 Ionis/Akcea/Novartis – TQJ230 Phase 3 Silence Therapeutics – pre-clinical 5 ◼ RNase H1 Mechanism ◼ siRNA Mechanism siRNA Duplex Nucleus Cell Membrane Cytoplasm RNase H1 RISC Sense Strand RNase H like Antisense nuclease Cell Strand Membrane mRNA mRNA-Antisense Duplex mRNA DNA Antisense Strand DNA Nucleus Cytoplasm Isis Pharmaceuticals Confidential 5 5

Antisense Drugs Target RNA Via Watson-Crick Base Pairing RNase H1-mediated Degradation is One Antisense Mechanism Gene ANTISENSE DRUG mRNA Prevents Formation of All Types of Protein TRANSCRIPTION RNA Destruction Less RNA = Less PROTEIN 6

Early Insights into Antisense Mediated Lp(a) Lowering Reduction in Lp(a) levels with ASO to apoB or apo(a) Apo(a), % change from baseline ApoB ASO Apo(a) ASO 40 Apo(a) Mice saline Lp(a), Mice Apo(a) Mice ASO control 120 20 Apo(a) Mice ASO 144367 Apo(a) -20 Lp(a), mg/dL 100 0 80 0 ASO control 0 2 4 -40 Mipomersen 60 * -60 40 -80 * * =P<0.001 * -76 20 ** -100 * * -86 * * * ** =P<0.004 ANOVA * 0 0 1 3 5 7 9 11 +2 +6 +10 Weeks Off therapy On therapy Merki E et al. Circulation 2008;118:743 – 53 Merki E et al. JACC 2011;57:1611 – 2 7

IONIS-APO(a) Rx Phase 2 trial in Patients with Lp(a) > 50 mg/dL Effects on Lp(a), OxPL and transendothelial migration Lp(a) OxPL-apoB OxPL-apo(a) Transendothelial monocyte migration Cohort A (50-175 mg/dL) Cohort B (>175 mg/dL) Placebo Viney et al, Lancet 2016;388:2239-2253 8

GalNAc Conjugated ASO to Apo(a) to Increase Potency ▪ Asialoglycoprotein Receptor (ASGPR) is abundantly expressed by hepatocytes Lp(a) ASO ▪ 500,000 – 1 million copies per cell ED 50 122 mg vs 4 mg 30-fold more potent ▪ 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 Viney et al, Lancet 2014 42:8796-807 2016;388:2239-2253 9

IONIS-APO(a)-L Rx (GalNac) Phase 1 trial is Subjects with Elevated Lp(a) Dose-dependent Significant Reductions in Lp(a) Up to 97% Reduction in Lp(a), Up to 99% Reduction in Lp(a), with Mean Reduction of 85% with Mean Reduction of 92% Single Ascending Dose Multiple Ascending Dose Mean % Change From Baseline (+/- SEM) Mean % Change from Baseline (+/- SEM) Lp(a) (nmol/L) Lp(a) (nmol/L) Study Day Study Day Placebo 10 mg 20 mg 40 mg 80 mg 120 mg Placebo 10 mg 20 mg 40 mg ▪ Mean Lp(a) reductions: Well tolerated with no safety 10 mg= ↓ 68% concerns 20 mg= ↓ 80% 40 mg= ↓ 92% Viney et al Lancet 2016;388:2239-53 10

AKCEA-APO(a)-L Rx (TQJ230) Phase 2 Trial Study Design and Endpoints ≤4 16 weeks follow up Treatment duration: 6-12 months weeks Screenin g R Five cohorts*, The primary endpoint was the mean percent change in N per cohort=54, randomized Lp(a) from baseline to week 25 – 27 depending on dose 5:1 regimen (45 active, 9 placebo) *Cohorts (SC administration): Secondary endpoints included: • Mean percent change in OxPL-apoB, OxPL-apo(a), 20 mg or placebo Q4W LDL-C, apoB and the percentage of patients reaching 40 mg or placebo Q4W Lp(a) <50 mg/dL (<125 nmol/L) 60 mg or placebo Q4W 20 mg or placebo Q2W 20 mg or placebo QW QW = every week; Q2W = every 2 weeks; Q4W = every 4 weeks; R = randomization; SC = subcutaneous. Tsimikas et al N Engl J Med 2020;382:244-55 11

AKCEA-APO(a)-L Rx (TQJ230) Phase 2 Trial 98% of patients reached goals of <50 mg/dL (<125 nmol/L) at highest dose 12 Tsimikas et al N Engl J Med 2020;382:244-55

Conclusions • AKCEA-APO(a)-L Rx Phase 2 Trial achieved its primary endpoint and all of its secondary endpoints • AKCEA-APO(a)-L Rx 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 13

CVOT Targeting Lp(a) – HORIZONS 14

Effect of various drugs on Lp(a) levels 15 Tsimikas JACC 2017;69:692-711 15

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 16