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Targeting PCSK9 Expanding knowledge and targeting new frontiers John JP Kastelein, MD, PhD, FESC University of Amsterdam The Netherlands DISCLOSURES John JP Kastelein Professor Kastelein is a consultant for Akcea, AstraZeneca, CiVi Biopharma,


  1. Targeting PCSK9 Expanding knowledge and targeting new frontiers John JP Kastelein, MD, PhD, FESC University of Amsterdam The Netherlands

  2. DISCLOSURES John JP Kastelein Professor Kastelein is a consultant for Akcea, AstraZeneca, CiVi Biopharma, Corvidia, CSL Behring, Daiichi Sankyo, Draupnir, Esperion Therapeutics, Gemphire, Madrigal Pharma, Matinas Bio, The Medicines Company, NorthSea Therapeutics, Novartis, Novo, Regeneron, REGENXBIO, Staten Bio 2 ORION-3 for NLA Version 8.0

  3. Summary of Effects of PCSK9i Evolocumab  LDL-C by 59% down to a median of 30 mg/dl •  CV outcomes in patients on statin • • Safe and well-tolerated HR 0.85 (0.79-0.92) P<0.0001 Placebo 14,6 15 HR 0.80 (0.73-0.88) 12,6 59% reduction P<0.0001 KM Rate (%) at 3 Years P<0.00001 9,9 10 7,9 Absolute  56 mg/dl 5 Evolocumab (median 30 mg/dl, IQR 19-46 mg/dl) 0 CVD death, MI, CVD death, MI, stroke stroke, UA, cor revasc An Academic Research Organization of Sabatine MS et al. NEJM 2017;376:1713-22 Brigham and Women’s Hospital and Harvard Medical School

  4. LDL Cholesterol 2034 patients w/ baseline LDL-C<70 mg/dL 100 90 Placebo 80 (median 66 mg/dl, IQR 56-78 mg/dl) (median 1.7 mmol/L, IQR 1.4-2.0 mmol/L) LDL Cholesterol (mg/dl) 70 60 50 66% mean reduction (95%CI 62-69), P<0.00001 40 30 20 Evolocumab 10 (median 21 mg/dl, IQR 11.5-37 mg/dl) (median 0.5 mmol/L, IQR 0.3-1.0 mmol/L) 0 0 12 24 36 48 60 72 84 96 108 120 132 144 Weeks An Academic Research Organization of Giugliano RP et al. and Sabatine MS. JAMA Cardiol 2017;2:1385-91 Brigham and Women’s Hospital and Harvard Medical School

  5. Clinical Outcomes by Baseline LDL-C CVD, MI, stroke, UA, or cor revasc HR (95% CI) P interaction 0.85 (0.79-0.92) All Patients Baseline LDL-C <70 mg/dL 0.80 (0.60-1.07) 0.65 Baseline LDL- C ≥70 mg/ dL 0.86 (0.79-0.92) 0.4 1.0 2.5 CVD, MI, or stroke 0.80 (0.73-0.88) All Patients Baseline LDL-C <70 mg/dL 0.70 (0.48-1.01) 0.44 Baseline LDL- C ≥70 mg/ dL 0.81 (0.73-0.89) 0.4 1.0 2.5 EvoMab better Pbo better An Academic Research Organization of Giugliano RP et al. and Sabatine MS. JAMA Cardiol 2017;2:1385-91 Brigham and Women’s Hospital and Harvard Medical School

  6. Benefit of EvoMab Based on Multivessel Disease Multivessel Disease No Multivessel Disease 11% RRR 30% RRR 12.6% D 3.4% HR 0.89 HR 0.70 NNT 29 CV Death, MI, or Stroke (95% CI 0.58-0.84) (95% CI 0.79-1.00) P=0.055 P<0.001 9.2% 8.9% 7.6% Placebo D 1.3% NNT 78 Evolocumab P interaction =0.03 0 6 12 18 24 30 36 0 6 12 18 24 30 36 An Academic Research Organization of Months after Randomization Sabatine et al. Circ 2018;138:756-66 Brigham and Women’s Hospital and Harvard Medical School

  7. CV Death, MI or Stroke in Patients w/ & w/o Peripheral Artery Disease An Academic Research Organization of Bonaca MP et al. & Sabatine MS. Circulation 2018;137:338-50 Brigham and Women’s Hospital and Harvard Medical School

  8. Major Adverse Limb Events An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Bonaca MP et al. & Sabatine MS. Circulation 2018;137:338-50

  9. Conclusions 1. Evolocumab reliably reduces LDL-C by ~60% 2. Reduces risk of major vascular events in Pts w/ ASCVD already on statin • Confirms benefit from lowering LDL-C to <1 mM • Benefit grows over time 3. Largest absolute risk reductions in Pts w/ highest baseline risk & largest amount of athero • Diabetes, CKD • Closer to MI, multiple prior MIs, multivessel CAD • PAD An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School

  10. BACKGROUND & RATIONALE Safety & efficacy of inclisiran not known beyond 1-year In ORION-1: • 300mg inclisiran given on day 1 & 90 demonstrated safe lowering of LDL- C by ≥50% and up to 88% ─ with minimal variability and at least 6 -months persistence 1 • Subjects were followed up to 1-year Could ORION-3 extend the treatment period for ORION-1 inclisiran subjects to enable the assessment of long-term safety and efficacy? 1. Ray KK et al. N EnglJ Med 2017; 376:1430-1440 10 ORION-3 for NLA Version 8.0

  11. METHODS ORION-3 Group-1 baseline 1 characteristics (N = 290) Representative of a typical moderate/high-risk ASCVD population Age 63.3 (11.1) Mean years (SD) Male 188 (65%) N (%) Diabetes 70 (24%) N (%) Prior PCI 125 (43%) N (%) MI 104 (35%) N (%) CABG 47 (16%) N (%) Hypertension 193 (67%) N (%) Current statin use 232 (80%) N (%) PCSK9 Mean ng/dL( ± SD) 428.4 (128.5) LDL-C Mean mg/dL( ± SD) 130.1 (57.3) 1. Baseline for ORION-1 11 ORION-3 for NLA Version 8.0

  12. OBJECTIVES Investigate the long-term safety and efficacy of inclisiran Safety: Incidence of adverse events and laboratory changes Efficacy: LDL-C, PCSK9 and other lipid parameters on day 210 of ORION-3 LDL-C, PCSK9 over the time course of ORION-1 & 3 combined 12 ORION-3 for NLA Version 8.0

  13. METHODS Design of investigation Total ~3 years treatment & observation 13 ORION-3 for NLA Version 8.0

  14. RESULTS Excellent tolerability and safety Highly consistent profile throughout ORION-1 and ORION-3 over ~3 years • Injection site reactions infrequent, mild-moderate and transient • No LFT elevations considered related to inclisiran • No myalgias or CPK elevations considered related to inclisiran • No renal adverse events or thrombocytopenia considered related to inclisiran • One cerebrovascular accident death in ORION-3 related to underlying ASCVD 14 ORION-3 for NLA Version 8.0

  15. RESULTS Persistent and robust efficacy Group-1 primary endpoint: Percent change in LDL-C on day 210 of ORION-3 Day 210 change from baseline 1 ITT p-value - 51% < 0.001 Mean (SD) (28) All patients (N=290) - 64 mg/dL < 0.001 Mean(SD) (39) LDL-C - 56% < 0.001 Mean(SD) (18) Patients randomized to 300 mg 2 dose starting regimen (N = 61) - 73 mg/dL < 0.001 Mean (SD) (31) PCSK9 - 77% < 0.001 Mean(SD) (8) Non HDL-C - 43% < 0.001 Mean(SD) (24) HDL-C + 9% ns Mean(SD) (15) Triglycerides - 6% ns Mean(SD) (42) 1. Average 22 months from baseline at the start of ORION-1 15 ORION-3 for NLA Version 8.0

  16. RESULTS Long-term effect of 300 mg inclisiran on LDL-C Consistent lowering of LDL-C >50% with no loss of effect over ~3 years 16 ORION-3 for NLA Version 8.0

  17. POTENTIAL IMPLICATIONS What could this mean for ongoing blinded Phase III trials? Inclisiran expected to lower LDL- C ≥50% and MACE by ≥ 25% ORION-9 ORION-10 ORION-11 HeFH U.S.ASCVD EU ASCVD/RE N = 482 N = 1561 N = 1617 Baseline LDL-C 161 mg/dL 110 mg/dL 112 mg/dL Simulation using dose-PD response model 1 o endpoint: Day 510 % LDL reduction 54% 54% 54% Time-averaged % LDL-C reduction 51% 51% 51% LDL-C reduction calculated 82 mg/dL 56 mg/dL 57 mg/dL Estimated 5 year MACE RRR 1 44% 30% 31% 1. MACE relative risk reduction estimate assumes 50% of effect year-1; 100% of effect thereafter; based on Cholesterol Treatment Tr ialists’ (CTT) Collaboration ( Baigentat al, 2005) 17 ORION-3 for NLA Version 8.0

  18. 18 ORION-3 for NLA Version 8.0

  19. ORAL PCSK9 INHIBITION Promises and challenges of oral PCSK9 inhibition • A small molecule oral PCSK9i is expected to reduce costs and confer convenience to patients • A cost effective pricing will significantly reduce the barriers for patient access to PCSK9i • Development of small molecule PCSK9i has proven very challenging from a medicinal chemistry perspective • Draupnir Bio is developing the first orally available PCSK9 inhibitor 19 ORION-3 for NLA Version 8.0

  20. ORAL PCSK9 INHIBITION PCSK9 activity depends on heparan sulfate proteoglycans (HSPG) • In the absence of PCSK9, LDLR removes LDL particles by endocytosis • LDL is metabolized in lysosomes while LDLR recycles • PCSK9 binds to HSPG on hepatocytes and the PCSK9/HSPG complex hijacks LDLR for degradation 20 ORION-3 for NLA Version 8.0

  21. ORAL PCSK9 INHIBITION Removal of HSPG/blocking PCSK9/HSPG binding protects the LDL receptor • Enzymatic removal of heparan sulfate 5 min before PCSK9 injection, results in complete LDLR protection in the liver of mice. • mAb 5E11 restores PCSK9- Evolocumab: mAb 5E11: induced reductions in LDL uptake to a similar extent as evolocumab 21 ORION-3 for NLA Version 8.0

  22. ORAL PCSK9 INHIBITION Structure-based design of small molecule PCSK9i PCSK9/HSPG binding involves several residues known from PCSK9 LOF variants 1. PCSK9/HSPG 2. PCSK9/HSPG/LDLR complex PCSK9 LDLR HSPG Heparan sulfate Plasma R93C LOF variant confers 50% reduction in risk of CAD membrane Tang et al. Nature Commun 2017 3. LDL receptor degradation 22 ORION-3 for NLA Version 8.0

  23. ORAL PCSK9 INHIBITION Draupnir PCSK9i increases LDL uptake and acts in synergy with statins 23 ORION-3 for NLA Version 8.0

  24. ORAL PCSK9 INHIBITION Draupnir PCSK9i reduces cholesterol and plaque burden in mice 24 ORION-3 for NLA Version 8.0

  25. ORAL PCSK9 INHIBITION Clinical development of oral PCSK9i • Draupnir is moving lead compound towards first in-human trials • Lead compound has unique mechanism of action and may provide therapeutic benefits by conferring additional protection of the vascular endothelium 25 ORION-3 for NLA Version 8.0

  26. Conclusion Exciting times ahead! Acknowledgements: Thanks to the Medicines Company and Draupnir Bio for providing the data 26 ORION-3 for NLA Version 8.0

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