ORION-1 Trial Inclisiran lowers LDL-C and PCSK9 irrespective of diabetes status without worsening glycemia Lawrence A Leiter, MD, FRCPC, FACP, FACE, FAHA St Michael s Hospital, Toronto 1
Presented on behalf of the Steering Committee Lead authors Principal investigator Chairman Members and national investigators Members Lawrence A Leiter, MD, FRCPC, FACP, FACE, FAHA Hwee Teoh, PhD Kausik K Ray, MBChB, MD, MPhil John JP Kastelein, MD, PhD, FESC Ulf Landmesser, MD, FESC Lawrence A Leiter, MD, FRCPC, FACP, FACE, FAHA R Scott Wright, MD, FACC, FESC, FAHA David Kallend, MBBS Peter Wijngaard, PhD 2
Disclosures for Lawrence A Leiter, MD Research grants Astra Zeneca, Amgen, Esperion, Kowa, Merck, Sanofi/Regeneron, The Medicines Company Advisory panels Astra Zeneca, Amgen, Merck, Sanofi/Regeneron 3
Major progress in ASCVD - but challenges remain PCSK9 inhibition is now a validated target for reducing LDL-C and ASCVD mab therapy requires 12-26 injections per year Adherence with PCSK9 mabs is not substantially better than that with statins 2 1. Sabatine MS et al. N Engl J Med. 2017;376:1713-1722 2. Hines D et al. J Am Coll Cardiol. 2017;69 (11 Suppl):159 Poor adherence and LDL-C variability are associated with poor outcomes 3 Approximately 9% of ASCVD risk is attributable to poor adherence 4 Limitations are most relevant in high risk patients 3. Bangalore S et al. J Am Coll Cardiol. 2015;65:1539-48 4. Chowdhury R et al. EHJ 2013;34:2940-8 4
Inclisiran: A novel agent to address unmet needs Inclisiran RNAi harnessing Viable option to inhibit PCSK9 and lower LDL-C 1 Synthetic sirna that inhibits PCSK9 synthesis in the liver 2 Phase I trial 300 mg inclisiran lowered LDL-C 50-60% for 84 days 3 1. Wittrup A, Lieberman J. Nat Rev Genet. 2015;16:543-52.. 2. Fitzgerald K et al. Lancet. 2014;383:60-68 3. Fitzgerald K et al. N Engl J Med. 2017;376:41-51 5
RNAi A natural process for inhibiting mrna Synthetic sirna dsrna Cleavage dicer Targeted gene silencing RISC Strand separation Complementary pairing mrna Natural process of RNA interference Cleavage mrna degradation 6
GalNAc-siRNA conjugate facilitates hepatic uptake Asialoglycoprotein receptor Expressed only by hepatocytes High rate of ligand uptake Inclisiran sirna conjugated to N-acetylgalactosamine GalNAc 3 Subcutaneous administration Targeted delivery to hepatocytes GalNAc-siRNA inclisiran conjugate ASGPR (ph>5) Hepatocyte cytoplasm Recycling ASGPR Clathrin-coated pit Endosome Clathrin-coated vesicle 7
Trial entry criteria Phase II dose-finding trial ASCVD LDL-C >70 mg/dl (1.8 mmol/l) 18 years old all patients on maximally tolerated statin ± other lipid-lowering Rx ASCVD risk equivalents LDL-C >100 mg/dl (2.6 mmol/l) ASCVD = atherosclerotic cardiovascular disease Ray KK et al. N Engl J Med. 2017;376:1430-1440 ClinicalTrials.gov NCT02597127. 8
Overall trial design Screening (Day -14 to Day -1) Placebo N=65 One dose starting regimen Given on day 1 200 mg N=60 300 mg N=61 500 mg N=65 Day 1 Stratified by country Rx Randomized (n=501) Primary evaluation: day 180 End of study visit: day 210 Extended evaluation: day 360 Placebo N=62 Two dose starting regimen Given on days 1 and 90 100 mg N=61 200 mg N=62 300 mg N=61 Ray KK et al. N Engl J Med. 2017;376:1430-1440 ClinicalTrials.gov NCT02597127 9
Overall trial results have been published Safety data No concerns Efficacy data All patients responded at 300 mg dose given 2x with significant LDL-C lowering Mean LDL-C at 6 months: 53% (absolute reduction 64 mg/dl) Maximum LDL-C at 6 months: 81% Future studies will have dosing at Day 1, Day 90 and every 180 days thereafter Ray KK et al. N Engl J Med 2017; 376:1430-1440 10
Analysis of patients without versus with diabetes Pre-specified protocol objective and methods To compare the impact of inclisiran in patients with and without diabetes at baseline on: PCSK9 levels Lipid profile Glycemic control 11
Patient baseline characteristics ITT One starting dose Two starting doses Without diabetes (n=223) With diabetes (n=27) without Diabetes (n=203) with Diabetes (n=43) Placebo (n=57) Inclisiran (n=166) Placebo (n=7) Inclisiran (n=20) Placebo (n=53) Inclisiran (n=150) Placebo (n=9) Inclisiran (n=34) Male (%) 61 69 86 60 59 67 22 65 Age (y) 63 65 61 69 64 66 61 63 A1C (%) 5.7 5.6 8.6 7.6 5.6 5.6 8.2 7.7 LDL-C (mg/dl) 120 119 91 110 110 120 127 119 PCSK9 (ng/ml) 403 417 402 377 411 406 378 404 hscrp (mg/l) 1.7 1.4 1.5 2.0 1.6 1.6 4.8 1.9 On statin (%) 74 83 86 80 85 83 56 77 Data are presented as % or median for the intention-to-treat population, which consisted of all participants who underwent randomization 12
PCSK9 levels similar lowering from Day 1-180 One starting dose Without diabetes (218) With diabetes (25) Placebo 200 mg 300 mg 500 mg Two starting doses Without diabetes (197) With diabetes (42) Placebo 100 mg 200 mg 300 mg LS mean % change in PCSK9 levels 0 19* -48-46 -55-59 -65-66 LS mean % change in PCSK9 levels 0-7 -51-65 -66-66 -69-71 *P = 0.0116 vs. group without diabetes; all others, P > 0.05 for the difference between participants with and without diabetes within each treatment arm at Day 180. 13
LDL-C levels similar lowering from Day 1-180 One starting dose Without diabetes (218) With diabetes (25) Placebo 200 mg 300 mg 500 mg Two starting doses Without diabetes (197) With diabetes (42) Placebo 100 mg 200 mg 300 mg LS mean % change in LDL-C levels 3-5 -28-28 -37-53 -41-46 LS mean % change in LDL-C levels 2-1.2-35 -37.2-43 -48.3-52 -55 Primary endpoint evaluation. P > 0.05 for the difference between participants with and without diabetes within each treatment arm at Day 180. 14
LDL-C lowering similar without versus with diabetes Placebo or inclisiran 300 mg given Day-1 One starting dose Placebo or inclisiran 300 mg given Day-1 and -90 Two starting doses 25 25 Mean percent change ± 95% CI 0-25 Diabetes, Placebo No diabetes, Inclisiran 300 mg No diabetes, Placebo 0-25 No diabetes, Placebo Diabetes, Placebo No diabetes, Inclisiran 300 mg -50-50 -75 Diabetes, Inclisiran 300 mg 0 30 60 90 120 150 180 Days from first treatment -75 Diabetes, Inclisiran 300 mg 0 30 60 90 120 150 180 Days from first treatment 15
HbA1c levels no differential change from Day 1-180 One starting dose Without diabetes (218) With diabetes (25) Placebo 200 mg 300 mg 500 mg Two starting doses Without diabetes (197) With diabetes (42) Placebo 100 mg 200 mg 300 mg LS mean % change in A1c levels 0.0 0.0 0.0 0.1-0.3-0.4-0.2-0.6 LS mean % change in A1c levels 0.1 0.0 0.1 0.1 0.0 0.0-0.3-0.3 P > 0.05 for the difference between participants with and without diabetes within each treatment arm at Day 180. 16
AE profile was similar in both groups Pre-specified safety population Without diabetes With diabetes Doses Treatment group N 1 AE 1 SAE Death Myalgia N 1 AE 1 SAE Death Myalgia 1 2 Placebo 57 72% 5% 0% 5% 7 71% 0% 0% 0% Inclisiran (200 to 500 mg) 166 75% 10% 1% 5% 20 75% 10% 0% 5% Placebo 53 81% 9% 0% 4% 9 89% 11% 0% 11% Inclisiran (100 to 300 mg) 150 79% 12% 1% 10% 34 71% 18% 0% 6% No unexplained or persistent elevations in any liver parameter considered related to inclisiran No symptomatic/clinically significant elevations of creatinine kinase in any inclisiran-treated group 17
Summary For the primary efficacy endpoint at 180 days, 300 mg inclisiran given at Day 1 and 90 Lowered LDL-C by >50% in persons with ASCVD or ASCVD-risk equivalents, regardless of whether they had diabetes or not Had no effect on glycemia Displayed no clinically important safety signals 18
Conclusions Inclisiran may represent an excellent alternative to monoclonal antibodies to PCSK9 in individuals both with and without diabetes Inclisiran is characterized by a much lower injection frequency and a clean safety profile to date, attributes that could help with therapeutic adherence and clinical efficacy for cardiovascular risk reduction 19