Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol (ORION-10 and ORION-11)

Authors, Journal, Affiliations, Type, DOI

• Kausik K. Ray, R. Scott Wright, David Kallend, Wolfgang Koenig, Lawrence A. Leiter, Frederick J. Raal, Jenna A. Bisch, Tara Richardson, Mark Jaros, Peter L.J. Wijngaard, John J.P. Kastelein, for the ORION-10 and ORION-11 Investigators
• N Engl J Med 2020; 382:1507–19 (published online March 18, 2020)
• Imperial College London; Mayo Clinic; the Medicines Company (Zurich/Parsippany); Deutsches Herzzentrum München; University of Toronto; University of the Witwatersrand (Johannesburg); University of Amsterdam
• Phase 3, double-blind, placebo-controlled, parallel-group RCTs (two separate trials)
• Sponsored by the Medicines Company
• DOI: 10.1056/NEJMoa1912387

Overview

ORION-10 and ORION-11 are twin Phase 3 RCTs establishing the efficacy and safety of inclisiran — a GalNAc-conjugated siRNA targeting hepatic PCSK9 mRNA — in 3,178 high-risk patients with LDL-C elevation on maximally tolerated statin therapy. Inclisiran 284 mg SC administered on day 1, day 90, and every 6 months thereafter reduced LDL-C by approximately 50–54% versus placebo over 540 days in both trials, with consistent effects across all subgroups. Safety was comparable to placebo except for mild injection-site reactions, with no excess liver, renal, or haematologic toxicity and no difference in deaths or cancer. The twice-yearly dosing schedule — made possible by intrahepatic RISC binding providing durable PCSK9 mRNA silencing after plasma clearance within 24–48 hours — represents a major adherence advantage over daily pills or biweekly injections.

Keywords

Inclisiran, siRNA, PCSK9, LDL cholesterol, GalNAc, RNA interference, lipid-lowering therapy, atherosclerotic cardiovascular disease, familial hypercholesterolaemia, injection, statin add-on

Key Takeaways

Background and Rationale

• Circulating PCSK9 protein binds and promotes lysosomal degradation of the LDL receptor; PCSK9 monoclonal antibodies (evolocumab, alirocumab) block this process and reduce LDL-C by ~60%, validated in large CVOTs (FOURIER, ODYSSEY Outcomes)
• Inclisiran uses RNA interference rather than protein-level antagonism: a synthetic double-stranded siRNA cleaves PCSK9 mRNA inside hepatocytes, reducing PCSK9 protein synthesis at the source
• GalNAc conjugation provides hepatocyte-selective uptake via the asialoglycoprotein receptor (ASGPR), minimising off-target delivery
• Phase II (ORION-1): 300 mg inclisiran → ~52.6% LDL-C reduction at 180 days; at 360-day follow-up, LDL-C reduction persisted, suggesting a twice-yearly maintenance dosing schedule

Mechanism of Inclisiran

• Structure: Chemically synthesised double-stranded siRNA (guide strand + passenger strand) with triantennary GalNAc conjugated to enable hepatocyte-selective ASGPR binding
• Pharmacokinetics: Peak plasma levels ~4 hours post-injection; cleared from plasma within 24–48 hours; no plasma accumulation
• Intrahepatic mechanism: After ASGPR-mediated endocytosis, siRNA escapes to the cytoplasm and loads into the RNA-induced silencing complex (RISC); the RISC-bound guide strand catalytically cleaves multiple copies of PCSK9 mRNA → sustained PCSK9 protein synthesis reduction
• Duration: RISC complex is stable intracellularly → LDL-C-lowering effect persists months after plasma clearance; reversal rate ~2%/month if injections discontinued (effects may persist up to ~2 years)
• Approved dose: 284 mg SC (equivalent to 300 mg inclisiran sodium) — dose confirmed in ORION-1

Study Design

• Two separate Phase 3 RCTs with identical protocols, conducted in parallel
• ORION-10: United States; adults with established ASCVD (prior MI, stroke, symptomatic PAD); LDL-C ≥70 mg/dL on max tolerated statin ± other LLD
• ORION-11: Europe and South Africa; adults with ASCVD or ASCVD risk equivalent (type 2 diabetes, HeFH, or 10-year CVD risk ≥20% by Framingham); LDL-C ≥70 mg/dL (ASCVD) or ≥100 mg/dL (risk equivalent) on max tolerated statin
• Randomisation 1:1 to inclisiran 284 mg SC vs matching placebo on days 1, 90, 270, and 450; end-of-trial visit day 540
• Co-primary endpoints: (1) placebo-corrected % change in LDL-C from baseline to day 510; (2) time-adjusted % change in LDL-C from baseline after day 90 through day 540

Participant Characteristics

• ORION-10: n=1,561 (781 inclisiran/780 placebo); mean baseline LDL-C 104.7 mg/dL; 89.2% on statin (68.0% high-intensity); 9.9% on ezetimibe; 11% HeFH; higher diabetes/hypertension than ORION-11
• ORION-11: n=1,617 (810/807); mean baseline LDL-C 105.5 mg/dL; 94.7% on statin (78.6% high-intensity); 7.1% on ezetimibe; 12.6% in risk-equivalent category (65% diabetes, 14.8% HeFH, 20.2% high-risk Framingham)
• Trial completion: 90.6% (ORION-10) and 95.2% (ORION-11) at day 540; 2,166 person-years of inclisiran exposure; 6,075 total inclisiran injections

Efficacy — Primary Endpoints

Efficacy — Key Secondary Endpoints (at day 510)

• Triglycerides, Lp(a): reduced in both trials
• HDL-C: increased in both trials
• Consistent effect across all prespecified subgroups (age, sex, BMI, race, diabetes, metabolic syndrome, statin intensity, renal function, risk category, geographic region)

Pharmacodynamic Pattern

• LDL-C reductions were stable throughout the dosing interval — inclisiran group maintained consistent reductions with minimal within-patient variability between trough and peak measurements (in contrast to wide variability in the placebo group)
• PCSK9 levels increased over time in the placebo group (progressive increase from baseline) but decreased in nearly all inclisiran patients — confirming consistent hepatic PCSK9 mRNA silencing

Safety (540 days, 6,075 injections)

• Overall adverse events: similar inclisiran vs placebo (73.5% vs 74.8% ORION-10; 82.7% vs 81.5% ORION-11)
• Injection-site adverse events (ISAEs): More common with inclisiran: ORION-10 2.6% vs 0.9%; ORION-11 4.7% vs 0.5%; majority mild (mild reaction excess: 0.8 pp and 2.4 pp respectively); none severe or persistent
• Liver function, renal function, CK, hsCRP, platelet count: Similar between inclisiran and placebo groups in both trials
• Deaths: 12 (1.5%) inclisiran vs 11 (1.4%) placebo (ORION-10); 14 (1.7%) vs 15 (1.9%) (ORION-11) — no difference
• Cancer: Incidence of cancer-related deaths and new/worsening/recurrent cancer: low and similar in both groups
• Serious adverse events: 22.4% vs 26.3% (ORION-10); 22.3% vs 22.5% (ORION-11)
• Antidrug antibodies: Detected in 2.0–2.5% of post-treatment samples; consistent with assay background rate (not drug-induced); low titer, often transient; not associated with any change in pharmacologic or clinical variables; no treatment-boosted antibodies

Exploratory Cardiovascular Endpoint (non-adjudicated, underpowered)

• MedDRA-defined cardiovascular basket (cardiac death, cardiac arrest, nonfatal MI, stroke):
  • ORION-10: 7.4% inclisiran vs 10.2% placebo
  • ORION-11: 7.8% inclisiran vs 10.3% placebo
• Directionally consistent favorable trend; insufficient power to draw conclusions; ORION-4 CVOT (n=15,000; 5 years; HPS-4/TIMI 65) ongoing to address this

Adherence Rationale

• Poor long-term adherence to oral lipid-lowering therapy is common and associated with higher CV event rates (Khunti 2018 JAMA Netw Open; Rodriguez 2019 JAMA Cardiol)
• HCP-administered twice-yearly SC injection eliminates daily medication burden and self-injection dependence — may improve real-world persistence compared to daily statins, biweekly PCSK9 mAbs, or biannual self-injected inclisiran
• A reversible effect (~2%/month off therapy) provides a safety margin: even without further injections, the effect can persist ~2 years — important for patients who miss doses

Limitations of the Document

• No cardiovascular outcomes data: CVOT (ORION-4) was ongoing at time of publication; LDL-C lowering efficacy does not guarantee MACE reduction without a direct outcomes trial
• Exploratory CV endpoint non-adjudicated and underpowered — trend favourable but not statistically definitive
• 18-month follow-up (540 days) only; long-term safety beyond 18 months not reported in this paper
• ORION-11 predominantly European white population; broader racial/ethnic generalizability limited
• No head-to-head comparison against evolocumab or alirocumab; slightly lower LDL-C reduction (~50% vs ~60% for PCSK9 mAbs)
• Fixed 6-monthly dosing — no dose-titration studied in Phase 3; all patients received same dose regardless of LDL-C achieved

Key Concepts Mentioned

• concepts/PCSK9-Inhibitors — inclisiran is the siRNA modality of PCSK9 inhibitor class; mAb comparators evolocumab and alirocumab
• concepts/Lipid-Gene-Therapy — inclisiran as the siRNA end of the RNA therapeutics spectrum; contrast with base editing (VERVE-102) for permanent genomic inactivation
• concepts/Dyslipidemia-Management — stepwise LDL-C lowering; inclisiran as statin add-on
• concepts/Familial-Hypercholesterolemia — HeFH enrolled in both trials; COR 2a in FH patients not at goal

Key Entities Mentioned

• entities/Inclisiran — the drug studied; ORION-10/11 are the Phase 3 efficacy/safety trials
• entities/Evolocumab and entities/Alirocumab — mAb comparator class context

Wiki Pages Updated

• wiki/sources/inclisiran-orion-nejm-2020.md — created (this file)
• wiki/entities/Inclisiran.md — updated with full ORION-10/11 Phase 3 data
• wiki/concepts/PCSK9-Inhibitors.md — added ORION-10/11 data to Inclisiran section
• wiki/sourceindex.md — added entry
• wiki/wikiindex.md — added Inclisiran entity entry; updated FH concept entry date
• log.md — new entry at top