ORION-10

Purpose: to evaluate the safety and efficacy of inclisiran, a drug in the siRNA class, in patients with ASCVD and high LDL-C.

Trial Design: 145 sites. N=1561. 18-month follow-up. Phase 3, placebo-controlled, double-blinded study; Patients randomized 1:1 to inclisiran 300 mg or placebo. Inclisiran dosed initially, then at 3 months, and then twice a year and maximally tolerated statins.

Co-primary Endpoints: % LDL-C change from baseline at day 510 and avg. % change from day 90 to day 540.

Results: Twice-yearly inclisiran injections safely reduced LDL-C in ASCVD patients with high LDL-C while on maximum tolerated statin dose.

Recommended

• ORION-10 Abstract
• R. Scott Wright's presentation slides (PDF)
• Discussant slides (PDF)

Related Science

• Effect of an siRNA Therapeutic Targeting PCSK9, Circulation 2018
• ORION-1 Trial: Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol, New England Journal of Medicine, 2017

Background: Atherosclerosis cardiovascular disease (ASCVD) remains the leading cause of death globally. Lipid lowering with life style modifications and statin is cornerstone of treatment for ASCVD. Adjunctive therapy with ezetimibe and PCSK9 inhibitor are adjunctive strategies to reduce LDL-C. Inclisiran is a small interfering RNA therapeutic that inhibits production of PCSK9 in the liver, and offers a novel modality to further reduce LDL-C in patients at high ASCVD risk after treatment with statins and other agents.

Purpose: The goal of ORION 10 is to assess efficacy and safety of Inclisiran 300 mg compared to placebo in a high risk population of ASCVD subjects using an 18-month placebo controlled trial.

Key Findings:

• Highly significant lowering of LDL-C relative to placebo
• No evidence of liver, kidney, muscle or platelet toxicity
• No difference in serious adverse between Inclisiran group and Placebo

Impression: Twice-a-year injectable, RNAi (Inclisiran) lowered LDL-C by ≥50% safely.

Primary Endpoints Results:

• Percentage Change in LDL-C from Baseline to Day 510
  • Inclisiran- Imputed (-51%)
  • Placebo- Imputed (+1%)
  • Difference- Imputed (-52%)

Secondary Endpoints Results:

• Time-adjusted Percentage Change in LDL-C Levels from Baseline after Day 90 and up to Day 540
  • Inclisiran- Imputed (-51%)
  • Placebo- Imputed (+3%)
  • Difference- Imputed (-54%)

Safety Endpoint:

• Treatment emergent adverse event (TEAE)
• Patients with at least one TEAE- Inclisiran (74%), Placebo (75%)
• Diabetes Mellitus- Inclisiran (15%), Placebo (14%)
• Hypertension- Inclisiran (5%), Placebo (5%)
• Back Pain- Inclisiran (5%), Placebo (5%)
• Bronchitis- Inclisiran (6%), Placebo (4%)
• Upper respiratory tract infection- Inclisiran (5%), Placebo (5%)
• Dyspnea- Inclisiran (5%), Placebo (4%)

Injection site Adverse Events

• Reaction, erythema, rash, pruritus, hypersensitivity- Inclisiran 20 (2.7%), Placebo 7 (0.9%)
  • Mild- Inclisiran 13 (1.7%), Placebo 7 (0.9%)
  • Moderate- Inclisiran7 (0.8%), Placebo 0
  • Injection site pain- Inclisiran 25 (3.1%), Placebo 4 (0.5%)
     
• Liver, kidney, muscle and platelet toxicity
  • Abnormal liver function- Inclisiran 15 (1.9%), Placebo 13 (1.7%)
  • Abnormal kidney function (creatinine >2 mg/dL)- Inclisiran 30 (3.9%), Placebo 30 (3.9%)
  • Signs of muscle damage (CK>5x ULN)- Inclisiran 11 (1.4%), Placebo 10 (1.3%)
  • Platelets count <75x109/L- Inclisiran1 (0.1%), Placebo 0
     
• Serious adverse events
  • All cause death Inclisiran 12 (1.5%), Placebo 11 (1.4%)
  • Cardiovascular death- Inclisiran 7 (0.9%), Placebo 5 (0.6%)
  • Cancer- Inclisiran 1 (0.1%), Placebo 3 (0.4%)
  • New, worsening or recurrent malignancy- Inclisiran 26 (3.3%), Placebo 26 (3.3%)
     
• Pre-specified exploratory cardiovascular endpoint
  • Cardiovascular death- Inclisiran 7 (0.9%), Placebo 5 (0.6%)
  • Fatal or non-fatal MI or stroke- Inclisiran 32 (4.1%), Placebo 26 (3.3%)

Trial Design — A randomized, phase 3, placebo-controlled, double blind, parallel assignment randomized clinical trial to evaluate the effect of 300 mg of Inclisiran sodium given as subcutaneous injections in subjects with ASCVD and elevated LDL-C.

1. Inclisiran sodium 300 mg given as subcutaneous injections
2. Placebo

Trial Population:

• 1561 participants (18 years and older) with stable ASCVD and elevated LDL-C (≥ 70 mg/dL) despite maximum tolerated oral statin therapy were randomized in a 1:1 fashion to Inclisiran sodium 300 mg (administered at Day 1, Day 90, Day 270 and Day 450) or placebo administered at same interval.
• Median age was 66 years with majority male
• Coronary heart disease was present in >90%; between 10-20% had prior cerebrovascular disease or peripheral arterial disease. Diabetes was present in approximately 45%.
• Mean baseline LDL-C was 110 mg/dL, >90% received statins, >80% received high-intensity statins and 10% were on ezetimibe

Primary Endpoints

• Percent change from baseline in LDL-C at Day 510
• Time-adjusted average percentage change from baseline in LDL-C between Day 90 up to Day 540

Secondary Endpoints

• Mean absolute change in LDL-C at Day 510
• Time averaged absolute reduction in LDL-C from baseline between Day 90 up to Day 540
• Changes in other lipids and lipoproteins

Safety Endpoints

• Treatment emergent adverse event (TEAE) (diabetes mellitus, hypertension, back pain, bronchitis, upper respiratory tract infection, dyspnea)
• Injection site Adverse Events (reaction, erythema, rash, pruritus, hypersensitivity, injection site pain)
• Liver, kidney, muscle and platelet toxicity
• Serious adverse events (all cause, cardiovascular death, cancer, new, worsening or recurrent malignancy)

Sponsor

• The Medicines Company