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4. Efficacy and Safety of Lerodalcibep in Patients With or at High Risk of Cardiovascular Disease: A Randomized Clinical Trial

Author

Klug, Eric Q., Llerena, Sara, Burgess, Lesley J., Fourie, Nyda, Scott, Russell, Vest, Jeff, Caldwell, Kate, Kallend, David, and Stein, Evan A.

Abstract

IMPORTANCE: Recent changes in national and international lipid guidelines for reducing cardiovascular events recommend additional drugs, greater reductions, and lower targets for low-density lipoprotein cholesterol (LDL-C) if not attained with statins. The achievement of these targets with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has not yet been evaluated in a randomized clinical trial. OBJECTIVE: To evaluate the 52-week safety and efficacy of lerodalcibep, a small anti–PCSK9-binding protein, in patients with cardiovascular disease (CVD) or who are at very high or high risk of CVD and requiring addition LDL-C–lowering treatment. DESIGN, SETTING, AND PARTICIPANTS: This was a randomized, double-blind, placebo-controlled phase 3 trial. The trial was conducted at 66 clinics in 11 countries between April 23, 2021, and November 15, 2023. Individuals 18 years and older taking maximally tolerated statin therapy with LDL-C of 70 mg/dL or greater with CVD or 100 mg/dL or greater if at high risk of CVD were included. INTERVENTIONS: Patients were randomized 2:1 to monthly 1.2-mL subcutaneous lerodalcibep, 300 mg, or placebo for 52 weeks. MAIN OUTCOMES AND MEASURES: The safety analysis included all randomized patients. The co-primary efficacy end points were percent change from baseline in LDL-C at week 52 and the mean of weeks 50 and 52. Secondary efficacy outcomes included additional lipid apolipoprotein measures and achievement of guideline-recommended LDL-C targets. RESULTS: Of 922 randomized participants (mean [range] age, 64.5 [27-87] years; 414 [44.9%] female; mean [SD] baseline LDL-C, 116.2 [43.5] mg/dL), 811 (88%) completed the trial. The mean (SE) placebo-adjusted reduction in LDL-C with lerodalcibep by modified intention-to-treat (mITT) analysis was 56.2% (2.2%) at week 52 and 62.7% (1.9%) for the mean of weeks 50 and 52; 49.7% (2.4%) and 55.3% (2.2%) by ITT with imputation using a washout model, and 60.3% (2.3%) and 65.9% (1.9%) by per-protocol analysis at week 52 and the mean of weeks 50 and 52, respectively (P < .001 for all). With lerodalcibep, 555 of 615 participants (90%) achieved both a reduction in LDL-C of 50% or greater and recommended LDL-C targets during the study. Treatment-emergent adverse events were similar between lerodalcibep and placebo, except for injection site reactions. These occurred in 42 of 613 participants receiving lerodalcibep (6.9%) compared to 1 of 307 receiving placebo (0.3%), were graded mild or moderate, and did not result in higher discontinuation of treatment, at 26 of 613 (4.2%) and 14 of 307 (4.6%), respectively. Sporadic in vitro antidrug antibodies were detected, which had no impact on free PCSK9 or LDL-C–lowering efficacy. CONCLUSIONS AND RELEVANCE: In this trial, lerodalcibep, a novel anti-PCSK9 small binding protein, dosed monthly and stable at ambient temperatures significantly reduced LDL-C in patients with CVD or at high risk of atherosclerotic cardiovascular disease with a safety profile similar to placebo. These results support long-term use of lerodalcibep in patients with CVD or at high risk of CVD who are unable to achieve adequate LDL-C reduction while receiving maximal tolerated statins alone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04806893

Published
2024
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10. Long-term efficacy and safety of lerodalcibep in heterozygous familial hypercholesterolaemia: the LIBerate-HeFH trial.

Author

Raal, Frederick, Fourie, Nyda, Scott, Russell, Blom, Dirk, Basson, Matthys De Vries, Kayikcioglu, Meral, Caldwell, Kate, Kallend, David, Stein, Evan, and Investigators, LIBerate-HeFH

Subjects
LDL cholesterol, CHIMERIC proteins, RECOMBINANT proteins, CLINICAL trials, CARRIER proteins
Abstract

Background and Aims Lerodalcibep, a novel small recombinant fusion protein of a proprotein convertase subtilisin/kexin type 9 gene–binding domain (adnectin) and human serum albumin, demonstrated highly effective low-density lipoprotein cholesterol (LDL-C) reduction with monthly 300 mg in 1.2 mL subcutaneous dosing in Phase 2. In this global Phase 3 trial, the safety and efficacy of lerodalcibep were evaluated in heterozygous familial hypercholesterolaemia patients requiring additional LDL-C lowering. Methods Patients were randomized 2:1 to monthly subcutaneous injections of either lerodalcibep 300 mg or placebo for 24 weeks. The primary efficacy endpoints were the per cent change from baseline in LDL-C at Week 24 and the mean of Weeks 22 and 24. Results In 478 randomized subjects [mean age (range); 53 (18–80) years, 51.7% female, mean (SD) baseline LDL-C 3.88 (1.66) mmol/L], lerodalcibep reduced LDL-C, compared with placebo by an absolute amount of 2.08 (0.11) mmol/L [LS mean (SE); 95% confidence interval −2.30 to −1.87] with a percentage difference of −58.61 (3.25)% at Week 24 and by 2.28 (0.10) mmol/L (95% confidence interval −2.47 to −2.09) with a percentage difference of −65.0 (2.87)% at the mean of Weeks 22 and 24 (P <.0001 for all). With lerodalcibep, 68% of subjects achieved both a reduction in LDL-C ≥ 50% and the recommended European Society of Cardiology LDL-C targets during the study. Except for mild injection site reactions, treatment-emergent adverse events were similar between lerodalcibep and placebo. Conclusions Lerodalcibep, a novel anti-proprotein convertase subtilisin/kexin type 9 gene small binding protein dosed monthly as an alternative to monoclonal antibodies, significantly reduced LDL-C in subjects with heterozygous familial hypercholesterolaemia with a safety profile similar to placebo. [ABSTRACT FROM AUTHOR]

Published
2023
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12. EFFICACY AND SAFETY OF INCLISIRAN BY BASELINE BODY MASS INDEX: A POST HOC POOLED ANALYSIS OF THE ORION-9, ORION-10 AND ORION-11 PHASE III RANDOMIZED CONTROLLED TRIALS

Author

Leiter, Lawrence A, primary, Kallend, David G, additional, Koenig, Wolfgang, additional, Landmesser, Ulf, additional, Ray, Kausik K, additional, Schwartz, Gregory G, additional, Wright, R Scott, additional, Chiang, YannTong, additional, Orozco, Lorena Garcia Conde, additional, and Raal, Frederick J, additional

Published
2023
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17. †Efficacy and Safety of Inclisiran in Patients with Established Cerebrovascular Disease: Pooled Post hoc Analysis of the Phase 3 ORION-9, ORION-10, and ORION-11 Randomized Controlled Trials

Author

Ray, Kausik, primary, Kallend, David, additional, Landmesser, Ulf, additional, Leiter, Lawrence, additional, Schwartz, Gregory, additional, Conde, Lorena Garcia, additional, Jaros, Mark, additional, Raal, Frederick, additional, Wright, R Scott, additional, and Koenig, Wolfgang, additional

Published
2022
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18. †Efficacy and Safety of Inclisiran in Patients with Polyvascular Disease: Pooled Post hoc Analysis of the phase 3 ORION-9, ORION-10, and ORION-11 Randomized Controlled Trials

Author

Ray, Kausik, primary, Kallend, David, additional, Landmesser, Ulf, additional, Leiter, Lawrence, additional, Schwartz, Gregory, additional, Conde, Lorena Garcia, additional, Wright, R Scott, additional, Jaros, Mark, additional, Raal, Frederick, additional, and Koenig, Wolfgang, additional

Published
2022
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19. Supplement to: A highly durable RNAi therapeutic inhibitor of PCSK9.

Author

Fitzgerald, Kevin, White, Suellen, Borodovsky, Anna, Bettencourt, Brian, Strahs, Andrew, Clausen, Valerie, Wijngaard, Peter, Horton, Jay, Taubel, Jorg, Brooks, Ashley, Fernando, Chamikara, Kauffman, Robert S., Kallend, David, Vaishnaw, Akshay, and Simon, Amy

Published
2017

24. A Highly Durable RNAi Therapeutic Inhibitor of PCSK9

Author

Fitzgerald, Kevin, White, Suellen, Borodovsky, Anna, Bettencourt, Brian R., Strahs, Andrew, Clausen, Valerie, Wijngaard, Peter, Horton, Jay D., Taubel, Jorg, Brooks, Ashley, Fernando, Chamikara, Kauffman, Robert S., Kallend, David, Vaishnaw, Akshay, and Simon, Amy

Published
2017
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25. Inclisiran and cardiovascular events: a patient-level analysis of phase III trials.

Author

Ray, Kausik K, Raal, Frederick J, Kallend, David G, Jaros, Mark J, Koenig, Wolfgang, Leiter, Lawrence A, Landmesser, Ulf, Schwartz, Gregory G, Lawrence, David, Friedman, Andrew, Conde, Lorena Garcia, Wright, R Scott, and investigators, ORION Phase III

Subjects
CLINICAL trials, MAJOR adverse cardiovascular events, LDL cholesterol, STROKE
Abstract

Background Inclisiran, an siRNA administered twice-yearly, significantly reduced LDL cholesterol (LDL-C) in Phase III trials. Whether lowering LDL-C with inclisiran translates into a lower risk of cardiovascular (CV) events is not yet established. Methods and results Patient-level, pooled analysis of ORION-9, −10 and −11, included patients with heterozygous familial hypercholesterolaemia, atherosclerotic CV disease (ASCVD), or ASCVD risk equivalent on maximally tolerated statin-therapy, randomized 1:1 to receive 284 mg inclisiran or placebo on Days 1, 90, and 6-monthly thereafter for 18 months. Prespecified exploratory endpoint of major cardiovascular events (MACEs) included non-adjudicated CV death, cardiac arrest, non-fatal myocardial infarction (MI), and fatal and non-fatal stroke, evaluated as part of safety assessments using a standard Medical Dictionary for Regulatory Activities basket. Although not prespecified, total fatal and non-fatal MI, and stroke were also evaluated. Mean LDL-C at baseline was 2.88 mmol/L. At Day 90, the placebo-corrected percentage reduction in LDL-C with inclisiran was 50.6%, corresponding to an absolute reduction of 1.37 mmol/L (both P < 0.0001). Among 3655 patients over 18 months, 303 (8.3%) experienced MACE, including 74 (2.0%) fatal and non-fatal MIs, and 28 (0.8%) fatal and non-fatal strokes. Inclisiran significantly reduced composite MACE [OR (95% CI): 0.74 (0.58–0.94)], but not fatal and non-fatal MIs [OR (95% CI): 0.80 (0.50–1.27)] or fatal and non-fatal stroke [OR (95% CI): 0.86 (0.41–1.81)]. Conclusion This analysis offers early insights into the potential CV benefits of lowering LDL-C with inclisiran and suggests potential benefits for MACE reduction. These findings await confirmation in the larger CV outcomes trials of longer duration. [ABSTRACT FROM AUTHOR]

Published
2023
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31. Abstract 11033: Efficacy and Safety of Inclisiran by Baseline Glycemic Status: A Post Hoc Pooled Analysis of the ORION-10 and ORION-11 Phase III Randomized Controlled Trials

Author

Leiter, Lawrence A, primary, Kallend, David G, additional, Koenig, Wolfgang, additional, Landmesser, Ulf, additional, Raal, Frederick J, additional, Ray, Kausik K, additional, Schwartz, Gregory G, additional, chiang, yanntong, additional, Garcia Conde Orozco, Lorena, additional, and Wright, R S, additional

Published
2021
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32. Abstract 11143: Efficacy and Safety of Inclisiran by Baseline Body Mass Index: A Post Hoc Pooled Analysis of the ORION-9, ORION-10 and ORION-11 Phase III Randomized Controlled Trials

Author

Leiter, Lawrence A, primary, Kallend, David G, additional, Koenig, Wolfgang, additional, Landmesser, Ulf, additional, Ray, Kausik K, additional, Schwartz, Gregory G, additional, Wright, R S, additional, chiang, yanntong, additional, Garcia Conde Orozco, Lorena, additional, and Raal, Frederick J, additional

Published
2021
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34. Effect of inclisiran on lipids in primary prevention: the ORION-11 trial.

Author

Ray, Kausik K, Kallend, David, Leiter, Lawrence A, Raal, Frederick J, Koenig, Wolfgang, Jaros, Mark J, Schwartz, Gregory G, Landmesser, Ulf, Conde, Lorena Garcia, Wright, R Scott, and Investigators, ORION-11

Subjects
LIPIDS, LDL cholesterol, APOLIPOPROTEIN B, RNA, LIPOPROTEINS
Abstract

Aims Patients often require combination therapies to achieve LDL cholesterol (LDL-C) targets for the primary prevention of atherosclerotic cardiovascular disease. This study investigates the effect of inclisiran, a small interfering ribonucleic acid targeting hepatic proprotein convertase subtilisin/kexin type 9 production, in primary prevention patients with elevated LDL-C despite statins. Methods and results This pre-specified analysis of the placebo-controlled, randomized ORION-11 trial included 203 individuals at risk of, but without prior, cardiovascular events and LDL-C ≥2.6 mmol/L, despite maximally tolerated statins. Inclisiran 284 mg or placebo was administered on Days 1, 90, and thereafter every 6 months up to 540 days. Co-primary endpoints were percentage LDL-C change from baseline to Day 510 and time-adjusted change from baseline after Day 90 and up to Day 540. Key secondary endpoints included percentage and absolute changes in atherogenic lipoproteins. Safety was assessed over 540 days. The mean baseline (SD) LDL-C was 3.6 (1.5) mmol/L. At Day 510, the placebo-corrected LDL-C change with inclisiran was −43.7% [95% confidence interval (CI): −52.8 to −34.6] with a corresponding time-adjusted change of −41.0% (95% CI: −47.8 to −34.2); (P < 0.0001). The placebo-corrected absolute change in LDL-C at Day 510 with inclisiran was −1.5 mmol/L (95% CI: −1.8 to −1.2), with a respective time-adjusted change of −1.3 mmol/L (95% CI: −1.6 to −1.1). Inclisiran significantly lowered non-HDL cholesterol and apolipoprotein B (apoB) at Day 510 vs. placebo (P < 0.0001 for both), with a greater likelihood of attaining lipoprotein and apoB goals, and was well-tolerated except for mainly mild, treatment-emergent adverse events at the injection site. Conclusion Inclisiran was generally well-tolerated in primary prevention patients with elevated LDL-C, who derived significant reductions in atherogenic lipoprotein levels with twice-yearly maintenance dosing. [ABSTRACT FROM AUTHOR]

Published
2022
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38. ESTIMATED CARDIOVASCULAR BENEFITS OF INCLISIRAN IN PATIENTS WITH ATHEROSCLEROTIC CARDIOVASCULAR DISEASE

Author

Ray, Kausik Kumar, primary, Conde, Lorena Garcia, additional, Gunn, Laura H., additional, Raal, Frederick, additional, Wright, R. Scott, additional, Gosselin, Nathalie H., additional, Bonnefois, Guillaume, additional, Smith, Patrick F., additional, Leiter, Lawrence A., additional, Koenig, Wolfgang, additional, Schwartz, Gregory S., additional, Kallend, David G., additional, and Landmesser, Ulf, additional

Published
2021
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39. EFFICACY AND SAFETY OF INCLISIRAN IN PATIENTS WITH CHRONIC KIDNEY DISEASE - A POOLED ANALYSIS FROM THREE PHASE 3 CLINICAL TRIALS (ORION-9, -10 AND -11)

Author

Landmesser, Ulf, primary, Ray, Kausik K., additional, Raal, Frederick, additional, Conde, Lorena Garcia, additional, Jaros, Mark, additional, Koenig, Wolfgang, additional, Leiter, Lawrence A., additional, Schwartz, Gregory G., additional, Kallend, David G., additional, and Wright, R. Scott, additional

Published
2021
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41. Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome

Author

Schwartz, Gregory G., Olsson, Anders G., Abt, Markus, Ballantyne, Christie M., Barter, Philip J., Brumm, Jochen, Chaitman, Bernard R., Holme, Ingar M., Kallend, David, Leiter, Lawrence A., Leitersdorf, Eran, McMurray, John J.V., Mundl, Hardi, Nicholls, Stephen J., Shah, Prediman K., Tardif, Jean-Claude, and Wright, R. Scott

Published
2012
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44. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol

Author

Ray, Kausik K., primary, Wright, R. Scott, additional, Kallend, David, additional, Koenig, Wolfgang, additional, Leiter, Lawrence A., additional, Raal, Frederick J., additional, Bisch, Jenna A., additional, Richardson, Tara, additional, Jaros, Mark, additional, Wijngaard, Peter L.J., additional, and Kastelein, John J.P., additional

Published
2020
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45. Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia

Author

Raal, Frederick J., primary, Kallend, David, additional, Ray, Kausik K., additional, Turner, Traci, additional, Koenig, Wolfgang, additional, Wright, R. Scott, additional, Wijngaard, Peter L.J., additional, Curcio, Danielle, additional, Jaros, Mark J., additional, Leiter, Lawrence A., additional, and Kastelein, John J.P., additional

Published
2020
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46. Effect of inclisiran, the small-interfering RNA against proprotein convertase subtilisin/kexin type 9, on platelets, immune cells, and immunological biomarkers: a pre-specified analysis from ORION-1

Author

Landmesser, Ulf, primary, Haghikia, Arash, additional, Leiter, Lawrence A, additional, Wright, R Scott, additional, Kallend, David, additional, Wijngaard, Peter, additional, Stoekenbroek, Robert, additional, Kastelein, John Jp, additional, and Ray, Kausik K, additional

Published
2020
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47. Dalcetrapib Reduces Risk of New-Onset Diabetes in Patients With Coronary Heart Disease

Author

Schwartz, Gregory G., primary, Leiter, Lawrence A., additional, Ballantyne, Christie M., additional, Barter, Philip J., additional, Black, Donald M., additional, Kallend, David, additional, Laghrissi-Thode, Fouzia, additional, Leitersdorf, Eran, additional, McMurray, John J.V., additional, Nicholls, Stephen J., additional, Olsson, Anders G., additional, Preiss, David, additional, Shah, Prediman K., additional, Tardif, Jean-Claude, additional, and Kittelson, John, additional

Published
2020
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48. Association of high-density lipoprotein particle concentration with cardiovascular risk following acute coronary syndrome: A case-cohort analysis of the dal-Outcomes trial

Author

Salahuddin, Taufiq, primary, Kittelson, John, additional, Tardif, Jean-Claude, additional, Shah, Prediman K., additional, Olsson, Anders G., additional, Nicholls, Stephen J., additional, Leitersdorf, Eran, additional, Leiter, Lawrence A., additional, Kallend, David, additional, Black, Donald M., additional, Barter, Philip J., additional, Ballantyne, Christie M., additional, and Schwartz, Gregory G., additional

Published
2020
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