Safety and efficacy of inclisiran in South African patients at high cardiovascular risk: A subanalysis of the ORION phase III clinical trials
Authors:   Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa, Raal F , Ableson M ,   Vergelegen Mediclinic, Somerset West, Western Cape, South Africa, Blignaut S ,   Paarl Research Centre, Paarl, South Africa, Burgess L ,   Tread Research, Cardiology Unit, Department of Medicine, Tygerberg Hospital and Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa, Coetzer S ,   Accelerated Enrollment Solutions, Helderberg Clinical Research Centre, Somerset West, Western Cape, South Africa, Ebrahim I ,   Netcare Unitas Hospital, Centurion, Gauteng, South Africa, Gibbon A ,   Medical Affairs, Novartis, Waterfall City, Gauteng, South Africa, Jansen van Rensburg D ,   Park Medical Centre, Emalahleni, Mpumalanga, South Africa, Jaros M ,   Summit Analytical, Denver, Colo., USA, Lombard L ,   Kuilsriver Netcare Hospital, Cape Town, South Africa, van Nieuwenhuizen E ,   Accelerated Enrollment Solutions, Watermeyer Clinical Research Centre, Pretoria, South Africa, Pretorius M ,   Tiervlei Trial Centre, Cape Town, South Africa, van Tonder A ,   Medical Affairs, Novartis, Waterfall City, Gauteng, South Africa, Urbach D ,   Accelerated Enrollment Solutions, Helderberg Clinical Research Centre, Somerset West, Western Cape, South Africa
Published: June 2022

Background. Inclisiran significantly reduced low-density lipoprotein cholesterol (LDL-C) in individuals with heterozygous familial hypercholesterolaemia, established atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalents (type 2 diabetes, familial hypercholesterolaemia or a 10-year risk of a cardiovascular event ≥20%) in the ORION phase III clinical trials. Infrequent dosing at days 1, 90, 270 and 450 resulted in a mean LDL-C reduction of ~50%. A total of 298 participants from South Africa (SA) were enrolled. Local data are needed to support the use of inclisiran in the SA population, potentially addressing an unmet need for additional LDL-C-lowering therapies. Objectives. To analyse the ORION phase III trial data to assess the efficacy and safety of inclisiran in SA participants. Methods. ORION-9, 10 and 11 were randomised, double-blind, phase III trials. Participants were receiving maximally tolerated statins with or without other lipid-lowering therapies (excluding protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors). Participants were randomised 1:1 to inclisiran sodium 300 mg/284 mg (free acid) or placebo administered at days 1, 90, 270 and 450. The co-primary endpoints were the LDL-C percentage change from baseline to day 510 and the time-averaged percentage change in LDL-C from baseline after day 90 up to day 540. Key secondary endpoints included the absolute change in LDL-C from baseline to day 510, the time-averaged absolute change from baseline after day 90 up to day 540, and changes in other lipids and lipoproteins. Results. The mean age of the participants was 58.6 years (56% male). The mean LDL-C level at baseline was 3.6 mmol/L. At day 510, inclisiran reduced LDL-C levels by 54.2% compared with placebo (95% confidence interval (CI) –61.3 - –47.2; p<0.0001). The corresponding time-averaged reduction in LDL-C was 52.8% (95% CI –57.9 - –47.8; p<0.0001). Treatment-emergent adverse events at the injection site were more common with inclisiran compared with placebo (10.1% v. 0.7%); however, all were mild or moderate in nature and none were persistent. Conclusion. Inclisiran, given in addition to maximally tolerated standard lipid-lowering therapy, is effective and safe and results in robust reductions in LDL-C in SA patients at high cardiovascular risk.