ESC 2024: New Data on Innovative Lipid-Targeting Therapies

The European Society of Cardiology Congress 2024 is scheduled in London from 30 August to 2 September. On 1 September, the third day of this prestigious event, notable discussions were held focusing on new data and strategies for lipid targeting in cardiovascular patients.

Dr. Lorenz Raber, a Cardiology Professor and Director of the Catheterisation Laboratory at Bern University Hospital, presented on PCSK9 inhibition for reducing low-density lipid (LDL) cholesterol. He highlighted the significance of novel lipid-targeting drugs and shared insights from various clinical trials.

"Human genetic studies have largely driven the development of PCSK9 inhibition, leading to the identification of at least four key mechanisms in a relatively short span," Raber mentioned. He proceeded to outline four strategies for PCSK9 inhibition: monoclonal antibodies (mAbs) like alirocumab and evolocumab, small interfering RNA (siRNA) such as inclisiran, oral cyclic small molecule inhibitors like MK-0616, and gene editing.

Inclisiran, marketed as Leqvio by Novartis, and mAbs like alirocumab (Praluent) and evolocumab (Repatha) from Regeneron Therapeutics and Amgen, respectively, were specifically discussed. Raber elaborated that mAbs, typically administered subcutaneously every two to four weeks, can lower LDL-C levels by 60%. Leqvio, approved in 2021 for biannual injections, provides LDL reduction of 45-50%.

MSD's MK-0616 (enlicitide chloride), an oral daily medication, promises around a 60% reduction in LDL levels. A Phase III trial is on the horizon, with potential approval by 2027.

Discussing the effects of mAbs on plaque regression, Raber pointed out that Praluent and Repatha combined with high-intensity statin therapy can reduce plaque by 2% per year at the vessel level. He noted that evaluating the therapy at the lesion level is also crucial for patient outcomes.

Raber referred to an analysis of the PACMAN-AMI trial, which examined lesion-level effects of LDL-C-lowering therapy in acute myocardial infarction (AMI) patients. The study observed a 2% reduction at the vessel level, a 5% reduction at the lesion level, and a 10% reduction at the narrowest part, known as the minimum lumen area (MLA), in the Praluent group compared to the placebo group.

He introduced a new concept termed "strike strong and early in acute coronary syndrome (ACS)," supported by results from the EVOPACS and PACMAN-AMI trials. Early administration of mAbs, in addition to statins, can reduce LDL levels by 80%, he noted. He emphasized the importance of results from the EVOLVE-MI study, an open-label trial enrolling 4,000 patients to further understand early Repatha administration.

The legacy effect, which examines the impact of discontinuing a drug, was also discussed. Raber referred to the ODYSSEY trial, which showed significant cardiovascular event reduction with eight months of Praluent exposure, and the FOURIER OLE study, which demonstrated better cardiovascular outcomes in patients who received early Repatha treatment.

Looking ahead, three significant trials—ORION-4, VICTORION-2-PREVENT, and VICTORION-1-PREVENT—are currently evaluating Leqvio's clinical outcomes against a placebo in various patient groups.

Regarding gene editing, Raber discussed the VERVE 101 study, which achieved a 55% reduction in LDL levels with the highest dose in ten high-risk familial hypercholesterolemia patients. Although there were temporary safety concerns and three serious adverse events, these were deemed consistent with the high-risk patient group, allowing the study to continue.

Raber concluded by stating that the field of PCSK9 inhibition is promising in reducing atherosclerosis and associated risks. Advances in genetic research have enabled the rapid development of PCSK9-targeting therapies, paving the way for personalized LDL-lowering strategies in clinical practice.

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