On the third day of the ESC Congress European Society of Cardiology (ESC) Congress (1 September), several discussions centred on the latest data on approaches for targeting lipids in patients with cardiovascular disorders.

Dr. Lorenz Raber, professor of Cardiology and Director of the Catheterisation Laboratory in Bern University Hospital, focused on PCSK9 inhibition for the lowering of low density lipid (LDL) cholesterol, while outlining novel lipid-targeting drugs and discussing data from multiple clinical trials.

“PCSK9 inhibition was largely driven by human genetic studies…and in a very short time frame at least four important targets [mechanisms] were developed”, Raber said in the opening statements of his presentation. Raber reviewed four strategies for PCSK9 inhibition; monoclonal antibodies (mAbs) (such as alirocumab and evolocumab), small interfering RNA (siRNA) (such as inclisiran), oral cyclic small molecule inhibitors (such as MK-0616), and gene editing.

Inclisiran is marketed as Leqvio by Novartis, while alirocumab and evolocumab are marketed as Praluent and Repatha, by Regeneron Therapeutics and Amgen, respectively.

Evidence for mAbs to lower LDL

Raber initially outlined that with mAbs—which are administered subcutaneously every two to four weeks—LDL-C can be robustly lowered by 60%. Leqvio, which received approval for twice-yearly injections in 2021, achieves LDL lowering of 45-50%.

MSD’s MK-0616 (enlicitide chloride), a daily oral drug can achieve a relatively high LDL lowering of 60%. A Phase III trial for the drug is planned and a potential approval decision is anticipated in 2027.

Raber went on to discuss mAbs, and in particular their effect on plaque regression. Praluent and Repatha in addition to high intensity statin therapy reduce plaque per year by 2% at the vessel level analysis, said Raber. However, evaluating a therapy at the lesion level is also important for the patient, he highlighted.

Raber presented an explorative analysis of the PACMAN-AMI (NCT03067844) trial focusing on the lesion-level effects of LDL-C-lowering therapy in patients with acute myocardial infraction (aMI). He noted a “A 2% reduction in vessel-level analysis, a 5% reduction at the lesion level, and a 10% reduction in the most narrow spot, called minimum lumen area (MLA)” of Praluent compared to the placebo group in the study.

Raber shed light on a new concept that he called “strike strong and early in acute coronary syndrome (ACS)”. The EVOPACS (NCT03287609) and PACMAN-AMI trial results showed that if mAb are administered early, at day one of ACS presentation, on top of statins, the LDL levels can be reduced by 80% consistently, he said. Raber emphasised that it will be crucial to see the results of EVOLVE-MI (NCT05284747), an open label study that will enroll 4,000 patients to understand the concept of early administration of Repatha.

The legacy effect, which examines the impact of discontinuing a drug, is also an important consideration, said Raber, while referencing the ODYSSEY trial (NCT01663402), which showed that eight months of Praluent exposure significantly reduced cardiovascular events. Similarly, the FOURIER OLE study (NCT03080935) data, demonstrated a noticeable legacy effect with better cardiovascular outcomes observed in patients who received Repatha earlier in the trial.

Upcoming trials to watch

Three large-scale trials ORION-4, VICTORION-2-PREVENT and VICTORION-1-PREVENT, which are currently underway, are evaluating the clinical outcomes and superiority of Leqvio compared to placebo in different patient groups.

With regard to gene-editing, the speaker referenced the VERVE 101 study (NCT05398029) where gene editing was used to achieve a 55% reduction in LDL levels with the highest dose in ten high-risk patients with familial hypercholesterolemia. Although there were temporary safety concerns regarding liver function and three serious adverse events (SAEs), these were considered consistent with the high-risk nature of the patient group, and the study was allowed to continue, he said.

In his concluding remarks, Rader said that “the field of PCSK9 inhibition is exciting and holds substantial promise for reducing the risk of atherosclerosis and associated events”. Advances in genetic research have led to the development of PCSK9-targeting therapies with “unprecedented speed”, enabling personalised LDL-lowering strategies in clinical settings, he said ending his presentation.