Our liver cells have LDL receptors on the outside of them. These receptors attach to LDL cholesterol when it passes by in the blood. The receptor takes the cholesterol out of the blood and into the liver to be broken down. The more LDL receptors we have, the easier it is for us to keep our blood cholesterol low.

The PCSK9 protein breaks down the LDL receptors, meaning we have less of them and our blood cholesterol rises. PCSK9 inhibitors stop the protein from working so that we have more LDL receptors on our liver cells and less cholesterol in the blood.

The figure below shows normal, physiological LDLR recycling. LDL low density lipoprotein, LDL-C low-density lipoprotein cholesterol, LDLR low density lipoprotein receptor

The figure below shows the negative impact of PCSK9. When a PCSK9 attaches to a LDL receptor, it also gets degraded during the LDL degradation process and as result doesn’t get recycled. This results in significantly fewer LDL receptor making it back to the surface of the hematocye, which results in less LDL capture from the blood stream.

The figure below shows the mechanism of action of PCSK9 inhibitor (MAb). By attaching to the the PCSK9, the MAb prevents it from attaching to the LDL receptor.

This results in the LDL receptor not being also degraded during the LDL degradation process and thus making it back (LDL-R recycling) to the surface of the hematocyte to capture the next LDL.

Repatha has been extensively studied in clinical trials, including the FOURIER trial, which demonstrated its efficacy in reducing major adverse cardiovascular events in high-risk patients.

Praluent has been studied in trials such as ODYSSEY, which showed its ability to reduce LDL-C levels and cardiovascular events in specific patient populations. Both drugs were approved by the FDA in 2015

The FOURIER trial was a multicenter, randomized, double-blind, placebo-controlled trial that enrolled over 27,000 patients with atherosclerotic cardiovascular disease (ASCVD) and elevated LDL cholesterol (LDL-C) levels despite optimized statin therapy. Patients were randomized to receive either Repatha or placebo in addition to statin therapy.

The primary endpoint of the study was a composite of cardiovascular death, myocardial infarction (MI), stroke, hospitalization for unstable angina, or coronary revascularization. The trial aimed to assess whether the addition of Repatha to statin therapy could further reduce the risk of these adverse cardiovascular events.

This trial demonstrated significant benefits with the use of Repatha. The study found that Repatha, when compared to placebo, led to a 15% reduction in the risk of the primary composite endpoint. This reduction was consistent across various subgroups, including patients with high LDL-C levels, diabetes, and prior cardiovascular events. Repatha also showed significant reductions in the individual components of the primary endpoint, including cardiovascular death, MI, and stroke.

LDL-C Lowering: Repatha achieved robust LDL-C lowering in the trial. Patients receiving Repatha experienced a median reduction of LDL-C levels by approximately 59% compared to placebo, in addition to background statin therapy.

The safety profile of Repatha was generally favorable, with no significant increase in adverse events compared to placebo. Injection site reactions and myalgia were the most commonly reported adverse effects, but the overall incidence was low and comparable to the placebo group.

The ODYSSEY clinical trial program consists of several trials conducted to evaluate the efficacy and safety of Praluent (Alirocumab) in reducing LDL cholesterol (LDL-C) levels and cardiovascular events in various patient populations. These trials included a total of about 24,000 patients

The ODYSSEY Phase III trials evaluated the efficacy and safety of Praluent in different patient populations, including those with hypercholesterolemia and high cardiovascular risk. The ODYSSEY LONG TERM trial assessed the long-term efficacy and safety of Praluent in patients with hypercholesterolemia who were unable to achieve their LDL-C goals despite maximally tolerated statin therapy. The ODYSSEY COMBO I and II trials investigated the efficacy and safety of Praluent in combination with maximally tolerated statin therapy in patients with heterozygous familial hypercholesterolemia (HeFH) or atherosclerotic cardiovascular disease (ASCVD). The ODYSSEY FH I and II trials focused on evaluating the efficacy and safety of Praluent in patients with HeFH, an inherited condition associated with high LDL-C levels. The ODYSSEY OPTIONS I and II trials examined the efficacy, safety, and tolerability of Praluent in patients with statin intolerance, either due to muscle-related side effects or statin-associated neurocognitive effects.

The ODYSSEY clinical trial program demonstrated that Praluent, in combination with statin therapy or as monotherapy, significantly reduced LDL-C levels compared to placebo. Praluent consistently showed superior LDL-C-lowering effects across various patient populations, including patients with HeFH, statin intolerance, and those at high cardiovascular risk. The study demonstrated that Praluent significantly reduced the risk of MACE, including cardiovascular death, MI, stroke, and unstable angina requiring hospitalization.

Praluent demonstrated a generally favorable safety profile across the ODYSSEY trials. It was well-tolerated in the studied patient populations The incidence of adverse events was comparable to placebo, with injection site reactions being the most commonly reported adverse effect.

Since a PCSK9-i works in different ways to lower cholesterol than statins, they have a very different side effect profile.

Because statins work by inhibiting an enzyme in the liver called HMG-CoA reductase and thus impact a biochemical pathway in the liver, they may have side effects such as muscle pain and weakness, liver damage, and increased blood sugar levels. However, PCSK9-i specifically works on the process of cholesterol recycling rather than its production. Consequently, they don't interfere with the liver's biochemical pathways as statins do.

The most common side effects include injection-site reactions, flu-like symptoms, and myalgia. However, these adverse events are typically mild and transient. In rare cases, patients treated with PCSK9 inhibitors may develop antibodies against the drug, potentially leading to reduced drug efficacy. Additionally, allergic reactions, although rare, have been reported. Regular monitoring for immunogenicity is recommended.

Early concerns regarding neurocognitive effects associated with PCSK9 inhibitors have been largely alleviated through extensive clinical evaluation. Multiple trials have demonstrated no increased risk of cognitive impairment or neurocognitive events in patients treated with PCSK9 inhibitors compared to placebo. Long-term safety data on PCSK9 inhibitors are continually being collected through post-marketing surveillance and extended follow-up of clinical trials.