Darapladib was an investigational medication developed to address cardiovascular disease, particularly atherosclerosis. It was explored as a potential treatment to prevent serious cardiovascular events, such as heart attacks and strokes. The drug aimed to manage the progressive nature of arterial plaque buildup by understanding specific biological pathways involved in heart disease.
The Intended Target of Darapladib
Atherosclerosis is a chronic condition characterized by the hardening and narrowing of arteries due to the accumulation of fatty deposits, known as plaques, within the vessel walls. These plaques can grow over time, restricting blood flow and potentially leading to severe health complications. Plaque formation involves complex inflammatory responses within the arteries.
A specific enzyme, lipoprotein-associated phospholipase A2 (Lp-PLA2), plays a role in this inflammatory process. Lp-PLA2 circulates in the bloodstream, primarily associated with low-density lipoprotein (LDL) particles, and is transported into the arterial wall as atherosclerosis develops. Within the plaque, Lp-PLA2 breaks down oxidized phospholipids, releasing substances like lysophosphatidylcholine and oxidized free fatty acids.
These breakdown products are pro-inflammatory, contributing to the inflammatory environment within the plaque. Elevated levels of Lp-PLA2 are linked to increased inflammation, which can make atherosclerotic plaques more unstable. An unstable plaque is more susceptible to rupture, an event that can trigger the formation of a blood clot, leading to a heart attack or stroke. Lp-PLA2 is considered a marker of vascular inflammation, indicating rupture-prone plaques.
Mechanism of Action
Darapladib was designed as a selective and direct inhibitor of the Lp-PLA2 enzyme. An inhibitor works by binding to an enzyme, preventing its usual function. By blocking Lp-PLA2 activity, darapladib aimed to reduce the production of pro-inflammatory substances derived from oxidized phospholipids.
The intended therapeutic effect was to lessen inflammation within the arterial walls. Reducing inflammation was hypothesized to stabilize existing atherosclerotic plaques, making them less prone to rupture. This approach aimed to lower the risk of heart attacks, strokes, and other cardiovascular events.
Clinical Trial Outcomes
Darapladib underwent extensive evaluation in major Phase III clinical trials: STABILITY and SOLID-TIMI 52. The STABILITY trial involved approximately 16,000 patients who had chronic coronary heart disease. The SOLID-TIMI 52 trial enrolled over 13,000 patients who had recently experienced an acute coronary syndrome, such as a heart attack.
These large-scale studies aimed to determine if darapladib could reduce major adverse cardiovascular events. Despite effectively lowering Lp-PLA2 levels, neither trial demonstrated a statistically significant reduction in their primary endpoints. These primary endpoints included a composite of cardiovascular death, heart attack, stroke, and urgent coronary revascularization procedures. The drug did not show a clear benefit in preventing these events when compared to a placebo, even when added to standard medical care.
Observed Side Effects and Drug Status
During clinical trials, darapladib was associated with several reported side effects. Patients commonly experienced diarrhea. Another distinct side effect was a noticeable body odor, which could manifest as skin, urine, or fecal odor. These odor-related side effects were reported by a small percentage of patients: 2.2% for fecal odor, 1.4% for urine odor, and 2.2% for skin odor.
Due to the lack of demonstrated clinical efficacy in reducing major cardiovascular events in its large Phase III trials, GlaxoSmithKline discontinued darapladib’s development. Consequently, the drug was not approved for use by regulatory agencies worldwide.