Maintaining levels of LDL (low density lipoprotein) cholesterol within a certain range lowers the risk of stroke and heart attack. Where diet has proven insufficient in maintaining those levels, the so-called statin drugs become standard of care over the past 20 years. In 2012, statin drugs were the biggest-selling class of pharmaceutic in the world with sales of US$40 billion. That position has changed dramatically with statin patents now expiring.
Just over 10 years ago, a new target was identified that was predicted to provide a superior drug over the statins, in addition to creating a new patented drug opportunity. That target was a plasma protein known as PCSK9.
LDL cholesterol articles are removed from blood by a LDL receptors present on the surface of liver cells. The cholesterol-receptor complex is internalised by the liver cell, the cholesterol broken down, and the LDL receptor then recycled to the outside of the cell. This is a crucial loop in dampening down LDL cholesterol levels in the blood.
PCSK9 works by binding to the cholesterol-receptor complex once it forms. When this larger complex (PCSK9-cholesterol-receptor) enters the liver the cell, the entire complex is broken down, including the LDL receptors, which are not available to be recycled. Less LDL receptors = less removal of LDL cholesterol levels from blood = higher blood levels.
The challenge then became to develop a drug that would prevent the PCSK9 protein binding to the LDL receptor (itself a protein). Without that binding, the LDL receptors would avoid being degraded, and would be available for recycling.
Early attempts proved unsuccessful, leading to a general belief that the surface of the PCSK9 molecule was unsuitable for getting a small molecule drug (like a statin drug) to attach to the molecule. The pharmaceutical industry consequently went down the road of developing an antibody that by its very definition, would bind to the PCSK9 protein, effectively inhibiting its ability to bind to the LDL receptor. In 2015, the first monoclonal antibody product entered the market to significant acclaim, although its requirement of being injected fortnightly or monthly (for life) and at considerable cost (USD$14,000 p.a.), has meant that this approach is limited.
NYX-330 is the result of Australian computational chemists identifying a pocket on the surface of PCSK9 that permits the attachment of a small molecule. NYX-330 attaches to this pocket, effectively blocking the ability of the PCSK9 molecule to bind to the LDL receptor.
NYX-330 is undergoing development as a small molecule drug to be taken orally, daily, for the treatment of hypercholesterolaemia.