Early Evidence Suggests An Experimental Drug May Shrink Fatty Plaques

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Atherosclerosis refers to the accumulation of fatty deposits – primarily composed of cholesterol – within the walls of arteries, causing them to narrow. Narrowed arteries raise blood pressure, force the heart to work harder, and increase the risk of clots blocking the artery and causing a stroke or heart attack. Current treatments for atherosclerosis focus mainly on mitigating these risks, for example with blood pressure-lowering drugs. Some of these treatments, alongside lifestyle interventions, can also slow down the growth of fatty plaques or even slightly shrink them for a time. Unfortunately, it is impossible to prevent plaque growth indefinitely, and even healthy individuals will accumulate some fatty plaque with age.

It would be far better if we could actively remove these fatty deposits from the arteries, producing a lasting reversal of atherosclerosis. This is what a company called Cyclarity Therapeutics has been trying to do with their drug candidate, UDP-003. When clinical trials for UDP-003 were announced last year, we promised to keep you updated when results became available, and we can now happily do just that!

How It Works

Cholesterol, which forms the main component of the fatty plaque, can under normal conditions be removed from the walls of the arteries by high density lipoprotein (HDL). Cholesterol that is not removed this way can also be broken down by white blood cells, with the breakdown products being released back into the blood. Unfortunately, some cholesterol undergoes a modification called oxidation, which prevents it from being broken down. White blood cells become bloated with oxidised cholesterol and trigger inflammation to bring in more white cells to help, and this has the regrettable effect of causing more cholesterol to be oxidised.

UDP-003 was designed to break this cycle by extracting oxidised cholesterol from the fatty plaque. It achieves this via its specialised structure. UDP-003 is a cyclodextrin, or ring of sugar molecules, with a central cavity into which 7-ketocholesterol (7KC, the main form of oxidised cholesterol in the fatty plaque) fits snugly. The inside of the ring is also hydrophobic (attracts organic molecules like cholesterol) while the outside is hydrophilic, meaning that the whole structure can dissolve in water. This allows UDP-003 to freely enter white blood cells alongside other water-soluble molecules, encapsulate 7KC that is stuck inside, and then carry that cholesterol back out. The drug then returns to the blood and, still carrying the 7KC, is excreted into the urine.

The Trial

The trial was randomised, double-blind and placebo-controlled, meaning that participants were randomly assigned to receive either UDP-003 or a placebo, and neither the recipients nor the people administering the treatment knew which one they were receiving. There were 84 participants in total, some of whom had a history of major adverse cardiac events. Those who received UDP-003 received it at one of 6 dosing levels, either as 6 separate doses over 17 days or in a single dose.

The Results

The trial showed that participants receiving UDP-003 excreted 7KC in their urine. This excretion was dose-dependent, meaning that participants who received higher doses of UDP-003 excreted more 7KC. There were no serious side effects, and UDP-003 was found to have a half-life of just 3 hours (meaning that UDP-003 levels in the blood halved roughly every 3 hours). This is a good thing – it means that UDP-003 didn’t stick around for long (by comparison, caffeine has an average half-life of around 6 hours) but was still able to do its job.

The Implications

These are encouraging early results. While the trial did not measure plaque shrinkage (the trial may not have lasted long enough for plaques to shrink measurably), the lack of side effects and short half life suggest that patients could receive UDP-003 long-term to gradually achieve a reduction in plaque size. It would not require much of a reduction to have a significant health impact. Some studies suggest that a 1% reduction in coronary plaque (plaque in the coronary artery that supplies blood to the heart muscle) is associated with up to 25% lower risk of major cardiovascular events.

The trial included participants from a wide range of ages, some of whom were healthy. It isn’t clear from the press release whether the healthier or younger participants, who would have had less fatty plaque, excreted less 7KC. Regardless, since UDP-003 is delivered intravenously, it might not be something most people would want to take regularly unless they were specifically identified as being at risk.