The treatment of atherosclerosis is trapped in a rut, and has been for some time. Near all of the development in this field is focused on producing ever more innovative ways to reduce LDL-cholesterol in the bloodstream. Unfortunately, this cannot do more than modestly slow the condition; it can’t reverse existing plaque to any great degree. By the time a plaque has formed, it has become a self-sustaining lesion, inflamed and attracting ever more immune cells to become overwhelmed by the toxic plaque environment and die, adding their mass to the plaque. The input of LDL-cholesterol from the bloodstream, while creating the tipping point of plaque formation in the early stages, becomes a minor contribution at that later stage of the condition.
Cyclarity is one of the few groups attempting to break out of the rut, along with Repair Biotechnologies. Cyclarity is testing whether or not targeted removal of the toxic modified cholesterol known as 7-ketocholesterol can improve the state of the disrupted plaque tissue environment far enough to enable some form of repair and reversal by otherwise overwhelmed tissue maintenance systems. Since animal models would be fairly uninformative on this question, the company is instead taking a very fast path to human trials based on tissue models and safety data alone. It will be interesting to see how well this works at the end of the day.
The development of therapeutics to combat atherosclerotic cardiovascular disease (CVD) forms a significant part of humankind’s battle against chronic disease. The basic pathological process of atherosclerosis has been characterized for over a century. Despite its multifaceted nature, the major clinical focus for treatment of atherosclerosis has involved targeting cholesterol metabolism to reduce the rate of plaque accumulation within blood vessels or improving recovery after a cardiovascular event. Of all therapeutic interventions, cholesterol-lowering statins dominate the CVD market. In fact, statins are the most commonly-prescribed drug in the world. In essence, the field of CVD therapeutics has adopted a strategy of slowing the rate of disease progression and reducing the risk of complications from disease (i.e. cardiovascular events, like heart attacks). Although this strategy has played a role in the significant increase in average human lifespan over the past century, it is essentially a disease management approach that has failed to erase CVD from the list of humanity’s most prolific killers.
There are several downstream events that transform cholesterol into a toxic waste product. Most importantly, the development of atherosclerosis is contingent upon cholesterol penetrating blood vessels and becoming oxidized – making it non-degradable and toxic. This corrupted form of cholesterol ultimately drives an insidious cycle of low level chronic inflammation (inflammaging), macrophage dysfunction, and plaque accumulation. Cyclarity Therapeutics works to rehabilitate the cardiovascular system’s own, natural self-repair mechanism, removing the toxic byproducts that cause macrophage dysfunction and restoring their natural ability to manage and reduce plaque. This is a “first in class” therapy that could redefine the treatment paradigm for atherosclerosis, paving a path for a new class of disease-modifying therapeutics. For the first time in the history of mankind’s fight against chronic disease, the possibility of disease reversal has been enabled.
Cyclarity’s candidate UDP-003 belongs to a class of compounds known as cyclodextrins. Cyclodextrins have special chemical properties that give them powerful fat/cholesterol binding capabilities. Cyclarity uses its novel computational platform technology to engineer cyclodextrins to enhance target specificity, safety, and efficacy relative to generic cyclodextrins. UDP-003 is designed to precisely bind and clear a toxic form of oxidized cholesterol, 7-ketocholesterol (7-KC), that builds up in immune cells (macrophages), transforming them into foam cells – the root cause of plaque formation.