Fight Aging!

Cyclarity is taking a fast path to the clinic for clearance of 7-ketocholesterol, a toxic altered form of cholesterol that contributes to the dysfunction of macrophage cells that lies at the root of atherosclerosis. To the degree that macrophage cells can be rescued from the local excess of cholesterol and altered cholesterol present in an atherosclerotic plaque, they will work to dismantle that plaque. The question is whether removing only 7-ketocholesterol will produce a bigger effect on established atherosclerotic plaque than the presently established approach of lowering LDL-cholesterol in the bloodstream. This is a low bar, as even greatly lowered LDL-cholesterol, while slowing the progression of the condition, actually does very little to reverse existing plaque.

Our lead drug candidate is a cyclodextrin that targets an oxidized cholesterol called 7-ketocholesterol that accumulates in various cells and tissues with age, and the main type of tissue that we are looking at is in the artery where, as I'm sure everyone knows, cholesterol is considered the bad guy that accumulates and causes plaque, the buildup inside of your arteries. What a lot of people don't know is that the most toxic and the most atherogenic is the oxidized cholesterol form. Atherosclerosis is the buildup of plaque inside of your arteries, which is formed by the accumulation of this oxidized cholesterol form. Additionally, unlike cholesterol, which you absolutely need to survive, you don't need any of this oxidized form. And so that's our target. Our lead drug candidate can go into cells and tissues and even penetrate plaque and grab onto that oxidized cholesterol, pull it out and then float away with it, so you can safely excrete it.

We studied all the cyclodextrins in the chemical catalog, and then we did all this computational modeling, and we figured out that the best way to grab onto our target was to dimerize it to basically take two cyclodextrin molecules, stick them together in the right configuration, and then modify it chemically in particular ways to give it the right shape in the binding cavity. Then what it does is, it grabs it and then it eats a single molecule of its target, a bit like Pac-Man, then wraps around it, and the inside cavity forms a shape around the target that fits it. It can then bind it with extremely high affinity and specificity and float away with the 7-ketocholesterol.

We're well into the process of preparing for clinical trials. We've brought on board a noted expert in developing cardiovascular drugs, and are building a team to plan, initiate, and run the clinical trials. Importantly, this is going to start in months, not years. We're going to start clinical trials in 2023, and.we're well along the path of getting ready for that. There's a certain number of things that you need to do with a drug candidate to be ready for that, and you can put them into two basic categories. First is safety testing your drug and the other is in the manufacturing process, and so we're in the final stages of doing the safety testing. Then we need to manufacture the actual version of the drug that will go into people. We're making several kilograms of the final drug product right now, and that's already begun. Then, all the data on both the manufacturing of the drug and the safety testing will be submitted to the regulatory body, at which point we ask for permission to initiate clinical trials.

Link: https://www.lifespan.io/news/ending-atherosclerosis-cyclarity-and-dr-matthew-oconnor/