Cavadex (dihydroxypropyl) ß cyclodextrin for the treatment of atheromatous disease. Prof L.G. Howes. March 2023.
By Professor Laurie Howes - MBBS PhD FRACP FCSANZ. (Australia)
What is atheromatous vascular disease?
1. Atheromatous disease occurs when cholesterol infiltrates and causes inflammation and damage in the artery wall of arteries (called plaques) which cause thrombosis, the net effect being to block the artery’s blood flow, leading to tissue damage. Examples of atheromatous diseases are myocardial infarction, angina, stroke, and peripheral vascular disease.
2. Atheromatous vascular disease is the most prevalent non-infective disease in humans. The cost of detecting and managing the consequences of atheromatous disease is close to US$1 trillion per annum in the US alone.
What are cyclodextrins ? (Cavadex™)
3. Cyclodextrins are a family of compounds that have a ring of glucose molecules with hydroxyl groups that are attracted to water pointing outwards and an inner ring which is attracted to fatty molecules such as cholesterol. Cholesterol in plaques is attracted to the middle of the cyclodextrin ring and is taken from the plaques and eliminated from the body. Cyclodextrins have been used in high concentrations for many decades as a carrier to improve the performance of other drugs. They are approved by regulatory bodies for this purpose and are very safe.
4. The optimal number of glucose molecules in the cyclodextrin ring for the capture of cholesterol molecules is 7, otherwise known as a ß ring. Cyclodextrins may also have a side chain attached to the outer surface of the ring. This attachment affects the pharmacological properties of the compound and the substitution on Cavadex appears to assist with the uptake of cholesterol. Cavadex is a dihydroxypropyl ß cyclodextrin. Cavadex is given rectally at a dose of 3g/day (as a suppository) or intravenously at a dose of 6mg/day. It is not active when given by mouth.
5. Intravenous infusions of dihydroxy propyl ß cyclodextrin have been administered to mice with experimental atheromatous disease and cholesterol plaques, and rapid reductions in the content of cholesterol accompanied by resolution of the plaques were observed. Laboratory studies have demonstrated the molecular pathways involved in the removal of cholesterol from arterial plaques in response to dihydroxy propyl ß cyclodextrin administration.
Have cyclodextrins been used to treat atheromatous disease in humans?
6. So far the human data in atheromatous diseases have been from observations of individuals and groups of individuals with atheromatous disease treated with for one to several months. There have been only a few published clinical trials of cyclodextrins. However, over 170 people with atheromatous have received Cavadex and there is observational evidence for plaque regression after only one to 2 months. These effects occur after either intravenous or rectal administration. In addition, in patients suffering from angina (chest pain), angina rapidly resolved after only a few weeks. This most likely occurs because the removal of cholesterol has immediate effects to reduce local chemical molecules that modulate inflammatory responses and vasodilation in and around plaques.
7. The rapid resolution of angina symptoms has been reported by a cardiologist in a US Mid West Clinic. Twenty patients with active angina were treated with Cavadex using rectal administration. A marked improvement or resolution of angina occurred in 18 (90%) compared with an expected spontaneous improvement of about 10% (Ghandi et al). Putting these figures into a 2x2 contingency table comparing the 20 patients with 20 fictitious untreated controls the probability of a 90% improvement rate being spontaneous is P< 0.0001 by Fishers' Exact Test or the Chi Squared test.
8. These effects must be considered to be specific for Cavadex as the pharmacological characteristics of cyclodextrins varies with changes in the size of the polysaccharide ring, the nature of the chemical group attached to the external part of the ring and the degree of polymerisation of the Cavadex molecules (the number of molecules stacked on top of each other).
Do other treatments cause plaque regression and rapid resolution of angina ?
9. Plaque regression has been observed in about 80% of patients following intensive, high dose statin therapy to reduce LDL cholesterol to less than 1.8 mmol/L. However, the process is slow, about a couple of mm in plaque size over one to several years. Other methods are undergoing clinical trials using the protein constructs of HDL eg Apoprotein A infused intravenously. The treatment is more invasive than Cavadex and if it is ever marketed it will be much more expensive than Cavadex.
What products will Cavadex be in competition with?
10. Cavadex will be a new additive therapy used in conjunction with other established therapies for the treatment and prevention of atheromatous disease. Cyclodextrins will have no immediate competitors for reducing plaque cholesterol and will be given along with statins. It is expected that Cavadex will lead to less requirement for percutaneous coronary intervention and less anti anginal drug use.
What is the potential market size?
It is difficult to comprehend the size of the market for Cavadex. The first drug to the market that causes rapid plaque regression will be enormously popular. I would not be surprised if sales in the first year were constrained by logistics rather than the attraction of customers. It will be the greatest therapeutic advance in cardiovascular medicine since the introduction of the statins.
Professor Laurie Howes MBBS PhD FRACP FCSANZ.
Preeminent Consultant Physician (Cardiology)
Professor of Pharmacology and Therapeutics
