| Clinical data | |
|---|---|
| Other names | CER-001, CER 001 |
| Routes of administration | Infusion |
| Identifiers | |
| CAS Number | |
| DrugBank | |
CER-001 is a recombinant high-density lipoprotein (HDL) mimetic that has orphan drug status. [1] It is in early-stage clinical trials for the potential treatment of hypoalphalipoproteinaemia, [2] acute coronary syndrome (ACS), [3] acute kidney injury (AKI), [4] [5] [6] atherosclerosis [7] and lecithin cholesterol acyltransferase (LCAT) deficiency. [8] CER-001 is also under investigation as possible agent for treating hyperinflammatory states based on lipid profile alterations due to COVID-19. [9] [10]
CER-001 is an artificially synthesized mimetic of recombinant human apolipoprotein AI (ApoA1), the main structural protein of natural HDL, together with two phospholipids, which are: sphingomyelin and dipalmitoyl-phosphatidylglycerol. [11]
CER-001 is designed to mimic the natural structure and function of nascent HDL, also known as pre-beta HDL. [12] This mimicry stimulates cholesterol efflux from macrophages, captures cholesterol and eliminates it via reverse lipid transport (RLT) pathway, also known as reverse cholesterol transport (RCT) pathway. [13]
CER-001 was given in clinical human studies by intravenous infusion. [14] It did not appear to affect clinical chemistry, hematology or coagulation parameters and is considered safe. [14]
High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are typically composed of 80–100 proteins per particle. HDL particles enlarge while circulating in the blood, aggregating more fat molecules and transporting up to hundreds of fat molecules per particle.
Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). LDL delivers fat molecules to cells. LDL is involved in atherosclerosis, a process in which it is oxidized within the walls of arteries.
Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. These lesions may lead to narrowing of the arterial walls due to buildup of atheromatous plaques. At onset there are usually no symptoms, but if they develop, symptoms generally begin around middle age. In severe cases, it can result in coronary artery disease, stroke, peripheral artery disease, or kidney disorders, depending on which body part(s) the affected arteries are located in the body.
Hypercholesterolemia, also called high cholesterol, is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia, hyperlipoproteinemia, and dyslipidemia.
Dyslipidemia is a metabolic disorder characterized by abnormally high or low amounts of any or all lipids or lipoproteins in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular diseases (ASCVD), which include coronary artery disease, cerebrovascular disease, and peripheral artery disease. Although dyslipidemia is a risk factor for ASCVD, abnormal levels don't mean that lipid lowering agents need to be started. Other factors, such as comorbid conditions and lifestyle in addition to dyslipidemia, is considered in a cardiovascular risk assessment. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood. This is often due to diet and lifestyle. Prolonged elevation of insulin resistance can also lead to dyslipidemia. Likewise, increased levels of O-GlcNAc transferase (OGT) may cause dyslipidemia.
Apolipoproteins are proteins that bind lipids to form lipoproteins. They transport lipids in blood, cerebrospinal fluid and lymph.
Hyperlipidemia is abnormally high levels of any or all lipids or lipoproteins in the blood. The term hyperlipidemia refers to the laboratory finding itself and is also used as an umbrella term covering any of various acquired or genetic disorders that result in that finding. Hyperlipidemia represents a subset of dyslipidemia and a superset of hypercholesterolemia. Hyperlipidemia is usually chronic and requires ongoing medication to control blood lipid levels.
Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein, is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. It collects triglycerides from very-low-density (VLDL) or Chylomicrons and exchanges them for cholesteryl esters from high-density lipoproteins (HDL), and vice versa. Most of the time, however, CETP does a heteroexchange, trading a triglyceride for a cholesteryl ester or a cholesteryl ester for a triglyceride.
Apolipoprotein A-I Milano is a naturally occurring mutated variant of the apolipoprotein A1 protein found in human HDL, the lipoprotein particle that carries cholesterol from tissues to the liver and is associated with protection against cardiovascular disease. ApoA-I Milano was first identified by Dr. Cesare Sirtori in Milan, who also demonstrated that its presence significantly reduced cardiovascular disease, even though it caused a reduction in HDL levels and an increase in triglyceride levels.
Lecithin–cholesterol acyltransferase is an enzyme, in many animals including humans, that converts free cholesterol into cholesteryl ester, which is then sequestered into the core of a lipoprotein particle, eventually making the newly synthesized HDL spherical and forcing the reaction to become unidirectional since the particles are removed from the surface. The enzyme is bound to high-density lipoproteins (HDLs) (alpha-LCAT) and LDLs (beta-LCAT) in the blood plasma. LCAT deficiency can cause impaired vision due to cholesterol corneal opacities, anemia, and kidney damage. It belongs to the family of phospholipid:diacylglycerol acyltransferases.
Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein cholesterol, in the blood and early cardiovascular diseases. The most common mutations diminish the number of functional LDL receptors in the liver or produce abnormal LDL receptors that never go to the cell surface to function properly. Since the underlying body biochemistry is slightly different in individuals with FH, their high cholesterol levels are less responsive to the kinds of cholesterol control methods which are usually more effective in people without FH. Nevertheless, treatment is usually effective.
Lecithin cholesterol acyltransferase deficiency is a disorder of lipoprotein metabolism. The disease has two forms: Familial LCAT deficiency, in which there is complete LCAT deficiency, and Fish-eye disease, in which there is a partial deficiency.
Cholesteryl ester, a dietary lipid, is an ester of cholesterol. The ester bond is formed between the carboxylate group of a fatty acid and the hydroxyl group of cholesterol. Cholesteryl esters have a lower solubility in water due to their increased hydrophobicity. Esters are formed by replacing at least one –OH (hydroxyl) group with an –O–alkyl (alkoxy) group. They are hydrolyzed by pancreatic enzymes, cholesterol esterase, to produce cholesterol and free fatty acids. They are associated with atherosclerosis.
Apolipoprotein AI(Apo-AI) is a protein that in humans is encoded by the APOA1 gene. As the major component of HDL particles, it has a specific role in lipid metabolism.
Apolipoprotein C-III also known as apo-CIII, and apolipoprotein C3, is a protein that in humans is encoded by the APOC3 gene. Apo-CIII is secreted by the liver as well as the small intestine, and is found on triglyceride-rich lipoproteins such as chylomicrons, very low density lipoprotein (VLDL), and remnant cholesterol.
Apolipoprotein D (ApoD) is a protein that in humans is encoded by the APOD gene. Unlike other lipoproteins, which are mainly produced in the liver, apolipoprotein D is mainly produced in the brain and testes. It is a 29 kDa glycoprotein discovered in 1963 as a component of the high-density lipoprotein (HDL) fraction of human plasma. It is the major component of human mammary cyst fluid. The human gene encoding it was cloned in 1986 and the deduced protein sequence revealed that ApoD is a member of the lipocalin family, small hydrophobic molecule transporters. ApoD is 169 amino acids long, including a secretion peptide signal of 20 amino acids. It contains two glycosylation sites and the molecular weight of the mature protein varies from 20 to 32 kDa.
ATP-binding cassette transporter ABCA1, also known as the cholesterol efflux regulatory protein (CERP) is a protein which in humans is encoded by the ABCA1 gene. This transporter is a major regulator of cellular cholesterol and phospholipid homeostasis.
Apolipoprotein A-V is a protein that in humans is encoded by the APOA5 gene on chromosome 11. It is significantly expressed in liver. The protein encoded by this gene is an apolipoprotein and an important determinant of plasma triglyceride levels, a major risk factor for coronary artery disease. It is a component of several lipoprotein fractions including VLDL, HDL, chylomicrons. It is believed that apoA-V affects lipoprotein metabolism by interacting with LDL-R gene family receptors. Considering its association with lipoprotein levels, APOA5 is implicated in metabolic syndrome. The APOA5 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.
Reverse cholesterol transport is a multi-step process resulting in the net movement of cholesterol from peripheral tissues back to the liver first via entering the lymphatic system, then the bloodstream.
Apabetalone is an orally available small molecule created by Resverlogix Corp. that is being evaluated in clinical trials for the treatment of atherosclerosis and associated cardiovascular disease (CVD). In the phase II clinical trial ASSURE in patients with angiographic coronary disease and low high-density lipoprotein cholesterol (HDL-C) levels, apabetalone showed no greater increase in HDL-cholesterol (HDL-c) and apolipoprotein A-I (ApoA-I) levels or incremental regression of atherosclerosis than administration of placebo, while causing a statistically significant greater incidence of elevated liver enzymes. However, pooled analysis of the effect of apabetalone in three phase II clinical trials ASSERT, ASSURE, and SUSTAIN demonstrated increases in HDL-cholesterol (HDL-c) and apolipoprotein A-I (ApoA-I) levels, as well as decreases in the incidence of major adverse cardiac events (MACE). Reduction of MACE was more profound in patients with diabetes mellitus. In a short-term study in prediabetics, favorable changes in glucose metabolism were observed in patients receiving apabetalone. An international, multicenter phase III trial, “Effect of RVX000222 on Time to Major Adverse Cardiovascular Events in High-Risk Type 2 Diabetes Mellitus Subjects with Coronary Artery Disease” (BETonMACE) commenced in October 2015. The trial is designed to determine whether apabetalone in combination with statins can decrease cardiac events compared to treatment with statins alone.