Bempedoic acid, sold under the brand name Nexletol among others, is a medication for the treatment of

hypercholesterolemia Hypercholesterolemia, also called high cholesterol, is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia (high levels of lipids in the blood), hyperlipoproteinemia (high levels of lipoproteins in the blood), ...

(high blood

cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...

levels). Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged. The most common side effects include

hyperuricemia Hyperuricaemia or hyperuricemia is an abnormally high level of uric acid in the blood. In the pH conditions of body fluid, uric acid exists largely as urate, the ion form. Serum uric acid concentrations greater than 6 mg/dL for females, 7&nbs ...

(high blood levels of uric acid), pain in arms or legs, and

anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...

(low red blood cell counts). Bempedoic acid blocks an enzyme in the liver called adenosine triphosphate-citrate lyase, which is involved in making cholesterol. Bempedoic acid was approved for use in the United States in February 2020, and for use in the European Union in April 2020. The U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) considers it to be a

first-in-class medication A first-in-class medication is a pharmaceutical that uses a "new and unique mechanism of action" to treat a particular medical condition. While the Food and Drug Administration's Center for Drug Evaluation and Research tracks first-in-class medicat ...

Medical uses

In the US, bempedoic acid is indicated for the treatment of hypercholesterolemia in combination with diet and the highest tolerated

statin Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs. Low- ...

therapy in adults with

heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

familial hypercholesterolemia Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein (LDL cholesterol), in the blood and early cardiovascular disease. The most common mutatio ...

, or with established

atherosclerotic Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no sy ...

cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...

, who need additional lowering of

LDL cholesterol 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 (aka ULDL by the overall densit ...

. In the EU, bempedoic acid is indicated in adults with primary hypercholesterolaemia (heterozygous familial and non familial) or mixed dyslipidaemia, as an adjunct to diet in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin; or alone or in combination with other lipid-lowering therapies in patients who are statin intolerant, or for whom a statin is contraindicated.

Side effects

Common adverse effects in clinical trials were

muscle spasm A spasm is a sudden involuntary contraction of a muscle, a group of muscles, or a hollow organ such as the bladder. A spasmodic muscle contraction may be caused by many medical conditions, including dystonia. Most commonly, it is a muscle c ...

s (3.6% of treated patients, as compared to 2.3% under

placebo A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures. In general ...

), pain in the back (3.3% versus 2.2%) or in a

limb Limb may refer to: Science and technology *Limb (anatomy), an appendage of a human or animal *Limb, a large or main branch of a tree *Limb, in astronomy, the curved edge of the apparent disk of a celestial body, e.g. lunar limb *Limb, in botany, ...

(3.0% versus 1.7%),

gout Gout ( ) is a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot and swollen joint, caused by deposition of monosodium urate monohydrate crystals. Pain typically comes on rapidly, reaching maximal intensit ...

(1.5% versus 0.4%), and

gastrointestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...

problems such as diarrhea. A less common but more serious adverse effect was

tendon rupture Tendon rupture is a condition in which a tendon separates in whole or in part from tissue to which it is attached, or is itself torn or otherwise divided in whole or in part. Examples include: * Achilles tendon rupture * Biceps tendon rupture * A ...

in the

rotator cuff The rotator cuff is a group of muscles and their tendons that act to stabilize the human shoulder and allow for its extensive range of motion. Of the seven scapulohumeral muscles, four make up the rotator cuff. The four muscles are the supraspi ...

of the shoulder, the

biceps tendon The biceps or biceps brachii ( la, musculus biceps brachii, "two-headed muscle of the arm") is a large muscle that lies on the front of the upper arm between the shoulder and the elbow. Both heads of the muscle arise on the scapula and join t ...

or the

Achilles tendon The Achilles tendon or heel cord, also known as the calcaneal tendon, is a tendon at the back of the lower leg, and is the thickest in the human body. It serves to attach the plantaris, gastrocnemius (calf) and soleus muscles to the calcaneus (h ...

(0.5% versus 0.0%).

Interactions

Bempedoic acid does not interact with the

cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...

enzyme system in the liver and only weakly inhibits the transporter proteins

SLCO1B1 Solute carrier organic anion transporter family member 1B1 is a protein that in humans is encoded by the ''SLCO1B1'' gene. Pharmacogenomic research indicates that genetic variations in this gene are associated with response to simvastatin. Clinical ...

SLCO1B3 Solute carrier organic anion transporter family member 1B3 (SLCO1B3) also known as organic anion-transporting polypeptide 1B3 (OATP1B3) is a protein that in humans is encoded by the ''SLCO1B3'' gene. OATP1B3 is a 12-transmembrane domain influx tra ...

and

SLC22A7 Solute carrier family 22 member 7 is a protein that in humans is encoded by the gene ''SLC22A7''. The protein encoded by this gene is involved in the sodium-independent transport and excretion of organic anions, some of which are potentially toxi ...

(the latter possibly being responsible for the increase of

uric acid Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the metabolic breakdown of ...

in the blood, and therefore the adverse effect gout). Despite this, the drug increases blood levels of statins. The effect is most pronounced with

simvastatin Simvastatin, sold under the brand name Zocor among others, is a statin, a type of lipid-lowering medication. It is used along with exercise, diet, and weight loss to decrease elevated lipid levels. It is also used to decrease the risk of heart ...

and

pravastatin Pravastatin, sold under the brand name Pravachol among others, is a statin medication, used for preventing cardiovascular disease in those at high risk and treating abnormal lipids. It should be used together with diet changes, exercise, and w ...

, whose AUC is increased about twofold. No other clinically relevant interactions have been found in studies.

Pharmacology

Mechanism of action

Bempedoic acid is a

prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...

. It is activated to the

thioester In organic chemistry, thioesters are organosulfur compounds with the functional group . They are analogous to carboxylate esters () with the sulfur in the thioester playing the role of the linking oxygen in the carboxylate ester, as implied by t ...

with

coenzyme A Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a subs ...

by the enzyme

SLC27A2 Very long-chain acyl-CoA synthetase is an enzyme that in humans is encoded by the ''SLC27A2'' gene. The protein encoded by this gene is an isozyme of long-chain fatty-acid-coenzyme A ligase family. Although differing in substrate specificity, subc ...

in the liver. The activated substance inhibits

ATP citrate lyase ATP citrate synthase (also ATP citrate lyase (ACLY)) is an enzyme that in animals represents an important step in fatty acid biosynthesis. By converting citrate to acetyl-CoA, the enzyme links carbohydrate metabolism, which yields citrate as an ...

, which is involved in the liver's biosynthesis of cholesterol upstream of

HMG-CoA reductase HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, official symbol HMGCR) is the rate-controlling enzyme (NADH-dependent, ; NADPH-dependent, ) of the mevalonate pathway, the metabolic pathway that produces cholesterol and oth ...

, the enzyme that is blocked by

s. The substance also activates

AMP-activated protein kinase 5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme (EC 2.7.11.31) that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cell ...

, but this effect is likely not relevant in humans.

Pharmacokinetics

Following oral intake, bempedoic acid reaches highest blood plasma concentrations after 3.5 hours. Food does not affect its absorption. When in the bloodstream, 99.3% of the substance are bound to

plasma protein Blood-proteins, also termed plasma proteins, are proteins present in blood plasma. They serve many different functions, including transport of lipids, hormones, vitamins and minerals in activity and functioning of the immune system. Other blood pr ...

s. About a fifth of the substance is reversibly converted by an

aldo-keto reductase The aldo-keto reductase family is a family of proteins that are subdivided into 16 categories; these include a number of related monomeric NADPH-dependent oxidoreductases, such as aldehyde reductase, aldose reductase, prostaglandin F synthase, xyl ...

enzyme to a

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

(called ESP15228) that is also pharmacologically active in form of its coenzyme A–thioester. Of ESP15228, 99.2% are bound to plasma proteins. Both bempedoic acid and the metabolite are inactivated by

glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve glycosid ...

of their

carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...

groups. Bempedoic acid has a

biological half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

of 21±11 hours. Over 95% of the substance are excreted in form of metabolites; about 70% with the urine and 30% with the feces.

History

There were two clinical trials that evaluated the benefits and side effects of bempedoic acid. The trial designs were similar. All enrolled subjects were on a lipid-lowering diet and taking the highest dose of a statin (drug commonly used to lower cholesterol) for high cholesterol. In both trials, subjects were randomly assigned to receive bempedoic acid or placebo tablets every day for 52-weeks. Neither the subjects nor the health care providers knew which treatment was being given. The trials measured percent change in

(LDL-C) blood levels from baseline to week twelve and compared bempedoic acid to placebo. In one clinical trial, bempedoic acid reduced LDL-C by about 20 mg/dl compared to

and had a similar frequency of side effects to placebo, although a higher percentage of drug receiving subjects dropped out of the study because of side effects (11% vs. 7% under placebo). In one

randomized controlled trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical te ...

, patients who could not tolerate therapy with statins had a reduced risk of major adverse cardiovascular events after being treated with bempedoic acid. In January 2020, the

Committee for Medicinal Products for Human Use The Committee for Medicinal Products for Human Use (CHMP), formerly known as Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regarding ...

(CHMP) in the European Union recommended granting of a marketing authorization for bempedoic acid as both a standalone drug (brand name Nilemdo) and as a

fixed-dose combination A combination drug or a fixed-dose combination (FDC) is a medicine that includes two or more active ingredients combined in a single dosage form. Terms like "combination drug" or "combination drug product" can be common shorthand for a FDC pr ...

medication with

ezetimibe Ezetimibe is a medication used to treat high blood cholesterol and certain other lipid abnormalities. Generally it is used together with dietary changes and a statin. Alone, it is less preferred than a statin. It is taken by mouth. It is also ...

(brand name Nustendi). Bempedoic acid was approved for use in the European Union in April 2020, and the combination bempedoic acid/ezetimibe was approved in March 2020. In February 2020, bempedoic acid was approved for use in the United States both as a standalone drug (brand name Nexletol) and in a fixed-dose combination with ezetimibe (brand name Nexlizet). The U.S.

(FDA) granted the approval of Nexletol to

Esperion Therapeutics Esperion Therapeutics, Inc. is a public American pharmaceutical company focused on the development of bempedoic acid, an orally available small molecule designed to lower elevated levels of LDL-C. The company is headquartered in Ann Arbor, Michi ...

. The FDA approved bempedoic acid based on evidence from two clinical trials (Trial 1/ NCT02666664 and Trial 2/NCT02991118) of 3009 subjects with high LDL cholesterol and known atherosclerotic cardiovascular disease or HeFH. The trials were conducted in United States, Canada, and Europe.

References

External links

* * * * {{Portal bar , Medicine Dicarboxylic acids Hypolipidemic agents