Lorcaserin, marketed under the brand name Belviq, was a

weight-loss drug Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat (adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other con ...

developed by Arena Pharmaceuticals. It reduces appetite by activating

serotonin receptor 5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in multiple tissues including the central and peripheral nervous systems. They mediate both ex ...

the 5-HT_2C receptor in the

hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...

, a region of the brain which is known to control appetite. It was approved in 2012, and in 2020, it was removed from the market in the United States due to an increased risk of cancer detected in users of Belviq.

Medical uses

Lorcaserin was used long term for weight loss in those who are obese. The safety and efficacy of Belviq were evaluated in three randomized, placebo-controlled trials that included nearly 8,000 obese and overweight patients, with and without type 2 diabetes, treated for 52 to 104 weeks. All participants received lifestyle modification that consisted of a reduced calorie diet and exercise counseling. Compared with placebo, treatment with Belviq for up to one year was associated with average weight loss ranging from 3 percent to 3.7 percent. About 47 percent of patients without type 2 diabetes lost at least 5 percent of their body weight compared with about 23 percent of patients treated with placebo. In people with type 2 diabetes, about 38 percent of patients treated with Belviq and 16 percent treated with placebo lost at least 5 percent of their body weight. Belviq treatment was associated with favorable changes in glycemic control in those with type 2 diabetes. The approved labeling for Belviq recommends that the drug be discontinued in patients who fail to lose 5 percent of their body weight after 12 weeks of treatment, as these patients are unlikely to achieve clinically meaningful weight loss with continued treatment. The drug's manufacturer was required to conduct six postmarketing studies, including a long-term cardiovascular outcomes trial to assess the effect of Belviq on the risk for major adverse cardiac events such as heart attack and stroke.

Side effects

There had been concern that lorcaserin could cause cardiac valvulopathy based upon the reports of subjects taking the drug in Phase 2 trials. However, a 2016 Phase 3 clinical trial found no statistically significant differences in valvulopathy rates compared to control, being 2.4% for the drug subjects and 2.0% for controls, and concluded that the drug was safe for the target population although more long-term data was needed. FDA required a post-marketing cardiovascular safety trial as a condition of lorcaserin's approval (a requirement for all weight management drugs since the withdrawal of sibutramine in 2010 due to cardiovascular harm). The CAMELLIA- TIMI 61 trial was conducted for this purpose, and it showed no difference in rates of major adverse cardiovascular events (" MACE+", a composite of "cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, heart failure, or any coronary revascularization") between lorcaserin and placebo. However secondary analysis of CAMELLIA-TIMI 61 by FDA showed a likely higher cancer risk in those taking lorcaserin. The trial was conducted in approximately 12,000 participants over five years and more patients taking lorcaserin were diagnosed with cancer compared to patients taking placebo. CAMELLIA-TIMI 61 was powered to detect differences in MACE, but was not adequately powered to detect differences in cancer rates over the five-year study period. In February 2020, the FDA requested that the manufacturer of lorcaserin voluntarily withdraw the drug from the US market because a safety clinical trial showed an increased occurrence of cancer. The drug manufacturer, Eisai, voluntarily withdrew the drug.

Overdose

Lorcaserin can produce

hallucinogen Hallucinogens, also known as psychedelics, entheogens, or historically as psychotomimetics, are a large and diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mo ...

ic effects and other

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s with

overdose A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. Retrieved on September 20, 2014.

. This can occur with single doses that are only 2- to 6-fold the usual single therapeutic dose. The effects are thought to be

serotonergic psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluci ...

effects and are believed to be mediated by activation of the

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

5-HT_2A receptor.

Pharmacology

Pharmacodynamics

Lorcaserin is a selective 5-HT_2C receptor

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

, and ''in vitro'' testing of the drug showed reasonable selectivity for 5-HT_2C over other related targets. 5-HT_2C receptors are located almost exclusively in the brain, and can be found in the

choroid plexus The choroid plexus, or plica choroidea, is a plexus of cells that arises from the tela choroidea in each of the ventricles of the brain. Regions of the choroid plexus produce and secrete most of the cerebrospinal fluid (CSF) of the central ...

cortex Cortex or cortical may refer to: Biology * Cortex (anatomy), the outermost layer of an organ ** Cerebral cortex, the outer layer of the vertebrate cerebrum, part of which is the ''forebrain'' *** Motor cortex, the regions of the cerebral cortex i ...

hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...

cerebellum The cerebellum (: cerebella or cerebellums; Latin for 'little brain') is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as it or eve ...

amygdala The amygdala (; : amygdalae or amygdalas; also '; Latin from Greek language, Greek, , ', 'almond', 'tonsil') is a paired nucleus (neuroanatomy), nuclear complex present in the Cerebral hemisphere, cerebral hemispheres of vertebrates. It is c ...

thalamus The thalamus (: thalami; from Greek language, Greek Wikt:θάλαμος, θάλαμος, "chamber") is a large mass of gray matter on the lateral wall of the third ventricle forming the wikt:dorsal, dorsal part of the diencephalon (a division of ...

, and

. The activation of 5-HT_2C receptors in the hypothalamus is supposed to activate

proopiomelanocortin Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is Protein biosynthesis, synthesized in Corticotropic cell, corticotrophs of the anterior pituitary from the 267-amino-acid-long Precursor polypeptide, pol ...

(POMC) production and consequently promote weight loss through

satiety Satiety ( /səˈtaɪ.ə.ti/ ''sə-TYE-ə-tee'') is a state or condition of fullness gratified beyond the point of satisfaction, the opposite of hunger. Following satiation (meal termination), satiety is a feeling of fullness lasting until the next ...

. This hypothesis is supported by clinical trials and other studies. While it is generally thought that 5-HT_2C receptors help to regulate appetite as well as mood, and endocrine secretion, the exact mechanism of appetite regulation was not known as of 2005. Lorcaserin has shown 100x selectivity for 5-HT_2C versus the closely related 5-HT_2B receptor, and 17x selectivity over the 5-HT_2A receptor.

Pharmacokinetics

The

elimination half-life Biological half-life (elimination half-life, pharmacological 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 blood plasma. ...

of lorcaserin is approximately 11 to 12hours.

Chemistry

The

chemical structure A chemical structure of a molecule is a spatial arrangement of its atoms and their chemical bonds. Its determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target m ...

of lorcaserin is similar to that of ''para''-chloroamphetamine (PCA). It is also similar to that of 7-AB.

History

Approval history

On 22 December 2009, a

New Drug Application The Food and Drug Administration's (FDA) New Drug Application (NDA) is the vehicle in the United States through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing. Some 30% or less of initial ...

(NDA) was submitted to the

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 respo ...

(FDA) in the United States. On 16 September 2010, an FDA advisory panel voted 9–5 against approval of the drug based on concerns over both efficacy and safety, particularly the findings of mammary gland tumors of female rats. On 23 October 2010, the FDA decided not to approve the drug based on the available data. This was not only because cancer promoting properties could not be ruled out, but also because the weight loss efficacy was considered "marginal". On 10 May 2012, after a new round of studies submitted by Arena, an FDA panel voted to recommend lorcaserin with certain restrictions and patient monitoring. The restrictions include patients with a BMI of over 30, or with a BMI over 27 and a comorbidity such as high blood pressure or type 2 diabetes. On 27 June 2012, the FDA approved lorcaserin for use in adults with a body mass index (BMI) of 30 or greater (obese), or adults with a BMI of 27 or greater (overweight) and who had at least one weight-related condition such as high blood pressure (hypertension), type 2 diabetes, or high cholesterol (dyslipidemia). On 15 July 2016, FDA approved the extended release version of lorcaserin for weight management with once-daily dosing instead of twice daily dosing. On 17 September 2020, FDA withdrew approval for lorcaserin and for extended-release lorcaserin tablets.

Society and culture

Legal status

In December 2012, the US

Drug Enforcement Administration The Drug Enforcement Administration (DEA) is a Federal law enforcement in the United States, United States federal law enforcement agency under the U.S. Department of Justice tasked with combating illicit Illegal drug trade, drug trafficking a ...

proposed classifying lorcaserin as a Schedule IV drug because it has

ic properties at higher than approved doses and users hypothetically might develop psychiatric dependencies on the drug. On 7 May 2013, the US

classified lorcaserin as a Schedule IV drug under the

Controlled Substances Act The Controlled Substances Act (CSA) is the statute establishing federal government of the United States, federal drug policy of the United States, U.S. drug policy under which the manufacture, importation, possession, use, and distribution of ...

References

External links

* {{Portal bar , Medicine 5-HT2A agonists 5-HT2B agonists 5-HT2C agonists Anorectics Benzazepines Chloroarenes CYP2D6 inhibitors Psychedelic phenethylamines Withdrawn anti-obesity drugs